CA2227292A1 - Anti-fungal peptides - Google Patents

Abstract

The present invention relates generally to anti-fungal peptides derived from or based on Domain III (amino acids 142-169) of bactericidal/permeability-increasing protein (BPI) and in vivo or in vitro uses of such peptides.

Description

WO 97/04008 PCT~US96/03845 ,~ This is a cnnt~nnqtinn-in-partofU~S~ Patent Al~l;r ,~;.~ Serial No. 08/504,841 filed July 20, 1995.

R~CKGROIJ~) OF T~F T~ NTION
S The pre~ent In~_-Lon relates ~n~qlly to an~-fimgal ~;~ s d~i~.~,d from or based on Domain m (amino acids 142-169) of ba~i-cidial/~ -' lity~ g protein (BPI) and ~ uses of such Pçrti~l~s BPI is a protein i~l~i from ~he ~r.qmll~s of .---........................ -~lian 10 pol~ ol~ lrar leu~tes (PMNs or l,~l-o~llils), which are blood cells c~ in the ~1 -f~ f against i~lv~l-ng mi~l~lE;O-~iQ-mQ- Human BPI prot~n has been i~ tf ' from PMNs by acid e-l.~ c<,lnb~ncd with dther ion eeC1~ .h~ Qb~h~ J Biol. Chcm., 254:11000(1979)]orE.
coli affinity cl,~ o~;.,.~.l.y tWeiss, et al., Blood, 69:652 (1987)]. BPI
obl~Lin~d in such a ~ ~ is l~f~l~d to herdn as natural BPI and has been shown to have potent b~t ~ Jal activity against a broad s~;llulll of g~
ne~ali~ b~ t~ ;A The ~k ~ r wdght of human BPI is ~ lv~ t~rly 55,000 daltons (55 kD). The an~ino acid s~ n~e of the entire human BPI
protein and the nucleic ac id s~~ n~ of DNA C~ ~r4~ the protein have been l~l~ ill Figure 1 of Gray et al., J. BioL Ch~m., 264:9505 (1989), incol~ldt~d herein by l~f~_lce. The Gray et al. DNA and an~ino acid S~l.~lC~S are set out in SEO ID NOS: 251 and 252 hereto.
BPI is a ~LIwlgly c~tinni-~. protein. The N ~ h~A1 half of BPI
A~4""l~ for the high net ~Dili~e charge; the C ~r ~ Al hlf of the ~
has a net charge of -3. [Fl~b~c~ and Weiss (1981), su~ra.] A proteolytic N-t~ ment of BPI having a m~ r weight of about 25 lcD has an A~ h;~ ch~rA~t~r~ C~ .;n,~ A~ I;Q~ llyLv~h ~ ~ and l~yd~u~ ic regions. This N t~ ~...;nAl r.~g...- ." of human BPI ~o~s the anti~ t~
~rlc~y of the n~tnr~lly-derived 55 kD human BPI holoprotein. [Ooi et al., J. Bio. C71em., 262: 14891-14894 (1987)]. In C~nt~ct to the N-tf~.. .;nAl portion, the C ~ ...;nAl region of the icnl f~d human BPI protein displays only slighfly d~ t~ anti-b~- t~,.;a1 activity against gram-ne~ urg~nicmc [Ooi et al., J. E~. Med., 174:649 (1991).] An N t - ...;1~1 BPI 1~gm~nt of apy~ a~ly 23 I~D, l~f~l~d to as ~rBPI23," has becn produced by 5 l~...hil.a~l means and also retains anti-h~- tJF--;Al activity against g~am-n~livc ~l~a";~",c [~'p77~nn-Santoro et al., I~fi~ct. Immun. 60:4754~761 (1992)]. In f~at pllhlir~finn~ an ~A~on vector was uscd as a source of DNA ~n~ g a l~c4...b;n~ s~o.l product (rBPI23). The vector was consllu~t~d to encode the 31-residue signal s~.lu~n-e and the first 199 amino 10 acids of the N t.~,- ...;....c of the mature human BPI, as set out in SEQ ID NOS:
251 and 252 taken from Gray et al., supra, e~cept that valine at positinn 151 is sl-Qr;r~A by GTG rather ~an GTC and residue 185 is glll~mir acid ;r.~d by GAG) rather than lysine (.~ ;r~d by AAG). p~...hil.=-.1 hGlo~lulein, also ~f~l~d to as rBPI, has also be~ plu luced having the sequence set out in SEQ ID NOS: 251 and 252 taken from Gray et al., supra, with ~e e~ nC noted for rBPI23. An N ~ ----;nal r ,.g.... ~" analog cign-t~d rBPI21 or rBPI21~cys has been ~sc- ihe~l in co-owned, co~n~
U.S. Patent No. 5,420,019 which is ih~ uldt~l herein by l~f~.lce. This analog comprises the first 193 amino acids of BPI holo~lvt~ as set out in SLQ ID NOS: 251 and 252 but wl.~l~in the ~iy~ e at residue llwlll~ 132 is s~r~ilu~d with _l_nin~ and with the e~fp~;ol~ noted for rBPI23.
The b~eteriA-id-Al effect of BPI has been l~ ~d to be highly q~fir to gram-negd~ive s~ri~-s, e.g., in Pl~hA~h and Weiss, Ir!/la~on:
Basic Principles and Clinical Correlates, eds. Gallin et al., Chapter 30, Raven 25 Press, Ltd. (1992). BPI is colllonly thought to be non-to~cic for other mi.;l~o~;~ni~m~, inA-lulling yeast, and for higher eukaryotic cells. Flch~rh andWeiss (1992), supra, l~l~d that BPI c ~hibil~ anti-ba~ 1 activity ~alds a broad range of gram-ncgdlive b~ct-ri- at OQ.~ ;O~lc as low as 1~8 to 10-9 M, but that 100 to 1,00~fold higher con~ n~ of BPI were non-to~ic 30 to all of the gram~ c b~ 1 s~--s, yeasts, and higher eukaryotic cells WO 97/04008 PCT~US96/03845 tested at that time. It was also l.,pol~d that BPI at a c~..c~ of 10~6 M
or 160 ~Lg/ml had no to~ic effect, when tested at a pH of either 7.0 or 5.5, on the gram~ , or~ni~m~ Stap~rylococcus al~KUS (four st~ains), St4~10coccus epi~e~rnidis, Slr~lJt~coc~-~s fn~Xn7~ 7~j~7~ subt~lis, 5 Mi~ oc,~s tys~eikno~, and LLteria mono~yl~g~s. BPI at 1~6 M
r~hdly had no to~ic effect on the fongi C'. ~id~ albicans and Candida pamrsi~osi~ at pH 7.0 or 5.5, and was non-to~cic to highOE eukaryotic cells such as h~ abbit and sheep red blood cells and several human tumor cell lines. See also Fl~h:-rh and Weiss, ~dvd..c~s in Inflammation Research, ed.
G. We~ n~ Vol. 2, pages 95-113 Raven Press (1981). l~s r~ul~
target cell s~ ;Ly was bel;_~_d to be the result of the strong ~ ;on of BPI for li~l?oly.~ P (LPS), which is unique to the outer ...~....1.1,-.-~. (or e.,~lo~) of g~am-ne~al;~e org~nicm~
The preci~ ~--~ --;c-, by which BPI Icills gram-~ aLi~_ 5 ~:~rf-.rj:~ iS not yet c~ , '.~ ly eluc~l~t~d, but it is bdie~cd that BPI must first bind to the surface of the bz~t~ ou~ hyd~ hobic and d&;L~ ir ;n~ l;n~ ~ ~n the c~tionir BPI protein and n~aLi~ y CI~E,~l sites on LPS. LPS has been ~;r~l.xl to as "F-~Aol~ " b~u~ of the potent i..n~ ~n~ thatitstim~ s~ i.e., therelea~ofl.~PJ;~ byhost infls.. ~l0. ~ cells which may ul- -- ly result in ~ ~ble Pn~1ot~,-;r, shock. BPI binds to lipid A, l~,~,t~d to be the most to~ic and most biolc~ir~lly active cn~ ~n -~l of LPS.
1~ s ~ gram-l~egaLi~e b~- t~-- ;A BPI l.;~-l;~ is tho -ght to disrupt LPS sLIuclulc~ leading to a ;~iv~ n of bart~ l cn~,y",es that 25 dP.~e llhosl~h-lipids and pP,rti~l~lyealls, altPring the ~..P~hility of the cell's outer ...c~.-h.,~n~, and ;..;I;;~;ng events that ul~ lely lead to cell death.
[P.l~b~rh and Weiss (1992), s~pra]. BPI is thought to act in two stages. The first is a sublethal stage that is ch~ ~ ~ by ;,1-.ll~ 1;,.l~ growth a~Test, ~.I.~ahili7~tir~n of the outer ,ll~ h~ e and selecLi~_ activation of k~t~
,~ 30 en~y"les that hydrolyze phnsrh-lip:~ and pepti~o~lycans. R~qrtPri~ at this W O 97/04008 PCT~US96/03845 stage can be l~ued by growth in serum albumin s~' mPnt~ media ninn et al., J. ~in. Invest., 85:853-860 (l990)]. The second stage, defined by growth inhihiti~n that cannot be ,~_. ~d by serum albun~in, occurs after pll l~n~ed e~ ul~ of the b~P~i~ to BPI and is ch~ t ~; -d by S ~t~ n~ and SLlu.~ n~ --1;n,~ a~ ,e to ~e inner ~ bl~ne.
Initial bin~ling of BPI to LPS leads to o~ n~l c1~
that probably result from bi~.di..g to the anionic groups in the KDO region of LPS, which nonnaUy st~'-i1i7~ the outer l~ltl"bl~,e ll~ugh binding of Mg++
10 and Ca++. ~ll~ck~cn~ of BPI to the outer l.._.l-bl~ne of gram-n_k~ e t ~ /lUdUCeS rapid ~ ...P~hili7qti- n of the outer ...- ..k."~ to hy~u~hobic agents such as ~- ~;..o...~cin D. Rin-iin~ of BPI and S~IJ~U~It gram-ne~alivc b-q-~Priql l~lling dep~ c~ at least in part, upon the LPS
~ly~ e chain length, with long ~chain bearing, ~smooth" ~ ni~-.-c 15 being more ~ nl to BPI bZ-~tr ;.~ ql effects than short ~chain b~qring~
"rough" u,~ ni~...c [Weiss et al., J. Clin. Invest. 65: 619-628 (1980)]. This first stage of BPI action, ~....~ jli7qtinn of the gram-l~eg~ e outer c.,~_lu~e, is l~ ible upon ~I;c~ n of the BPI, a process ~.l!~;.;n~ ~e ~nce of divalent cations and synthesis of new LPS [Weiss et al., J.
Irnmunol. 132: 3109-3115 (1984)]. Loss of gram-negali~_ b ~ 1 viability, hfJn~ is not l_~_~bed by ~l~S which restore the e~ ily, sv~ that the l)~t . ;~ l action is ,..~ t ~I by 7~1~1itinn~1 lesions ;~.-h~ed in the target ol~;ar~isll~ and which may be !CitU7tPd at the Cy~O,~ C.~if~
...f...k.,.ne [lU~nni-n et al., J. Clin. Invest. 86: 631 641 (1990)]. .~pe~ifif'25 investigation of this possibility has shown that on a molar basis BPI is at least as inl~il~ly of cylc,~ c...;C Ill_.llb~ e vesicle rul~cliol as PO1YIIIYAUI B [In't Veld et al., Infec~ion and Imrnunity 56: 1203-1208 (1988)] but the e~cact "~ nicm as well as the ~l ~ ce of such vesicles to studies of intact or~nicmC has not yet been ell~c;f~:~t~
Three s~ funrtinn~l dol-la,ns within the ~lllb~a~l 23 W0 97/04008 PC ~96,t03~45 ~D ~J f~ ;nA1 BPI ~4u~.lce have been discovered lLittle et al., J. Biol.
C71em. 269: 1865 (1994)]. These fim~tinn~l ~o...~;n.c of BPI d~-;gn~ a region of the amino acid ~u~n~ of BPI that C~t~ to the total binln~jr~1 a. Iivily of the protein and were e~ y defined by the a;LviL~s S of proteolytic cl~Lva~e r.,.~ -.L~, u.~ n~ lS-mer ~ if c and o~er ~ ic pepti~1ps- Domain I is defined ~c the amino acid SE.l~.. n~ of BPI
aJ..I~. ;.c;,~p from about amino acid 17 to a~out amino acid 45. Peptides based on this dom~in are ...~ t..l~ active in both the i~libiL~oll of LPS-in~h~c~
LAL a~;livily and in hP.~rin t!in~1in~ assays, and do not e~uhibit ~ ..;r.-~_n~
lû L.~ t~ ivily. Domain II is defined as the amino acid s~ n~ of ~.PI
~~~ P. from about amino acid 65 to about amino acid 99. ~p~ides ba~ed on ~is domain e~chibit high LPS and hPp?rin bi,l.l~ ca~il~ and are ba~t~ l Domain m is defined as the amino acid ~4u~lce of BPI
comrricin~ from about amino acid 142 to about a-m-ino acid 169. Peptides 15 based on ~is ~Inmqin e~chibit high LPS and hP~qrin bUIding a~;livil,~/ and are bz~rtP~iri~iql The b~ r~l a~1ivilies of r..nr1;nnal domain pepti~p-c may h~rlud~ LPS bin~ir~, LPS nPutr~li7~tinn, hq~qrin ~ l;n~, h~qrin nPntr~li7qtion or b~rt .;r;~l~l a.,L~
Fungi are eu~ ic cells ~at may le~luduce se~ually or 20 :Ic~ n~lly and may be birh~;C, with one form in nature and a dirr~ l form in the ;nr~t~ host. Fungal ~ P~cP5 are l~f~ d to as Illycoss. Some ~ coses are en~Prnir, i.e. infe~tion is acyu~,~d in the g,~.~l hic area that isthe natural habitat of th~t fungus. These e-.~ ;r IllyCO~:S are usually self-limited and ..-;--h lly s~ ..lalic. Some Illycos~s are chiefly uy~ u~ ;r-~
25 oc~...;.-g in i~ oc~ ise~ ti~ntc such as organ l"~"s~ ;. nl~
cancer F~ti~nt.c undcl~50ing chem~lcld~, burn p~tiPntc, AIDS ~1;~ nl~, or with ~ hetir l~Pt~r;~ocic Fungal infPcti~nc are b~ll.ing a major health c~ncf .. for a n~..l~ of reasons, inr~ iing the limited IIU1111~ of anti-fungal agents 30 available, the increasing inr;denre of syecies resistdnt to older anti-fungal W O 97/04008 PCT~US96/03845 agents, and the E;,.,wing population of h... noc{~ l~is3d L~ at risk for oypollul istic fungal infe~tinnc The inrid~nr~ of systemic fungal i..rc~;lions increased 600% in t~hir~ hos~it~l~ and 220% in non t~ ~h;ug ho~i~l~ during the 1980's. The most c4...... .nn clinical isolate is C'~7~~
S n7bi~n-L~ (co".l" ;~ about 19% of all isolates). In one study, nearly 40% of all deaths from hnsrit~l-a~ui,~d inf~inn~ were due to fungi. [St .,.k~
Scicnce, 266:1632-1634 (1994).]
Anti-fungal agents include three main groups. The major group ;~rlud~ polyene d~iv~ s, inrl~ ing ~".pl~ot~ .;rin B and the sL~v~t~ l1y 10 related cc,.nyuullds lly~lin and y;.~ . These are broad Syv;llulll anti-fungals that bind to ~,osL~l, a co...l~ nt of fungal cell, -- -..h...nF-s, and ~ ~y disrupt the ~ kl~s~ )hot~.;cin B is usually c;rr~ for systemic Illy~ses, but its ~ iminict~tinn is limited by to~ic effects that include fever and kidney ~ ~, and other ~C.Q~ yilg side effects such as qnPmiq, low blood ~ , hPq-lqrhe, nausea, v~ g and phlPbiti~. The ul~cla~d anti-fungal agent flucyl~sin e (S-n~lonx~,luslne)~ an orally absoll~d drug, is rl~u~ ly used as an adjunct to ~n~hot~ ~ ;rin B 1~ 1 for some forms of cqn~ iq~;~ and cly~loC~ . Its adverse effects include bone Illdll~ ~ dcl) ~;,;on with 1PU~ .A and lI-.~,I~lbo.;~lo~
Ille second major group of anti-fungal agents inrllldes azole d~iv~ ,. s which impair ~ltLes;s of ~I;os~ ol and lead to qrCumlll~tir~n of metabolites that disrupt the function of fungal ~f-~h~nF bound ~I-Ie ls (e.g., ~cl~l-.c P450) and inhibit fungal growth. .~ignifi~nt inhibition of ,,,~..,",Aliqn P450 results in ~ignifi-qnt drug ;.~tr i~cl;nn~. ThiS
group of gents inrll~d~p~ Jn~7~l--, clot e, mir-~
]-, o~ic~n-q-7rl-~ s~ A~n-q7~ c r 1-7 fl~ .F and .n~7~l~ These agents may be A~1ministPrcd to treat syster.~ic Illy~Ss.
K~ A~le, an orally ~~imini~tpred imi-lA7nl~i, is used to treat ~u~r....~ ;..g~l bl~...y~is,h~ .oY;~,c~~ridi~:~Q---yc~;~~n~ d~ y~_:s in non-i.. ~.. ~ln~lu,l,ised p~tiPnt~ and is also useful for oral and ~h~P~l cqntli~iqci~ Adverse effects include rare drug-inAnce~ hPE~qtitic;
~ tdc4~-~701e is also conL~ -q-tPd in ~ ~ncy. T~ n~ ~a,~ to have fewer side effects than ~ to-4~-a~r'- and is used for most of the same in~ qtinn.c Fhlr~n~ l~ also has fewer side effects than l~_~oc~ and is 5 used for oral and ~ha~r,~l c~n~ ci~ and ~ x4~c~
Mir4nq7nle is a ~n~ldl imi~ with errl~y in c~c~lin: io~-y~s and several other Illycoscs, but has side effects ;..~h~l;"g hy~~ ;d~miq and l-y~onahc.. ia.
The third major group of anti-fungal agents includ~s 0 a~yl-q~ SthioK~lb~ al~5, which are gP.nP~lly used to treat s~n infP~nnc This group in~hldes ~ rl~P. and n~rl;r~e.
Another anti-fungal agent is r~ orulvin~ a fimgirtqtir. agent which is qflminiQ~red orally for fungal infPctinnc of slcin, hair or nails that do not re~ond to topical l~r~ e ~1 Most en-i~Pmi~ yCO5~S are ac luilcd by the ~ ~J~y route and are minimqlly ~y~ llaLiC; cough, fever, hpu~ p~ and pleuritic pain may be seen. ~'l;'A~ ;OnAlly~ P.n~lP.mi~ llly~oscs may cause ~JlUgl~i~
pn1m~n~ry disease or systemic il~r~~ .. ~ir~ p1~L ..osic~ caused by Histoplasma, is the most COIlllllOlI P~ul_~..;C l~ uly Illy~jis in the United 20 States; over 40 million people have been ;--rfcb d The disease is non~4l~l~;vus and ol~ ~ily self-1imip~l~ butc-hrûnicpllh~ y infP~tinn and t d infP~tion may occur. p-11...o~ y inr~;o~ rarely l~Uil~,S
, but ~liC~.~I;n~t~l infe~tinn may be trcatPd with ~ hol~..;rin B.
~ocri~lioidollly~;s~ caused by ~criffioi~o~, is a m~nl~4~ Dnuc ~"~,;".~
25 mycosis prevalent in ~e sou~ United StatPs. It also is usu lly self-limited but may lead to chronic pu1...ol-~.y infP~tion or ~ .";i~ r. ~
AmphotPricin B or micon~7r1~ may be given for h ~ ,r-~l R~ u~-~y~G~iS, caused by Blasto~r~ces is a non~nnt~gis)us~ sub~rute or chronic en~l~Prnir~
mycosis most commonly seen in the southeast United States. Most pu1. . ~ . y infP~tionc are probably self-1imite~. Patients with p~ lung disease or ic~ P~CP, and ;~...... I-oc~.. ~ lised ~ ;, may be t~eated syst~nir~lly with ~ hot~ric~n B. p~r~rocci~lioidoll,ycosis, causPd by Paracoc~ , is a nnnr~nt~,jollC ~ ..y lllyCGSiS that is ~e most c~.. on sy~ llic mycosis in South ~mP jr~ It may be acute and self-limited S or may ~ludu~ ~ ug~ r~ pllh~OI~ y disPase or e~ctraplll..~ . y A~ n Di~--.;n-t~ disease is gPnPr~lly fatal in ~e s~hs~n~e~ of Sul~n~ le.s may be used but have a low success rate.
~",~hot. . ;r;" B produces a higher ,~l~nc~ rate but l~ld~s may still occur.
GyptOc~cc4s;cisan~ "-l~ious,ofteno~llullisticIllycosis.
10 It is chd~ t~ ~ by 1~ Y invol~ l or h....~C~f .,O~.c .I;.~ ....;n~ n, often with m~nir~itic A major etinlo~ic agent is C ncv/~".u~s. Most plll,"-~--,y il rr~;u,~c are ~ bably overlooked, but ~ t~occ~
which ~Co!~ L~ for 90% of ..,pv.tLd Ai~G, iS llrAm~tir and seldom ovPrloo~i Gy~ ~c c is a particular ~' m in h~ n~C4~ vlllis~
~I;~MI~;~ C1Y1~lQC4CC~1 mPningitic occurs in 7 to 10% of AIDS ~tiPntC The p; ~ sy~ nvlll of ~ h~ilic is hP~ t'hP; ,c~c;~ fin-lingc include mental cl-~ng~C, ocular sy l l~ c, hearing ~Pfi~itC, nausea, vo ili ~, and ~u.~ Without L~ .. nt, 80% of ~1;~ die within two years In , ,h~g;lic, cly~loc~-; can be obs~ d in India ink ~ ;nnc of 20 c~ .vs~lal fluid s~Ai - 1, and can be cultured from the c~.~nv~inal fluid T.,~ is gPnPrAlly ~-vith flr-~r~- le or the colllb~lalion of A l)l.,t~- ;cinB and llu~;ylv~~, although ~mrhn~ in B does not cross the blood brain barrier.
Aspergillosis is a term ~at cnco ~l~c~5 a variety of disPase 25 ~luces~s caused by ~spergillus ~eriPs~ Aspergillus species arc ubiquitous;
their spores are con~ntly being inhAl~A Of the more than 300 species known, only a few are onlin~ily ~l~ ic for man A. ~nugatus, ~.
~avus, A. niger, A. rddulans, A. terreus, A. sydowi, A. flavatus, and A
g~ucus. Aspergillosis is in~; ~s,llg in prevalence and is particularly a 30 problem among p~tiPnt~ with chronic ~ J~Y dise_se or W O 97/04008 PCT~US96/03845 ;----------ocG~ n~ sed p~ti~nt~ Among i.--.--~ c~lll~null~3~d ~
aspergillosis is second only to r~n~ ciC as the most cGIl.l~lon ~ppOlt~ iStiC
y~s;s and ~cc~.,~ for about 15% of the systemic llly~ses in ~his group.
Ol~llul~isLicp~ nb.,~aspcrgillosisiscl-z~ bywides~l~db~ c~
S erosion and ~ r..i.l;.~n~ followed by i..~as;on of the pn~ .n-.y vessels, withho~--c~ AI;~ and ~r~Lon. ~linir~lly, ;..r~ ,....a~.;r. st~ as a ing patchy llol~cl.. ~.-~,-.. I-i~ so................. ~ s with h~........... hz~E~r.
pul...- ~ y inÇ~iLon. In about 40% of cases, there is h~ ,e~ $ spread to other sites. Aspergillosis is also a rare but dcv~c~ ;ng c~mplir~tinn of bum 10 woullds; all.~u~Lion is often lGluihcd for cure. Invasive ,.~illncic is c~--------nly fatal, so ag~ ;v~ no~;C and ~ b~ n~ iS l_~lUil~d. Blood, urine and c~ inal fluid cu~tures are rarely posilivG, but fungi can be seen in smears and biopciAAs ~---ph-~t~ B can be given for L~ ",r~l Mnc~ y~ci,,;s iS an acute s~ u~ ;vG oppullu,~-slic mycosis that yluduces ~1.;noc. -~1dl, pnl.. ol~ or ~ .. .;n-t~d disease in ;. .~n-}
c4l,lpl~."ised ~I;~.nl~, and local or ~lic~ AI~l disease in ~t;~ with burns or open wounds. Tnf~tinn is caused by fungi in the chss Zygollly~s, and inrlude R~ iobolus, Conidiobolus, l~ ,~, Mucor, ~hsi~ia Mor~ierella, C~onunghGvnella, and Sak~enoea. ~l~;nocf-~ ~.. yCOSiS ~4u~ f~r about half of all cases of .~ s. It is one of the most rapidly fatal fungal ~ ~s, with death oc~iu~ ~ ;..g within 2-10 days in UnLl~t~
Early clinical signs include nasal sll~rl;n~-c~ bloody nasal .li~l.~.~", facial swelling and facial pain. The illr~Lion then spreads to the eyes, cranial nerves and bIain. Pul...o.~ ...yCO.iS is nearly as col~ on as 25 .l.;n~ ~ldl disease and ...~..;Ls~; with the same nec,vL~ing and infarction as asper~ si~ Fungi are virtually never seen or cultured from blood, sputum or ~.~r~-~inal fluid. D;A.~....;n~ CO....~;OSiS may follow Ful~ n~y or burn wound infection. Tr~l... .l is with ~ pl~ot~ in B.
~'~n~ is a general term for a variety of local and systemic 30 pll)CeSSeS caused by coloni7~tion or infection of the host by species of the yeast ~da. ~sln~ljAj:lci~ ocCurs world~,-vide; ~'1~ r; :~1 inf~tinn~ of the skin, mouth and other mucus ~ .k.,~ s are u"i~al. Il~v~i~ ,.l~ic disease has bO~-4"~F a pr~blem due to the use of high doses of anlil),olics thatdestroy normal ~ten~l flora, i.. ~s~ .p~l~s;v~ agents, and agents to~ic to 5 bone Illal~UW, e.g., during cancer therapy. Ne~L-up~..ia is a major risk factor for Candida ~ a~ n~ ci~ iS also seen among i... ~"~lul"ised individuals such as AIDS ~ , organ t~
~;F,..~ vi~lg~.ltr.dlnl~tnti(-n,andcancer~ und~ ,oi~
~ n ~ a~ and ch_..... ~hP.~y. It is the most Cl:t.. on ~~1 ullulli~lic mycosis in the world. The most co.. ~ - etiologic agent is Candida albicans.Other ;--r~.!;ou. species include C. tropicalis, G par~rsi~osi~, C. stellatoidea, C krusei, C. pur~r~Gi~ G lusitaniae, C pse~ ,u~;cal~s~ C. guilliertnondi and C. globrata. C~7n~i~ albicans is normally found in the mouth, throat, ga;,llu;..~ tract and vagina of hnmAn~ Non-albicans species fi~uel,lly 15 colonize skin. (~n~1ida species occur in two forms that are not ~
or host~o~ nl The usual colt~l-;,;ng forms are yeqsts that may assume a pseudo."y~lial confi~u I;n.~, çq~iqlly during tissue illv~iol~.
Pseudc"-,yceliae result from the s4u~ -lial budding of yeqsts into br.qn~hing chains of el~ g,.t d or~qni~m~
C~ albicans conlA;~ cell wall ~ noplo~ins that appear to he l,_~l~n~;hle for Att 'hmPnt of the yeast cells to specific host tissues. It has been l~l~d that the ...AnnA~l portion, rather than the protein portion, of the ~ nG~.ut~ns is l~onsil)le for adh~c;i-ce of fungal cells to spleen and lymph node tissues in mice. [Kanbe et al., Infechon l~nunity, 61:2578-2584 (1993).]
G albicans also binds avidly to e-trAcPlhllqr matri~ (ECM) -t~lS such as r~ el;i-, lAminin, and types I and IV colla~en, all of which contain hP~rin-binding do~ -ns. This ~ ~e~c1~ C albicans may e~cpress a h~rin-like surface m~ Adherence of C. albicans to the 30 ECM may be i~,lpoll~lt in the p~Lhoge,lf-~;c of ~;~C~ ~n;nAI~1 CAn~ iAci~c~ It has boen ~ ..nn~ t ~ that h~orin, h~ -,-. sulfate and ~.tran sulfate ~,lyc~...;l-~lycails (GAGs) inhibit ~dh~..ce of C albicans to ECM and ~ ECM ~l~,t~,~ns, possibly by a "~ aniQm ~h~vulv~l~g bihldi~lg of GAGs to ECM
~lut~ s, ~us ~ ;nE these s~ L~ on~ Klotz et al., FEMS
Microbiology Letters, 78:205-208 (1992).]
~lini~olly~ ",an;r _~ as ~ u-inf~ti-nQ, chronic ~ 4CU~n~ c c~n~ iiqQ;Q7 or systemic inrf~l;rn Su~enfiriql mucouvl;~n~ c inf~tinnQ can occur in any area of slcin or mucus ........ l,., nr Thrush, co~ ollly seen in AIDS pti.ont~, is c].-~ .-- t - ;,- d by a 10 patchy or conl;..~ us, creamy to gray pseudo,ln,llll,l~ e that covers the tongue, mouth, or other oluph~yllg~l j,--- r;--~ c and may be ~ ~n;~ by n f -~;m~
and n~~ s. I~yllg~al ilvol~ ~ll results in ho~less. r-~o~h~;l;c is often an ~ - h ..~:nn of o~l~h~yllE,c~l diseqse and may ...~.;f~ -q with ~...pl~of l~ mql pain and d~ h~;A Tn~. s~ l cqnflifliqe;c is cc--...-- nly 15 asy---plu---~l;c, but is a major source of hr..--_log~ illVa~;Oll in oc~lllplolllised individuals. Intertrigo i-~vc)l~_s the a~illae, groins, ;.. r.~.. ;-.. ~.y folds, and other warm, moist areas, and may .. ~-.;r s~ as red, oozing or dry, scaly lecion~ Tnrf~ u~.c may occur in other areas, in~ln-liT~
periqnAl and genit. l areas. P~ullycllia, infertinn of the n ils, often follows 20 chronic ~ --.c of the hands or feet to ,..~.slu-~. Some ~ with limited T-cell i.. -~-~oflf-r~i~n~y d~ lol) chronic ~ X~~ F".. C rq~lfli~liqci~ Thesepti.ont~ suffer frûm persistent sllrrfi~ql Candida infe~tinn of the skin, sc. lp, nails and mucus ~ .llb~ es.
Most cases of systemic ~qn-lirliqcic are caused by Candida 25 albicans and C tropicalis, and incn~Lsi.~gly, C. glabrata. I'lini~ql ;rf~t;.l;nn.c of C~ndida il,~:lion appe r mainly in the eyes, kidneys and skin. In the eyes, there may be single or mn'- '- raised, white, fluffy chorioretinal 1PC;On~ These lesions are a POl~nlia1 cauce of hlin~--f ;~
Involvement of the kidneys includes diffuse ab~c~ s, capillary ne~;1U3~S and 30 obstruction of the ureters. ~nfPc.tion may result in plU~ , renal W O 97/04008 PCT~US96/03845 in~nffiri~n~y. Systemic Can~ida inf~tion can also ...~.i r~ ~1 as m~ llk~nn slcin lesions sulluullded by a l~dd~-n~ area; these lesions have an ~ re similar to acne but are a major clue to a ~,llially lethal ~licP-q~ Other ~..AI.ifrs~.~;nnc of systemic cqn~ iq~ic may include osteomyelitis, arthritis, 5 ",r~ il;c~ and ~ c~s in the brain, he rt, liver, spleen and thyroid.
v.~ t of the lungs is also c~.. m-, but F~l.. n~.~ lesions are usually too sm~ll to be seen on chest X-ray. Finally, C~Zndida en~ Llis can occur in ~ c l~;Villg prnlon~ ih~ ou~ therapy or cardiac valve ;...~
or in ~ d~ OuS drug abusers. Fungal lesions appear on the valves, and can 10 embolize and oc~ de large blood vessels.
Su~ l inf~ctinn~ are tli~nosed by ll-icl.s~ ~ - e ~-~..; n of sc~rings or swabs of jj,r~t~ lesions in the yl~cnce of 10% ~1_C~
hydlo~de. C'~ ~ O~ can also be seen on gram st~in. r~ -diLs is rli ~nn~ by blood cultures or de nn~cl~t;m~ of bulky valvular lesions or 15 ec~h~---dicjgl~lly. Systemic c~ntli~ cic may be ~lifficult to ~l;~nos~. b~'~--~, the ~ of heavy ~ ~! - - i7~tion at the usual sites of infection inflir~tP-s, but does not prove, that ~ ;on has O~;U11~L The most reliable e vid~ Ice of systemic cAn~ c;c is biopsy .L -..~hl~l;nl~ of tissue invasion or l~U~_~y of yeast from fluid in a closed body cavity, such as cerebral spinal fluid, 20 pleural or ~-;I~.ne~l fluid. Simil~rly~ l~o~Li~ blood or urine or sputum cultures may inrlir~tP invasive disease or simply lnr~li7f~d disease around indwelling devices, c.g., c~lh- ~ or i~h..~e~.lous lines.
lU~-r~ll;-l-P~ ' inr~~ ..c may be treated with topical nS of ~ mrhot~P-ririn B, r~ ,o7~-l-, mir~nz-7r'-, hal~ ~gi,~
25 or gentian violet. Oluph~ngeal or e~ph~gf~l c~n~ ciC can be treated with systemic agents such as kelocoll~ole or Ill~con~ le. Ch~onic mn~ np~us ç~n~7itli~cic syndrome may respond to topical or systemic th~ ,l;c agents such as ~...phnt,~ ~ ;cin B or ~ ucon~ -7 but often l~>~S
when m~flir~tinn is rlicr"...l;..l.~ Cystitis may be treated with ~ l.h.J~ ;n 30 B bladder rinses, or a brief low-dose illhdvenous course of ~ hol~ ;n B

with or without oral flucytos~ne. Fn~A~lilis is PA~ nl;~11y i~ u~ 1P ~.ilLuul valve ~ Af "~ , a~---~ni~d by a 6 to lO week course of qmph~tericin B
and nu~ylosiile. Even with therapy, hu..~ c ' cure of PnA~ is is not always poscihlr-.
S The mortality rate from systemic ~qnAiAiqcic is about 50%.
Systemic cqntli~iqcic may be treated with flllr~nq7nle, a r~"g;c~l;r agent, or qmrh- ~ B, a fu~ r;A-q-1 agent although systemic use of ~e latter is limited by its to~cicity. Both drugs have ~ s~..l;~1 ad-,~ r~qrtinnC when used in col,-bi"alion with cyr1o,l~.;..r A, which itself can be n~ ic.
10 The r~..o~l of ~.~;~ factors such as i.lLId~..uus lines or c-lt.~ ~ ~ . is also illll)ulkull for controlling i~-r~ol;~-. Plu~;yl~ih~e therapy can be added to the q...l k--t.~ in B Ill~ld~ for 1,- -l--,- .l of systemic cqnAiAiq~;~, çq~ql1yin ~ that are not i..-...~.~-ul~l~...;~ In i.~ i~d ~I;F,~ , hu~ , these i,-r. ~ ,-C are ~o~' rnq1;r nd resist Grf~li~
15 L~ nl Mortality with systemic c~n~ ;c can be over 90% in such ~ U~ lllu~ chronic ~----C~--I; ~~ uc c~ c;c . nd cqnr~i ends~-~..liLis often show evidence of disease after having been de~ d cured.

There co-.~ s to e~cist a need in the art for new nti-fungal meth~lc aild mqtPri~lc In particular, ~rr~ive anti-fungal tl,el~ for 20 systemic Illy~s~ is limit~l. l~uduc~ and ..~ ods .~on~.~e to this need would ideally il~vclve s~t~..l;~11y non-to~ic co,,,~ounds available in large qnqntitif S by means of :~yll~lelic or l~co",bil~l ,--- Il-OAC. Ideal c~ o----dcwould have a rapid effect and a broad ~.,ulll of fimg~ q1 or fu~i~fqtir activity against a variety of dirr~ l fungal species when ~ t dl or 25 applied as the sole anti-fungal agent. Ideal co~ .uullds would also be usefulin col"bi"dlive l ~ ~ ~~ with other anti-fung. l gents, particularly where theseactivities would reduce the auloullt of anti-fung l agent l~uil~d for ,-th~ ~ul;r err~:ti~ s, enh~nre the effect of such agents, or limit ~ot .
to~ic l~ ~O~~s and high cost of ~
-W O 97/04008 PCTrUS96/03845 SVMMARY OF 1~ INVENTION
The present invention provides novel pepfirl~ps derived f~om or based on Domain m (amino acids 142-169) of bA~t~nr~ A~ hilit ~ ing protein (BPI) and 1~ ;r uses of such peptidp~c as anti-fungal 5 agents. Peptides of the invention are useful in ...~ l.odc of ll.dLing a subject s..rr -;ng from a fungal ;nr~l;nn by A~lminiotenn~ a flu.,.~ l;r~lly erf~ ,e ~IIOUllt of the pepti~l~P. This is based on the surprising dis~-~ that Domain m derived pel~ti~P-s have fimgjri~lAl/filngict~fir effects. A second surprising .li~.~,.~ is that such p~ti~s have LPS-neutralizing activity. This a~;Livil~~0 provides an ~Mifil n~l benefit in the use of peptides of f~e invention for g fungal infP~Atinnc Domain m derived p~pt~ Pc may be A~ ;n;~t~
alone or in conjun.;l;oll with known nti-fungal agents. When made the subject of adju~ tL~ , ~e ,-~ln-;n;~ ;nn of Domain m derived pepti~lPC may reduce the amount of anti-fungal agent needed for ~rr~L~e 15 tll~ ~, thus l;;l;.,g ~ l to~cic l~sllol-~ and/or high cost of l~ f~l ~-lmini.ctr,.tion of Domain m derived peptides may also enh_nr~ the effect of such agents, ~ the effect of such agents, or reverse l~;c~ rr of fungi to such agents. P~ ides accoldil~g to the invention include peptides SEQ ID
NOS: 1-250.
In AA-i~litinn, the illvcillion provides a method of killing or inl~ibiling growth of fungi co~ g ~...l~r~;..g the fungi with a Domain m derived peptide. This method can be pr~tir~d in viw or in a variety of in utro uses such as to ~ fluids and sllrf~ces and to sterili7P surgical and other mP~Iir~ ui~,-,cnt and ;...~ hlP devices, inrlufling l,lc,;, 25 joints and indwelling ulv~i~e devices.
A further aspect of the invention involves u~ of a Domain m derived peptide for the m~nllf~rt~-re of a mpAi~mpnt for tre~tmPnt of fungal infPc*nn. The mPAir~mPnt may incllld~P., in -~lditinn to a Domain m derivcd peptide, other cl,ell,ull~ -,.pt;ul;r, agents such as anti-fungal agents.
Nu~ ous ~ ition~Al aspects and advantages of the i~ .llion WO 97/04008 PCTtUS96tO3845 ~, will bo~ lc ap~,lt to those skilled in the art upon c~n~ rirl~ the following ~A~tqjlPd~A~ 1;nn of the invention, which ~ 5 the ~l~S~ yn~r~lod ."ho~l;..-C~ l~ thereof.

RR~FF DF.~('R~PIION OF 'l~ PRAW~('~
S Figure 1 provides results of broth assay tests of the activity of v~;ous peptides against C. albicans.
Figures 2A and 2B provide results of ~adial diLru ,;on assays of the activity of various peptides against C. albicans SLU-l (Fig. 2A) and C.
albicans SLU-2G (Fig. 2B).
Figure 3 provides results of broth assay tests of the activity of cc~ .;n~;nl-.c of peptide and ~...l.hot.~ . ;r;n B against C. albicar~.
Figures 4, 5, and 6 ~;.,.l-k;.-_lly l~,~we,AI survival data in mice after C. albicans chqllPn~e and ~ -t with p~ptiA~s or buffer control.
Figures 7 ~ .h;-~lly l~ s survival data in cyclosporin-15 treated mice after C. albicans rl~ .ng~. and h~l~l with peptides or buffer control.
Figure 8 provides results of RAW cell assay tests of the activity of various pepti~AeS~
Figure 9 gr~rhic~lly l~l,r~.,~ survival data in mice after chqllPng~P with E. coli 0111:B4 LPS and L~ nt with peptiA,e r~T~Tr Fn DF-~CRIPIIQN OF l ~i~ INVENTION
l~e present invention relates to the ~u~ g discu.~l~ that a Domain m derived peptide has fungir~ 1 activity and can be ~Aminict~ed to treat subjects s~rr .;ng from fungal inf~finn As used herein, "subject" is 25 meant to refer to higher org~nicmc, inrluding ~nim~1c (e.g., 1~ nc, co...~ ;on ~nim~1c such as dogs; livestock such as horses, cows and pigs;
poultry; in~c; fish; avian species) and plants. Also provided are .... 11,nflc O of ll~.Ling fungal infections with such peptides. U.. ~ ~ct~1y, Domain m CA 02227292 l998-Ol-l9 derived peptides were ~i~rno:lctr~qt~ to have anti-fungal a.iLiviLes both in in no Icilling assays and in in viw models of fungal illÇccLol., as lll~Sulc~l, for~. ~e~ by illl~ VCd su~vival or r~ducti~n of colony-~o~ ...;ng units in circlllqtion after fungal chqll~n~e. A va~iety of fung~ ;nr~ ~;....c, in~ g S infPpi~nc caused by ,~spergil~ fi ~ n.c caused by C",l,~oc. ~, such as c~ .;f.~;~;C, and .~ u~ .nd systen~ic c~nf~ iqQ;c caused by Gandida ~s, may be treated acco~ , to the ~ ioll. ALso, ly, Domain m derived peptitlps were de~nc..~l.,.l~d to have LPS-nP,Utr~li7i~ activity both in an in vi~o assay and an in viw model. Ihis 10 a.;livily provides an qd~li*~)nql benefit in the L~,~n.. ~1 of fungal ~Çc.,~i~ s where ~ 1 L;PS from l-~ or ~ nql inf~ ;- n is qC~
with the fungal i,-r ~ n As used herein "Domain m derived peptide" ;~ k-s ~,~ f-~having an amino acid s~3uP~re of BPI protein from about po ~ 142 to 15 about poSiLioll 169, Sul)~u~l~S thereof and v~idn~ of the ~ lu~r~ or ~4u~ce thereof, which posses ~ ;rv~g~l activity. Sp~;r~ y ;~
are those ~.I;r,..,~,~l pepti~les having SL~ to rOu~l~ amino acids and having the amino acid s~u~.~ of BPI protdn from about yos l;~-~- 148 to about ~oOlLon 161, ~ubs~ s thereof and V~ Ulki of the ~ re or ~b~u ~ r~
20 Certain pl~f~~ Ps have roulb~n amino acids and among the yl~,f~,~lod variant s4u~, -ces and ~ s~u n~s are those having K as an amino acid ~l~nd~ng to G at ~ n 152. ~,f~l~d peptide s~.lu. nr~5 with fuurt~
amino acids have a core amino acid sequence s~lPcl~d from the group c~n~i~ting of LIQL, IQLF, WLIQL, LIQLF and WLIQLF or a variant core 25 amino acid s4u~ce having at least 75% homology to said core amino acid s~ue~ce and include ~e pepti~1ps of SEQ ID NOS: 4 (XMP.13), ~19 (XMP.31-44),21-22 (XMP.82-83),23-25 (XMP.85-87),26-27 (XMP.91-92), 28-31 (XMP.94-97), 32-33 (XMP.10~101), 34 (XMP.104), 35-40 (XMP.106-111), 41 (XMP.113), 42 (XMP.116), 43-55 (XMP.123-135), 57-58 (XMP.138-139), 59-61 (XMP.142-144), 62 (XMP.146), 6~78 W 0 97/04008 PCTtUS96tO3845 . ~XMP.222-234), 8~88 (XMP.23~244), 89-109 (XMP.249-269) and 116 (XMP.283). This group of &~lifu~lg~l 14 mer peI~tiA~s in~ c va~iant ? sequence peptiA~ wh~l at least one BPI S~U~I~ residue has been ~ d by a D-isomer amino acid. See, c.g., SEQ ID NOS: 46(XMP.126), 48 S (XMP.128), 8~87 (XMP.242-243) and 92-93 (XMP.252-253). Vanants i..~,c~lvi.,~ BPI Y.lu ~ r~ by atypical amino acids such as ,B(1-~hlhyl)A, ,B(2-~ yl)A, para-amino F, cyclohe~yl A, a- and ~y-~...;nQl~u~ylic acids, a methyl A and N-methyl G, V and L are also in~ Aed within this group.
Among the ~ ly ~ ;rel.~d Domain m derived ~ntif~
s of the i..~ ~ IiOI having from seven to twelve amino acids co~ g -(a) a core s~uc~c~ of amino acids .~ 1rct~ " from the group C~fi.C;~ , Of LIQL, IQLF, WLIQL, LIQLF and WLQLF; and (b) one or more cqtinni~
amino acids ~lP~;d from the group cr~nc;~ g of K, R, H, ~..~.;l~.;..~ and 15 ~I;5u~ ylic acid at the amino and/or C~1JUAY tp~nin~l portion of the core s~u~ce. A subset of pepti~Pls have from seven to nine amino a-cids cû~p~ (a) a core s~u~nce of amino acids ~1F~-t~d from the group c~nQiQting of LIQL and IQLF; and (b) at least two r~tinni~ amino acids ,cF1r.~ from the group cnnQiQting of K, R, H, o".;ll,;"r and ~ .n;n~ulylic 20 acid at the amino and/or Wl~Ay t ~ l portion of ~e core ~ e Another subset of pepti~lp-s has from eight to ten amino acids compricing: (a) a core sequence of amino acids ~F1P~ from the group c~-c;~ of LIQLF
and WLQLF; and (b) at least two c~tionic amino acids sPlçct~ from the group c~n CiQ-ting of K, R, H, o. ~-;11-; .. c and ~;-5.. n~Ulylic acid at the amino 25 and/or ~buAy t~min~l portion of the core s~u~nce. Still anu~.cr subset of peptides has nine to twelve amino acids c~mpri~ing: (a) a core se~u~ ce of amino acids ~l~ d from the group c~n~i~ting of WLQLF; and (b) at least three r~ti. niC amino acids SPlÇct~d from the group c~n.~ of K, R, H, c...;ll.;n~ and d;~ û~ulylic acid at the amino and/or ~i~lvAy tPrmin~l 30 portion of the core sequence. Tlll~tr~tin~ these subsets are the peptides of W O 97/04008 PCT~US96/03845 SEQ ID NOS: 118-137 (XMP.285-304), 14~144 (XMP.307-311), 155-160 (XMP.322-327), 166-170 (XMP.335-339), 174-177 (XMP.343-346), 179-184 ~XMP.348-353), 186 (XMP.355), 188-190 (XMP.357-359).
It will be a~ from c~nQ;Aeration of the oLlu~;lul~ of the 5 above-A~ ;bed ~pLide,s that the Domain m SC~lu_~ of BPI amino acids from 148 to 161 inClud~ps the core s~u_nce(s) noted above as well as multiple cqtioni~ residues (K and H) flqnkir~ the core. This motif is carried fc,l~,vanl in the structures of s~s~uc~ceO of the 148 to 161 scquG~lce praviding a~lifun~;al peptiAPs of the invention and also ~l~.ved in ~ulLifu~gl va-~lls of the 148 to 161 s--lu~nce and Oubo~u_~ces thereof. Note, for e~ample ~at when the G residue nnnn~lly in the BPI s~u~ce at ~oiLiu n 152 is ,~
by K, this rep~ m~nt serves to provide a cqtinni-~ residue ;~"~f~;Atr~ly ja~f-.l to the yl~xlo..~ h~dluphobic core reQ;~Iurs. Se~lU_lCe and O~lb3~u~ ce ~ LS providing al-tirungal p~tidP-s acco ~-g to the i,.~ lio.l 15 thus include those p~yti~1es .. l.~ one or more r iQ~tin~ non~tinnir residuesGldil~ily fl~nkin~ the core sequ~.lce(s) are replaced by cationic re-Qi~iues Within the core S~lu~ n~(s), the neutral ~lirh~tic residues L and I are each rep~ hle by neutral ~lirh~tir residues G, A, V, I and L.
LikewiOe, the ~u ~-alic r~O;du_O W (BPI ~O;I;on 153) and F ~BPI yoOiLion 20 158) are rep~ hl~- by a dirr~ aromatic amino acid residues or by neutral aliphatic residues G, A, V, I and L. Mc,lw._., the core .~u~ r~ Q (BPI
residue 156) is l~ ble yl~f~.dbly by a neutral hydluyhilic amino acid T, S and N. As noted above, where v~ri~tinn~ are inL uduced into core Oubs~u~ce(s)~ it is yl~f~ e that the vanant core s~u_nce(s) retain 75%
25 homology to the s4.,_nces oc~ g in BPI.
A~lLirùngal Domain m p~ es of ~e invention have one or more D-isomer amino acids, as illucl~ d by the peptides of SEQ ID NOS:
164 (XMP.333), 165 (XMP.334), 173 (XMP.342), 194 (XMP.363) and 196 (XMP.365) and have the core s~u_nce amino acids cu~yllse D-isomer amino 30 acids in reverse sequence order as illu~l.,.l~d by p~tid~S having the amino ~, acid scqu~,nce set out in SE~2 ID NOS: 163 (XMP.332) and 198 (XMP.367).
The ~ntifiln~ can have an acelyla~d amino l~....;nAl amino acid ~ residue as ill5J~ ed by the pe~ s of SEQ ID NOS: 162 (XMP.331), 185 (XMP.354), 187 (XMP.356), 195 ~XMP.364), 199 (XMP.368) and 204 (XMP.373). Cyclic al~LiÇul.gal peptides as ill.. _h,.trd by SEQ ID NOS: 191-193 (XMP.360 362) are also within the scope of the i.~ ion.
;OnA1 Domain m a,-Liru.~ ides of the i.~ ,nLi~
jnClllde antifungal peptides SEQ ID NOS: 1 (XMP.5), 2-4 (X~DP.11-.13), 5 (XMP.29), 20 (~.55), 56 (~'.137), 79 (XM~'.235), 111-115 (X~P.271-.275), 117 (XMP.284), 132 (XMP.299), 138-139 ~XMP.305-.306), 145-154 (XMP.312-.321), 20~203 (XMP.369-.372), 171-172 (XMP.34~.341) and BPI residues 145-159 and 149-163 of SEO ID NO:206.
~ dr~ l Domain m A~lirv,~p,l ~d;~l~r, of the invention in~lur3e a.lL;r~g~ ~,l~1;dFS SEQ ID NOS:205-243 (XMP.374-.412) and SEO
ID NOS:244-250 (XMP.414-.420). Thus, peptides of the i,.~ ol~ include pept;-hs that have SEQ ID NOS: 1-250 as shown in Table 1 herein.
Ph~ eutic~l co~ ~s;l;o~c of the invention comprise a DO~ m denved peptide and a pharrn~eutic~lly -~ept~ rliluf~nt~
adjuv~ or carrier and are ~-lmini~tPred topically, illLIa~ Ously, o~ally or as 20 an aerosol.
~ n uitro Illelllods of the invention permit killing or inhil,iLingr~ r~tinn of fungi lllluugll cr,~ ;ng the fungi with an ahLirungal peptide or .h~ ti~1 co.-~ iLon eQ..I; ;.-;..g the same. Fungal infecti~n I~ P ~t methods of the ill~.lLion comrri~p~ ~rlmini~tPring to a subject s-,rr~illg f~om 25 a fungal infection a th~ J~ lly t;rr~liv~ ~mount of a Domain m a~ rull~;~
peptide and such Ll~t~ mPthy~s are applicable to infections by fungal inf~tion involves a fungal species !~PlP~,'~ f~om the group cQ~ ting of C~zndida (e~;~lly, C. albicans, C. glabrata, C. krusei, C lusitan~ae, C
par~ si~osi~ and C. tropicalis), Aspergillus and Cryptococcus ~ies As~escribedindetailmP~ s- ............ ft~/ph~ nt~ pos; I;cn~

d~ lop~d according to ~e i~ ellLion can include other ~ ;r~ gal agents in~ ing non-peptide agents or can be used in co...h;n~
,.,. Il.o-lc with other such agents.
Peptides derived from or based on BPI ~ludueed by 5 lc~~ l or ~llll.clic means (BPI-denved pepti~ S) have been cl~
in co-o vned and c~~ PCI Applir-q-ti~ n No. US94/10427 filed S~Jt -..bC-15, 1994, which c~ll~nds to U.S. Patent Applir-qtinn Serial No.
08/306,473, filed Sepb~mhPr 15, 1994, and PCT Appli~-q-tion No. US94/02465 filed March 11, 1994, which ~ll~nds to U.S. Patent Aprli~qtinn Serial No. 08/209,762, filedMarch 11, 1994, whichisac~.nl;.. l.~l;nn-in-partofU.S.
Patent Appli~-q-tinn Serial No. 08/183,222, filed January 14, 1994, which is a col.l;....-l;~ n-in-part of U.S. Patent AlJ~lic~ Ser. No. 08/093,202 filed July 15, 1993 (for which the cu~ ~n~ g ;~t. ."~ nql q~li~tinn is PCr Aprli~-q-tion No. US94/02401 filed March 11, 1994), which is a cQ~ ;ol~-in-part of U.S. Patent Appli~qtion Ser. No. 08/030,644 filed March 12, 1993 li~ln~cin~, inter alia, ~ g 15-mer peptid~c having BPI residues 145-159 and 149-163 of SEQ ID NO. 206), the ~liC~lo~ s of all of which are UICOl~ldl~:d herein by l~f,~nce. BPI-derived p~pti~l~$ having an amino acid sequence of BPI protein from about posiliol 142 to about position 169, 20 s~s~u~,ncFs thereof and Vdl~l~l~ of the sequ~,~ce or ~ bs~ u~n~R thereof, which possess a BPI anti-fungal b ~'o~l activity, were ~i~lns~d in co-owned and co-~ ;ng U.S. priority ~I~plir~tinn Serial No. 08/372,105 filed January 13, 1995, the ~lic~ c of which is illCOl~JUldt~d herein by lcf~cllce.
The Domain m derived peptide may be Zl~h~in;~
25 syst~mi~lly or topically. Systemic routes of s-~l...;,.;~l.~l;nn include oral, inLld~c~lous~ ;"l~i~""~ r or sub-;ul;~nF~uc injection (incll..l;..~ into depots for long-ter n release), int~nc~ r or retrobulbar, int~th~l, ;nt.,~ 1 (e.g.
by ;nl-,~ o--F~l lavage), transpl~h..~ .y using a~ li7~d or nebulized drug, or l.~.n~. .~ 1. Topical routes include ~-lmini~t~tinn in the form of 30 salves, ophth~lmic drops, ear drops, or irri~tion fluids (for, e.g., irrig~tinn of wounds).
The Domain m derived peptide may be ~lminir~ed in ~ conju,l~ilion with other anti-fungal agents. ~,f~ d anti-fungalagents for this ~Ul~O~C are ~ hot~ ~;~n B and n..~ o~ t r~ ;cl ~;nn Of S Domain m derived peptide with anti-fungal agents is ~ t~ to illllJlU.~, the l~u~;r err~~ , of the anti-fungal agents. This may occur ~I.,UUgll ring the c4.u~ n of anti-fungal agent l_lu l~d to f .~-l;rAI_ or inhibit fungal growth, e.g., reE!lir~tinn T~ G the use of some agents is limited by their systemic to~cicity or pçuLl~ cost, lo~ g the con~ l;f -- of 10 anti-fungal agent l~Ui~Vd for ~ lir err~ ess ,.~lu~s ~i~ily and/or cost of L.~ .. n~, and thus allows wider use of the agent. ~n~ .w~l :~A.";nicl.,.t;nn of Domain m derived peptide and ano~l.e~ anti-fungal agent may produce a more rapid or complete fi~r;~ /r~ g;r~ effect than could be achieved ~vith either agent alone. Domain m derived peptide 15 :~timini~ tion may reverse the l.,-:r~-nre of fungi to anti-fungal agents.
Domain m derived peptide ~ -- may also convert a ru.-~;cl-t;r, agent into a fil~jr~ agent.
An advantage provided by the present ill~cll~ion is the ability to treat fungal ;nrc~1;n..c, particularly C'n~id~' ;..r~ nc, that are p~llly 20 c~n~;d~ed i lC~ Another a~lv~ul~e is the ability to treat fungi that haveac lui~d ,~ .-re to known anti-fungal agents. A further adva l~ge of collcu~ l.,.l;nn of Domain III derived peptide with an anti-fungal agent having lmdeYir~hl~ side effects, e.g., ~ hot~ ;rin B, is the ability to reduce the ~mnunt of anti-fungal agent needed for ~rrecli~ tll~,.a~y. The 25 prescnt invention may also provide quality of life ~-.- r"Y due to, e.g., - d~l~ ~ll~tinn of 111~ , l~uoed stay in ill~.ls;ve care units or l~du~d stay overall in the hospit~l, with the concollli~ll ~luced risk of serious n osocc,lll.al (hn~it;l-acquired) inf~tion~
~ on-llrrent ~-iminiYtr~til~n" as used herein in~ des 30 ~t1miniYtr~ticm of the agents tc~c~h r, cimtll~nr-~.ui~ly or before or after each other. The Domain m derived peptide and anti-fungal agents may be ~ miniQtored by dirr~ rou~. For . ~'~, the Domain m derived p~ptide may be ~--.;.-;c~ d iuLId~lvui~ly while the anti-fungal agents are ~AminiQ~red il.l.,.. s,~.. l~rly, inL,dv~nuusl~, S~ FV~C1Y~ orally or 5 inlld~-;~ F'~lly. .~l~.~..;-l;~_ly, the Domain m denved peptide may be s-~1mini~t.o.red ;n~ ..;lone~lly while the anti-fungal agents are administered f - ;IO~F~11Y or i.l..la~_nousl~, or the Domain m derived peptide may be ~miniQ~ed in an aerost~li7pd or nebulized form while the anti-fungal agents are ~-lmini~t~ed, e.g., hlLld~-..ously. The Domain III derived peptide and 10 anti-fungal agents may be both ~lmini~t~red inLId~ nou~l~/. The Domain m denved peptide and anti-fungal agents may be given s~ lly in the same inlld~L,.lUU3 line, after an ;~t~ .FA;~Ie flush, or may be given in dirr~
ulLId~_.luuS lines. The Domain m denved peptide and anti-fungal agents may be ~-lminic~.red cim~ F~ ly or s~u~ y~ as long as they are given in 15 a Illa~ sllffi~nt to allow both agents to achieve ~ Lf~;li~ e c4n~F nl ~, t ;ol~-~ at the site of inff~ction ~ or~ nt ~ h~ ;on of Domain m derived peptide and another anti-fungal agent is ~ l~r.~d to provide more erf~;Li~e ~ " -.~ of fungal inf~tionc ~-ou~ nt ~lminictration of the two agents may provide 20 greater th~ ~ul;c effects in viw ~an either agent provides when :~ lmini.ct~red singly. For ~ ~ '~, cOhcull~. t ~imini.ctr~tinn may permit a recluctinn in the dosage of one or both agents with achi~ ,nl of a similar th-..~ l;ceffect. ~lh-~I;vely,the C~ll;ul~wll ~lmini.~tr~tinnmay plUdUCe a more rapid or complete fungjr~ l/f~ - effect than cûuld be acl 25 with either agent alone.
~ J~;c ~;rrocLi~ css is based on a s.~ -c~rul clinical ou~llle, and does not require that the anti-fungal agent or agents lcill 100%
of the or~ni~mc involved in the ;I~f~;nl~ Success ~q~n~1c on acl~i~ ; a level of anti-fungal activity at the site of infectinn that is sufficient to inhibit 30 the fungi in a .ll~ner that tips the balance in favor of the host. When host CA 02227292 l998-Ol-l9 W O 97/04008 PCT~US96/03845 ,r~n~5 are ,~ 11y effective, the anti-fungal effect l~u. cd may be .al, PeJ.~ ic... load by even one log (a factor of lO) may - permit the host's own ~l~f~ to control the inf~;n~ tinn~
an early fl~nE~ q-1/fi1ngi~tqtir effect can be more i~ l than 5 long-term f1ngi~ A1/ru.~p;~ effect. These early events are a ci~ifirqnt and cntical part of ~ i, sl1c~e~s, bc~-~ they allow time for host d~f~ ...~ ha~ to ac~;v~t~.
A Domain m denved peptide may ;..t~-~rl with a variety of host d~r ~-~ e~ present in whole blood or serum, in.-1---1;n~
cc~ nPnt plS and L~P, and other cells and co.ll~on~.l~ of the ;.. -~
system. Such i~-t~ c may result in ~>t nl; ~;nn of the aclivilics of the ~p!;AP. 1~..~ of these int~~finn~, DomAin m denved ~ ~1;A~5 can be ~ ~l~t~ to e~ert even greater ac~ivily in uvo th. n in utro. Thus, while in vi~o tests are predictive of in vivo utility, ~hs~.1r~ of activity in vitro does not 15 ~~ec~---;ly in~1ir~te Al~nrx of activity in viw. For ~ BPI h_s been obs~2d to display a greater b~ A1 effect on g~n-neg~ e bA- t~r - ;A in whole blood or plasma assays than in assays using collv~ ;onA1 media.
[Weiss et al., J. Clin. Invest. 90:1122-1130 (1992)]. This may be bc~.-s_ cc,ll~.~.lLiullal in vitro S~i,t~.llS Iack the blood e~ that f~ilitAt~ or 20 ~lc~ tP~ BPI's run;Lion in vivo, or b~use cc,-~-.l;onql media contain higher than physiological c~ nc of m~nf~;.. and c~ n, which are 1~l ~Ally inhil,ilc, ~ of the activity of BPI protein ~l~lu~b. Fu~l.P--~ re~ in the host, Domain m derived peptidPs are available to neutrrqli7~ translocation of gsm-ncgalive l,~rt~-;A and c~ncolni~ release of en~iot~in, a further 25 clinical benefit not seen in or predicted by in vitro tests of anti-fungal activity.
It is also c4~ t.~ that the Domain m derived peptides be a~lmini~t~red with other products that po~ the activity of the peptide, in~ln-linf~ the anti-fungal activity of the peptides. For ~ r~~ serum compl~m~ont pOtr-~ S the gram-negdLi~ c~ A1 activity of BPI protein - 30 products; the co--~ dLion of BPI protein product and serum co r~ nt W O 97/04008 PCT~US96/03845 provides syll~E,isLic b~rt~ri~ /growth inhibik,ly effects. See, c.g., Ooi et al. J. Biol. Chem., 265: 15956 (1990) and Levy et al. J. Biol. Chem., 268:
6038-6083 (1993) which address nqtl~r~ y~ . ;ng 15 lcD ~ )t ~ S
~t~ BPI ~nh~ t~ l activity. See also co-owned, co ~ g PCT
A~pl;~ n No. US94/07834 filed July 13, 1994, which cu~ Jonds to U.S.
Patent A~ ;ol- Serial No. 08/274,303 filed July 11, 1994 as a co..l;...J;~I;....-in-part of U.S. Patent Ap~lir~ticn Serial No. 08/093,201 filed July 14, 1993. These applirqtinnc~ which are all i~ pol~od herein by lef~,.lce, de~-. ;I* mPthnAs forp~ p g~n-llegaliv~b~t~ri~ activity 10 of BPI protein ~ lu~ by ~lmini~t~rin~ lipuyoly~ ch~ritle binding protein a,BP) and LBP protein ~JlUdUC15. LBP protein d~iv~-Li~,_s and d~iv~Li~,_ hybrids which lack CD-14 ;.. ---.n ~ ory lJ~u~ ies are de~,i~d in PCT
Ap~ tion No. US94/06931 filed June 17, 1994, which ~,l~ l~n-lc to co-owned, co~ U.S. Patent ~ ;n~ Serial No. 08/261,660, filed June 17, 1994 as a cu~ a~ -in-part of U.S. Patent Applir~tion Serial No.
08/079,510, filed June 17, 1993, the ~ res of all of which are hereby ~hlcul~ul~ d by l~f~ nce. It has also been obs~ d that p~ln,; ~.....
snrfz~rt~nt~ Pnhanr~ t-h-e anti-b~,ut . ;~1 activity of BPI protein ~luducl~, asde~ d in T~mhPrt, U.S. ~liratinn No. 08/372, 104 file~ January 13, 20 1995; pok..;...~. sllrf~r~nt~ may also enha~re the activity of anti-fungal agents.
WTilllùul being bound by a t-h-eory of the ihl~ llion, it is believe~
that Domain m derived p~ptidP~: may have several modes of action. The peptide, ll-luugh its hP~rin-binding ability, may int~L;e with the binding of 25 fungi to the P~t~rell~ r matri~c. For ~ ~e, hepann-like surface m~ lP~
of C~da are believed to ...~;~P adhesion of the yeast to P~ Pll~ r matri~ and host tissues. The peptide may also act directly on the cy~p~ ;r ~e.l~ e of fungi. In ~d~liti~ n, the peptide may bind to fungal cell wall ll~nl-.,~luleihls that are ~LIu~lul~lly similar to the LPS of gram-ne~ali~,~
30 or~ni~m~ or that are l~onsible for adherence to target host tissues, thus W o 97/04008 PCTAJS96/03845 .. L. ;n~ with fungal intP~~ti- n with host tissues. l~in~iinf~ to fungal .c may also promote access of ~e peptide to the inner ~;y~ ".;c ..... ,.l.,.. nF. In ~ litinn~ b~aus~ fungal .I.rccLion may cause stress~ urc~
tr~n~ tinn of bowel flora and/or LPS, the peptide may also act bPnPfi~ lly 5 by lcilling gram-ncgaLive b~ t - ;~ and nPlltr~ LPS. Finally, the A~lir~ l activity of Domain m pep~ides accc,ldi- g to the ~ tion may result from unique ;.llu~iLul~l r~lul~. For ~ a SLlC amino aci~d ~uence within Domain m (WLIQLF) and the in~ Pd five and four amin o acid s~u~,.,ces a~[QL, IQLF, WLIQL and LIQLF) are a~ ~scd of 10 hyLu~ obic an~ino acids with the e~ception of g ;-...in~ (C2) that is a neutral Ly~llu~hilic amino acid. This ll~lluyhObic stretch is ~oulld~d by highly r~ti~nir- (polar) lysines on the N- and C-b~ ~ ...;n;. This motif is le~ i~f .l of l_ader/signal y~ l~ as well as ~ .. ,kl~e ~Ll~ of .. ~.. k.~
y~ s. ~lirh~tic amino acids such as I, L, V, M, A, have a high 15 plu~.lsily to form ~ ..c~..e ..l..,~n~F a-helical sllu~ s within the h~u~?hoL -...~....l.".n~ vilonlll~ t when found in sF lue~ces of 12-15 nonyolar amino acids due to their ability to form bA~ "F hydlu~,~.l bonds. Aromatic llydluyhobic amino acids such as W and F can also incol~l~le into a llwlllbl~e a-heli.~c. The nPutr~l, hyilluphilic gl..~-...;n~ in the middle of a 20 Domain m hy~ hobic stretch may ~li~;iydl~ in hydlo~ bonding with other fungal ..~ h"~ unFnl~ such as t,l~us~ul and thus play an illl~l~ll role in the ~mgi~ 1 activity. A short 10 amino acid peptide (e.g., XMP.293) is not e l~ d to be long enough to span a lipid bilayer and ~l~bably has a much dirr~ l "~o~ --, of action than a lll~llblmle 25 di~upLillg, ~...l.h;~l.;c type of c~tioni~ ~ntimir~obial peptide. The short motif of si~ to twelve amino acid p~pti~le-s with a core of neutral amino acids bounded by ~tioniC amino acids is not long enough to span a fungal lipid bilayer and thus may be allowed to lld~ e the llltlllblane bilayer more effiri~ntly than longer pepti~l~s If lldns~ull~d inside the cell, the 30 r~tionic/neutral/r~tionic mol~c~llPs may inhibit the function of ~nl1~el.n!.c -WO 97/04008 PCTrUS96/03845 poly~u~ ~5 (~rnitlinlo, Spc ~ r,~UL~ e) by either colll~lilivc inh;l-;l;.~n of the poly~l,h.c regulation of cell wall c~l~o~ydldle sylllL~is and/or by fi~h_~A~ inlli~ iLon of polydu-~le S~ l~s.
In A~l~litinn, the "~ ,Lon provides a method of lcilling or 5 inh;l.;~ g growth of fungi comrri~ing c ,,~ g the fungi with a Domain III
derived peptide. This me~od can be ~ in viw or in a vanety of in utr, uses such as use in food ~ ~.;.l;r)n~ or to ~on1~..;n~ fluids and ~",. r;~ 5 or to s~ri1i7~ surgical and other mP~ir~ u;~ .l and j",~1_"~
devices, in~A1u~ling prosthPtic joints. These ...el1.o is can also be used for in 10 situ st~ri1i7-tinn of indwelling invasive devices such as intravenous lines and C~ r~ ~ which are often foci of inr~ ;on-A further aspect of the ~,vd~Lon ihl~ ,cs use of a Domain mde~ived peptide for the .n~...r~ e of a ...~1;~-~.... nl for t~ of fungal ;..r~;l;-,.. The...P.~ nlmayin~ ule,in ~ 1itinn toaBPIproteinp~lucL, 15 other çh-o nol1.P.~ "liA agents such as anti-fungal agents. The ~~-P-l;~-.- nl can optionally co...l.i~ a ~h~ ul;t~11y ~ le diluent, adjuv~ll or carrier.
The A~ ;n;~ I;nn of anLirullgal pepti~1PS is suitably 4...1.1;.~1.~ with a ~ Z~,,~;rA~ "~D;Lon comrri~ing a peptide and a 20 ~",~ 11Y ~ 1P~1ilnPnt, adjuvanl,orcamer. Thepeptidernaybe wilLuul or in conju, cLoll with known s~ r;~ , other cl,~,l,,ul1.~ .eu1ir agents or ~ i*t~n-l known anti-fungal agents.
Other aspects and advantages of the present i,l~_.,~n will be understood upon conQ;~*on of the following i111.cl.~l;v~ ~ _ r'e~ wh~
F.~ ad~l~DS~S peptide ~l~p~ .ll and purifiA~ti~n; F ~--~.e 2 addl~DSeD in v~tro anti-fungal testing of pep*~l~Ps; F-~mp'- 3 addresses additional in vitro and in viw testing of the anti-fungal effect of peptides on a variety of fungal ~-s, inrlll-ling Candida strains and antibiotic resistant strains; F~mp'~ 4 addlG~s the in vivo effect of peptides on survival of mice 30 rh~11Pnged with Gandida; E~sample 5 addresses ~e serum stability of peptides;

r.~ 6 ad~ll~ses the design and assay of anti-fungal peptides for ~LIu~
motif and .. ;--i.. f~m~tion~l se lu~.~ce analysis; P-~mrl~ 7 addresses L]DS
r.o~ i7~ n activities of anti-fungal pep~des; and F~mr'~ 8 addres9es peptide formnl~tir~n~

W O 97/04008PCT~US96/03845 E~xample 1 ~ll~E PREPARATION AND PURIFICATION
This ~ I le addresses the y~ )n and Fnnfirqtinn Of Domain m derived p~pti~lPC, SPeptide. may be y ~d acco ding to a vanety of synLll_~c ~l~lul~s. Some y~l;A~ (e.g., XMP.5) were pl~,~ku-d by solid phase pe-ytide syl~ es;s as .1~-. ;hefl in par~t U.S. Patent ApI-lirqfinn Serial Nos.
08/209,762 and 08/183,222 ac~uldillg to the ..-- ll,n~ of MP-.;r.~l~, J. ~m Ghern. Soc. 85: 2149 (1963) and MerrifiPl~l et al. ~nal. C~hem., 38: 1905-1914 (1966) using an Ayylied BiG~;,L~IIs, Inc. Model 432 peptide ~ l;vely~ Ps were sy~ eA;~f~ on a ~ger scale using solid phaLce peytide sy es;s on an Advonc~d ~h--.,~ (ACT-Model 357 MPS)$y~ P~;~ - utili7ingal-Fluo~ yllll~lllyl-uA,~ onyl(Fmoc)pl~
sLldte~;y with a double cvuylillg yl~lul~ employing N,N-diisuylu~ ;i...;dP (DIC)/l-hy.ln,Ayl~..,vt.;~7~1~ (HOBt) and 2-(1-H-benzotriazol- 1 -yl)- 1, 1, 3, 3, -tetramethyluronium he~a-fluorophosphate (~l U)/HOBt/diisol)lu~ lyl;~ c; (DIEA). The solid support used was a yolyi~lylene resin with 1% diviny~ f (DVB) cross-linlcing and an 4-20 (2 ' ,4 '~ yyhe.~yl-Fmoc-~ J. . ~ l)-yh~OAy (Fmoc-Rink amide) linker with a s.~ l;l..l;nn rate of 0.44 mm~ -/gram. The scale used was l~lwe~ll 0.1 grams and 5 grams of starting resin.
Di~ ylru~...A...itlP- (DMF) was the ~lilll~ solvent with a SO/SO soll~ti~)n of piperi~linP~DMF used for Fmoc dep,u~:lion in ~ree 25 con~.,l;ve Ll.-~t"'-~ of 1, 5, and 10 .~ s, l~ ly. A double CUU~)lillE, procedure was used in each cycle with a 4:1 amino acid to peptide ratio used in each coupling. The amino acids were dissolved in a 0.5M HOBt sol~-tion in N-lllelhyl~li(iinon~- (N~) at a con~f~ t;o~ also of 0.5M.
For the first coupling, an equimolar (to amino acid) amount of a 0.5M
30 s l--ti- n of diisoplu~ylcarb~iimid~p (DIPCDI) in NMP was used and allowed -CA 02227292 l998-Ol-l9 W O 97/04008 PCTrUS96/03845 to react for 45 ".;""t-s 'rhe second coupling utilized an e~ r (to amino acid) volume of a O.SM ~IBTU ~nln*nn in DMF with an equal volume of a - lM DIEA ~ll~tinn in NMP (2:1, DIE~.~minn acid) for a period of 30 ...;.-.~t.~
S Upon completion of the ;~ hf'~;~, the resin was treated with MeOH, dried under V~;UUlll, and then deaved using a co~ il cc,~ ~ of l.inuulu~ c acid (TFA): tl,;~q.~;colp elh~ nl (EDT): water, at a ratio of 36:2:1:1 (v~lulne was ~le~ e~-l on the ~mollnt of resin) for a ...;i-;....-... of 2 hours with . n _-ltliti~nql 30 ..~I.-.t ~ added for each ~u~ mle 10 (but not P.~c~A;.-g 3 hours) with the first 15 .~in~brs oc~u--;-~ in a wet ice bath. The sollltion~ were then dissolved in a 10% TFA in water snlllti~n, washed 3 times with methyl t-butyl ether ~IBE) and iyo~hili7PA
The amino termini of ~ . t~ l;dc~ were a~l~lated after ~ SiS on solid phase using an N l~....;n~l Fmoc lJlUI~;On SLI~ l as 15 dF~ d above. Subs~u~ to Fmoc removal with pi~rjtlinP and prior to peptide cl~v~_ with TFA, the peptide on the resin was de.ivali~d with a 10-fold molar e~ccess of acetic anhydride with a 2-fold molar eAcess of diisc,~luy~lelllyl ulline in dil-lL~Iylro...~ e for one hour or a double coupling p~,c~lul~ e..l~lu~ing N,N-diis~luy~lc~li;...;dP (DIC)/l-hydl~JAyb~ - le (HOBt) and 2-(1-H-b~n, ,~ l-yl)-1,1,3,39-tetramethyluronium heAa-fluorophosphate (~l U)/HOBt/diiso~lu~lc~ Lu- ,.e (DIEA) and one of the following building blocks was used for d~fiv;~ l;on caprylic acid, lauric acid, Fmoc-8-amino-ctonoic acid and FMoc-12-amino~ can~i- acid. The peptide was 25 then cleaved from the resin with the TFA cl~v~ge co~ il as de~libed above and purified as ~ ~d below. N-l~...;n~l acacylation of the ~ufirled peptide was ~.iLed by mass ~wLlullleh~.
For purity analysis of each newly synthe-~i7~1 peptide, dilute snll-tion~ of crude lyophili7~ peptides were ~ al~d and analy_ed on a 30 Michrom Ultrafast Micç~r~in Analyzer e~luip~d with a 150 mm X 1 mm, 5 IL particle, 300 A pore C-8 Zorba~ cnl-lmn The column oven was set to 40~C, the flow rate was 100 ~L/minute, and inje~tinn v~lu~lles were typically 5-10 ~L. HPLC was ~rul~l,ed using 5 % A~ ~ ;1P~O. 1% TFA in water as mobile phase A, and 80% -q-celo~ ;1P/o.o6s% T~A as mobile phase B. The S eluate was ~n~ d s~;llu~hol~ ;r-q-lly at 214 nm. Percent purity is crq-lrl-lqt~ from the peak area of the individual P"~ ;AF C (see Table 1).
Sf~1P~ peptides were ~ulir~ed by high ~îu~ n~ liquid d~u...alO~ .ky (HPLC), using a Waters Prep LC 2000 ~ ~d~
Ch-U~A~ y System (Water Corp., Milford, MA) e~lui~p~ with a Delta Pak C-18, 15 ~m, 300 A cartridge column con~i~ting of a 40 X 10 mm guard cartridge and a 40 X 100 mm Prep Pak cartridge. The column was equilihr~q-ted in 25% buffer B, where A=5% q~u~ ;lP~0.1% llillu~l~iC
acid and B=80% ~r~n;~ p/o.o659~ illuGIuac~lic acid. r~,tLdes were dissolved to ~20 mg/mL in buffer A and 200-800 mg were applied to the 15 column IL1~U~,II the LC pump o~-,.~ g at a flow rate of 8-17 mL/minute bound m~tPri~l was eluted with a gr~tliPnt of 25-35% buffer B/30 min applied at 8-17 mL/mimlte (Some pepti~es were ~u-irled with a ~ t of 23-33%B/30 minute). The eluate was ...m~ d at 220 and/or 280 and 300 nm withaWaters490Enu~ hl~MulLiw~ ,le.lE;l~ et~tQr. I~ 1;nncwe~e 20 cnll~t~d and as~o~ for the peptide of interest on an Ultrafast Mico~>~lein Analy~r (Michrom RioR~u.~, Inc., r1__c~ .", CA) e~lui~p~d with a Zorba~c C-8, 150 X 1 mm, 5 ~m, 300 A ...,.;~.I;.;n~l at 40~C. FT~rtinnc c~ n;ng the peptide of interest at >95% purity were pooled and lyo~hi1i7~d to dryness. Ihe purity of the .~d m~t~ri~l was d~t~-...;..F~l with 25 analytical .~vt;.:~-phase HPLC.

Example 2 IN VlTRO ANTI-FUNGAL EFFECTS
This e~cample addresses in vitro SC 1~.LUI~ of Domain m derived p~pti~l~S for anti-fungal activity in a broth assay and/or in a radial diffusion W O 97/04008 PCTrUS96/0384S

. ssay.
Table 1 below sets out p~pti~es derived from or based on Domain Il[I
- BPI ~u nces. Such p~ptirlPC may be idPntifiPA by peptide l~u~ber with a prefi~ XMP or BPI (e.g., XMP.1 or BPI.1, XMP.2 or BPI.2, etc.). Table 5 1 al o sets out the SEQ ID NO: of eqch p~ptitle, the amino acid s~u_.lce based on l~,f~ ce to ~0~ I;nn within BPI and the d~ q-ti~-n of amino acid ~bsl;lul;n~c and ~~ltlitinnc Also set out in Table 1 are HPLC e~ -c of purity of the pepti~lP-s The HPLC purity analysis was ~ r~.. P~ as ~ . ;l~d in F.~ ~s 1.
In each broth assay S~ U~, ~1U~, a colony of C.
albicans ~.C;~ted CA-1, Strain SLU-1 that was ~ d from the 1AhO~IO~;PS of G. Mqtll~hAk and A. T~.hnf~r, St. Louis Ul.i~ ~nsFitqll, St. Louis, MO, where the strain was ...~;..I~;nP~, was innclllqtpd into a tube c~.l~;..;..~ S mL S~~u~ D~llos_ broth (2% dw~llu~, 1% l~
15 and ;n.-ub~t ~ overnight at 37~C with chAkin~ The o._~.~l.t culture was diluted 1:50 into 5 mL of fresh broth and ;~ Jba'~ for 3 hours at 37~C.
O~ni~m~ were pPllPt~d by c~ ,I,iÇugalion in a n~ L~al~ J-6M c~,l.;r ~,e for 5 ...;..-~s at 3000 rpm (1500 ~c g) and the pellets were .~ in 5 mlL
phO~l.hA~e bur~d saline (PBS) and the optical density at 570 nm was 20 Id~t~ P~ On the basis of the d~t~ n that one OD unit equals 3 107 colony r~ g units/mL, yeast cells were diluted to 2 ~c 106 cells/mL in Saboulaud D~L,ose broth.
Domain m p~pti~1P5 derived from or based on BPI to be s~;l~ned were rri~in~lly con~ ,l~ in Dulbecco's-PBS, were diluted to 1 25 ~g/m]L in broth and were ~rially diluted 2-fold into wells of a 96 well sterile, flat bottom, non-~ g~nic tissue culture plate (Costar, Guu~l;dge, MA). AlLl assays were ~ r~....~ in triplir~tP 2 ~c 10~ or~ni~m~ were added at 100 ~1 per well; final volume was 200 luL/well; the plate was in~ b_t. ~ on a sha~r at 37~C for 18 hours; and the optical ~~Pn~itiP$ for each well were read at 5~D
30 nm. Figure 1 hereto gr~rhir~lly illu~ the dose l~,~n~ curves for five p~ptiAes (XMP. 13, XMP. 138, XMP. 139, XMP. 142 and XMP. 143). All t.~ pti~l~S ~_luced optical density of the cultures to below 0.1 at doses of less than about 50 ~Lg/mL, with XMP. 138 dis~layillg ~e best results of the ill~ d pepti~les at low dQ ~ ~s The broth assay data may be set out 5 in tenns of ...ii.;....~ y cn.~rf.~ ;nn (MIC), i.e. the lowest CO~ iull l~u~lCd to reduce ~e oE~tical density at 590 nm to below 0.1.
The MIC ~ug/mL) of e~ch of the five ~ s listed above in Figure 1 is 12.5, 3.13, 6.25, 12.5 and 25.0, ~ ly.
In the radial ~lirfu;.;oll assay ~l~lul~s, the CA-1 cultures and 10 p~ptide sollltion~ were ~Jlc~ll~d as in the broth assay pl~lul., d~rihed above. Ten mL of molten unde.la~ agarose c~,..~ 3% Sa~uul~ud D~L~u~ broth, 1% agarose a~ r ~ ~ ris~ld~ dy~ NJ), 0.02% Tween 20, and 10 mM sodium phn~ e at pH 7.4, was added to p~ly~ e tubes and F~ in a 56~C water bath until the 1~iitinn of yeast. Tubes were 15 cooled to a~ t~-ly 45~C, yeast were addcd to give a final cf,'~c~ ;n~
of 1 ~c 106 CFU/mL, and the tubes were mi~ced again by ~ .Lil~. The cnntr~l~ were poured into level square petri dishes and di~ ibut~d evenly.
The agarose snli~lifi~A in less than 30 ~2,-ds and had a ".~;r.. ~hirlrn~ of about 1 mm. A series of wells were ~u--cl-f~l into the hal'ldFn~ d a~ ~ using 20 a sterile 3 mm punch ~ '.hF~ to a vacuum ;,~ l.,c Peptides to be ~ss~y~d were 2-fold serially diluted in Dulbecco's PBS (D-PBS) st~ng from a c~n~f ..I~I;nn of a~7~7lu~;.--~t~ly 1 mg/mL. Five ~LL of each dil~ltinn were added to each well and the plates were ;I~c!~ d at 37 C for 3 hours. An u.~l~. of 10 mL of molten agarose comrri~ing 6%
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7.4, (at a~ ly 45~C) was then added and plates were i~ b~
overnight at 37~C. Following this overnight ;u. ul~l;m-, a dilute Co~ c~:r sol~-tion was poured into the plates and allowed to stain for 24 hours.
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W O 97/04008 PCT~US96/03845 mple 3 IN VITRO ~;ND IN VIVO ~FFECT OF ANTI-FUNGAL 1 ON A VARIETY OF FUNGAL SPECIES
This ~ ,le addl~ses in vitro and in vivo s, .~.~ of various S Domain m derived peptides for anti-fungal activity against a ~ of fungal s, inrll-di~ dida species and strains l~s~l to various anti-fungal agents, in a radial diCrusion assay. The ~ ~ 1P also addl~s the effects of co...~ of peptide and a~ .ot~ - ;rin B against Ca~l~li~7 strain SLU-I.
Domain m derived p~ptirl~ were tested for their fung~ri~
ctivity on ~.. l.I.f~t~,.;cin resistant Candida. ~2~cictqnt cc-lb~;e~c of Candida were j~lqt~ using a g.~ ;el-~ plate teollni~lue A slanted .S~ d~AL-ose agar plate was poured and allowed to h. rden. The plate was made level and qf~ ;..nal agar supple~ 1 wi~ ,~ , (Sigma, St. Louis, MO, cat. no.
N-3503) at a c~.~e~ n of 10 ~g/mL was poured. CeUs from the the CA-1 colony of C'-~i~7 albicans SLU-l st~ ;l~1 in F~ ,'- 2 (107 ceUs in a volume of 100 ~LL) were spread over the plate and ;".~ .a~.-d at 37~C
overnight ~itiaUy, minute c~?loniec were seen and l~ui~ iitinn:~l in.-vl~a~;On time to achieve ~e size of wildtype cnlnnips. El~ven ~nloniPs were ~P~cign~t~ SLU-2A though SLU-2K. These colonies were serially F~r~P~l 20 in ~Sz~ d deAhuse broth svF~l~ mentp~ with i.lcl~asing C~ c~ nc of a..l~ot.,.icin B, after an initial ~s~ge wi~ 2 ~Lg/mL A.nl,hnt~c. ;C;n B. After the final ~ in 20 ~g/mL ~nl~hot~ B, c-~]~ ni~os 2G, 2H, 2J and 2K
viable ~1.~ as the wildtype SLU-l st~ain 1~ n~ SC.IS;I to 1 fLg/mL amphotericin B. None of the l~;Sl.ull strains d~ c~at~xi germ tube 25 fr~ tion in fetal bovine serum. In ~Adition~ these isolates had a much slower growth rate than SLU-l and did not form hyphae at 37~C.
For the radial dirrus;oll assays, C;andida albicans SLU-l were grown as desf~rihed above and SLU-2G were grown overnight in Sa~uul~ud d~kose broth s.,~' m.onted with 10 f~g/mL ~...ph~ .;t';.. B and S ~g/mL
--- ~

~ c~r~one at 37~C. Cultl!res were diluted 1:25 into fresh, uns~ m~.nt~Y1 broth and allowed to grow for 5 hours at 37~C. Cells were pPll-t~ at 1,500 X g for S ...;..~ c at 4 ~C. S~ l was ~l~c~ d and ,~ ~~ with 5 mL
of 10 mM pho~l.h tr buffer, p~I 7.4. After oe~ iru~,aLioll the cell pellets wereS ~ 1~ with 5 mL l.1~o.,~ buffer for an OD570 d~t ~ h._l;~. One OD570 for SLU-l cells was 3 X 107 CFU/mL and for SLU-2G cells was 5 X
106 CF~J/mL.
Cells were added to 10 mL of mnlt~n, cooled (-- 45~C) agarose to a CQ~ r.l~l;n~ of 1 X 106/mL and ffle ~ u~ was 10 poured into a level square pe~i plate with gentle l~cl~;ing to allow c~en di~L.~uLi~ ~ and sn1i~lific~tinn to a !~ r~ thiclrn~occ of about 1 mm. Wells were cut into ~e ha~ ed ag~osc with a ~ i7fYi, 3 mm d;~ - punch with ~dCiUU Il.
Peptides were tw~fold serially diluted with D-PBS from a 15 ~ g C~ f--~ of ~nJ~ t~ly 1 mg/mL. ~ hnt~-;r;~ B and n~ Lin were ~imil:~rly diluted starting at 100 and 225 ~g/mL, ~
Five ~LL were added per well and allowed to diffuse at 37~C for 1.5-2.0 hours. Then 10 mL of molten ~ r agarose were added and the plates were inc"b~t~1 illvcl~d at 37~C ~J....n.ghl Plates were stained with a dilute 20 Coolll~ssie sol~-l;nn, in_ibition zones were I~ d with c~ P,rs and net areas were c~lrl~ht~d~ then c~ ,~Ld to pmol values by PROBIT analysis.
The results of a l,,pl~n~ lY- ;...I nl are shown in Figure 2A for the SLU-1 strain and Figure 2B for the SLU-2G strain. In Figu~Es 2A and 2B, the f~ ci-l~l activity is l~ lt~xl for XMP. 13 as open circles; for XMP.37 as closed circles; for XMP.97 as open tri~ngl~s; for XMP.127 as closed gl~s; for amphotericin B as open sluales; and for l~ Lill as closed squares. The pmol for a 30 mm2 zone of inhih;l;on were c~lc~ t~l to be:
for XMP.13, 689 pmol against SLU-1 and 129 pmol against SLU-2G; for XMP.37, 231 pmol against SLU-l and 75 pmol against SLU-2G; for XMP.97, 670 pmol against SLU-l and 161 pmol against SLU-2G; for XMP.127, 935 pmol ag,ainst SLU-l and 116 pmol against SLU-2G; for al.l~,holericin B, 36 pmol against SLU-1 and >541 pmol for SLU-2G; and for ll~r;~tnLul~ 98 pmol against SLU-1 and > 1,215 pmol against SLU-2G. As shown in Figures 2A and 2B, lc~ l;ve Domain m derived peptides XMP.13, XMP.37, XMP.97 and XMP.127 ~ t.A fim~,~jri~l activity~
against both the SLU-1 wild type strain and the SLU-2G A...l.hnt.~..;r.in ~
l~;r~ l strain, with better activity~ d~,.llo~ ,.led against the SLU-2G
10 ~ hot. .;rin B le~ strain. In c~ l.l.,~cl a Iy~hotelicin B was errc,~
against the oriprin~l SLU-l strain but did not kill the SLU-2G r~cirt~nt cells.
These results r1~m~.cl.~ that Domain m derived peptides ac~l~hlg, to the invention are err~live ~Inp.~ l ag~ents by a ~..P.'hAn;C.~ rr~nt from that of ~..... l)l~ol~ ;r.in B.
Fur~er e ~ nl~ were ~;lrull~led to ~tr-.. ;i~f the anti-fungal aetivily of Domain m derived peptides on c~l....~f--.,ially-available strains of Candida c~ d recistant to other anti-fungal agentc~
reCict~nt C. albicans (ATCC A~C~ No. 38247), 5-llu~lu ;ykls lle resistant C. albicans (ATCC No. 44373), azole-resistant C albicans (ATCC No.
62342), and 1~ t,~n~ ~ l~iSt~u~l C albicans (ATCC No. 64124).
Flm~iri~i~l activity of lc~ pPpti~ s XMP.13, XMP.36, XMP.97, XMP.127, and XMP.166 was not reduced on the above strains tested, ;",l;r~ g that the peptides are err~Li~e by a ...~-~.h~n;~... dirr~ t than that of the other anti-fungal agents.
The anti-fungal activity of Domain m derived p~pti~ was also evaluated in vitro against a variety of fungal s~ies, inr.~ inf~ Candida glabrata, Candida krusei, Candida lusitaniae, Candida par~,nsi~osi~, and Candida tropicalis. For these ~ .l~.. ;.. l~, one colony of each of the above-listed C~da strains was picked from a .s~ho~ s d~ se agar (SDA) plate and in~ t~ into S mL of Saboulaud~s d~ JsG broth (SDB, 29~
d~Llose and 1% n~p,~ .F.) or, for C krusei, Yeast Malt broth (YM, Becton Di~ n, Coclu~ ille, MD, cat no. BL11405) in 12 mL
S l~olyp~ cne snap-cap tubes. The tube cultures were ;t.cub~l~ u.
with ~h~king at 37 C.
Cultures were ~t~d when ~e OD570 of a 1:10 ~ih)tinn wa~
greater ~an or equal to the following values: 0.083 for Candida glabrata~
0.154 for ~ndida *rusei, 0.117 for ~nrA~j~ lusitaniae, 0.076 for ~
par~zrsi7Osi~, and 0.192 for ~ i~ tropica7is. Cells were c~ .~.;r.~C,.d for 7 ",j"ytr5 in an r.~ do. r miclc,fugG at 3,000 Ipm (about 1,500 g). The celD
pellet was l~ ~n~ed in 1 mL PBS and a~lvA;.. ~trl~ 1 X 107 cdls in about 0.5 mL were added to 10 mL of cooled u-~dc~ agar (3% SBD, 1 % ag.u~s~, 0.02% Tween 20, 10 mM sodium phfssl~hal~ buffer, pH 7.4 at about 45~C).
15 The s~ was poured into square petri plates, allowed to solidify, andl wells cut as de~;l;l~cd above.
Peptides were two-fold seri~lly diluted with D-PBS from about 20 ~LL of a sL~Ling cn~ n of ap~l~.Ai...-t ly 1 mg/mL. Five ~LL of peptide ~iilntion were added per well and allowed to diffuse for at least aboul:30 ~ -s into the agar at 37~C (to allow complete ~l;rfi,~ n) Then 10 mL
of molten ~ lay~ ag~os~ (6% SDB, 1 % ag~,se, 10 mM sodium ~ho~
buffer, pH 7.4 at about 45~C) were added and the plates were incubated inverted at 37~C u~ ..;rl-l Plates were stained with a dilute CQO,..~
solution, inl~ilion zones were Ill~s.l,~d with calipers and net areas were 25 CZllr~ tp~i~ then ~ll~ ~d to pmole values by PROBlT analysis. The results of a ~ l;ve e~rimPnt are shown in Table 2. F~ 5.y Domain m derived peptides XMP.13P, XMP.97P, XMP.127P, XMP.166P, XMP.286P, XMP.327P, XMP.331P, XMP.332P, XMP.333P and XMP.337P

mon.ctr~t~ some fimgjri~l~l activity against at least seve~al of the C~ndida strains tested. These results d~ nc~ that Domain m denved p~ti~1e,c acc~l~lihlg to the u~ Lion are c;rr~ fUngiriA~l agents in a broad S~ lu against a variety of Candida ~eriF-S.
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WO 97/04008 PCT~US96/03345 - The anti-fungal activity of Domain m derived peptides wasevaluated against a variety of fungal species, including species of Candida, Cryptococcus, Fusarium, Trichophyton, and Aspergillus, by an additional assay protocol ntili7ing Alamar Blue. Alamar Blue is an inrlic~tor dye 5 formulated to measure ~ lively the proliferation of a variety of human or animal cells, bacteria, or fungi. It consists of an oxidation-reduction (REDOX) indicator that yields a colorimetric change in response to metabolic activity.
For these e~ Pntc~ species of Candida and Cryptococcus 10 were grown in Sabouraud's dextrose broth (SDB) overnight. Strains of filamentous fungi (Aspergillus, Fusarium, Trichophyton) were obt~inPd by irri~tion of a confluent culture from a petri dish. Cells were washed andl adjusted to a conce.lllalion of 5.0 x 103/mL in fresh SDB. Peptides were two-fold serially diluted in SDB from a concentr~tiQn of 20 ~g/mL. Controls 15 included a,lll,hol~icin B, flucon~ole, ketoconazole and griseofulvin.
A~ILirull~al drugs were also diluted in the same ,llamler.
Assays were l,elrolllled in 96-well microtiter plates. Peptides were in a volume of 100~L per well followed by the addition of 100~4L of the fungal cell suspension. Final co~ .alion of fungi was 2.5 x 103/mL and 20 test antifungal colll~oullds started from a co~cr~ liQn of 10 ~g/mL. Alamar Blue was added at 20 ~L per well and plates were inc~lb~tyl for a period of 18 hours at 37~C for Aspergillus, Candida, Cryptococcus, 48-72 hours at 30~C for slower growing fungi (i.e., Trichophyton). Plates were celllliruged briefly (1,000 rpm, 1 minute) to pellet fungal cells or debris. 100 ,uL from 25 each well was transferred to new 96-well plates and an ODsgo reading was rolllled on an FT ~SA plate reader.
50~LL from the original 96-well plates were plated on Sabouraud's dextrose agar to determine filngici-l~l activity. The wells to be plated were detPrminPA by OD590 readings. The lowest concPntrAtinn of 30 peptide which m~int~ined the blue color (or OD reading) of the blank was chosen along with the next two higher concentrations. Plates were allowed to grow for 18-48 hours depending on the rate of growth of each fungus.
I~inim~l fimgici-1~l activity (MFC) was determined as a 99.9% killing of the starting inoculum. For fil~m~ntQus fungi, this was delG~ ed as the lowest S concentration of peptide which showed no growth (complete stlorili7~tion).
The results of these assays are shown for lclJlGsGll~Li~e peptides in Tables 3 and 4. These results demonsLl~tG that Domain m derived peptides according to the invention are effective fungicidal agents in a broad spectrum against a variety of fungal species.

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'': 2 ¢ ~,, ~ ~ ~ ~ ~ ~ ~ ~ ~ o ~ o W O 97/04008 . PCT~US96/03845 - In q~d;~ n~ ,nt~, a nuc;~.s~ e a~ivdl~xl cell sorter (FACS) based -qssay was developed to test the fungjci~i-q-l ac~vity of the peptiAe~ For these c-l~ nl.;, fungi were cultured and ~ q~ by plating on Saboulaud~s D~ hu~ (1% Neo~,pl~ , 2% D~L.u~e; Difco) agar.
S Seve~al crlc-ni~ were piclced from the agar plate and in~llqt~d into S mL of S~ 's D~ )~ media in a sterile 10 mL poly~lù~ c tube. The fungal cultures were incubated for about 18 hours at 30~C. At the end of i..-~.,l~ql;l l), 4 mL of the fungal culture were inocu1~t~ into a flaslc of 100 mL
of .~qhollrrq-lld's D~lluse broth (SDB). The 100 mL culture was inr~cll1qt~1 10 for about 5 hours or until log growth. When the culture l~ached log growth, the 100 mL culture was d~q~ into two 50 mL conical ~u~ u~ e c~--l-;r-ge tubes. The culture were ~ ;rugrd at 3000 rpm for 5 minutes (Sorvall RT 60OOB). After ~..I.;r.~p,~l;..-, ~e s~ ..l was decanted leaving the fungal pellets in the c~ - ;r.~; tubes. The p~llets were 15 ~ nd~l in 15 mL of SDB. Both ~ n~ were c~ bl,.cd into one tube and mi~ed to ~ lf; a stock culture. The con~'~nl~.~l;o.. of the fungal stock was .1~e. ---;n~ by either ~ tin~ a sample of the stock 1:10 with SDB
and then d~h- ...;..il,g the OD of the ~ihltinn by ;.~;~.vpho~...cl,~ at 570 nm (~him~ 160 ~U~hotu~ .) or by ~ lting the stock 1:10 with 20 Trypan Blue and eo~ l;ng the cells using a h~.~;ylullle~.. After d~ t ...;n;.,~
the c~ n~. l;on of the stock, .Ip~l~plldt~ di1lltit~n~ were made with Sabouraud's DCAllUSe media to obtain 100 mL of 1 ~c 106 ceWml.
Peptide so11ltinnc were ~ ~d in saline to cQn~ nl~l;on~ of a~ t~ 1 mg/mL. In a 96 well ~u~lo~lene plate (Costar 3790), the pepti~lPs were diluted 1:2 SiA times in a serial ~1i1ntion with PBS. Then 1 mL
of the 1 -A 106 cells/mL cell s~ n~:on was .ii~ into a~ lia~ IIUIIl~
of FACScan tubes (Falcon 2054), seven tubes per peptide and three tubes for assay contmls (~silive, n~live, and aulofluol~s~nc~ controls).
A~pl~ 20 ~1 of the peptide so1ution~ were added to the 1 mL cell s--~ n~ on to achieve a final peptide conce.lLIdLion in the tube of 20, 10, 5, 2.5, 1.25, 0.625, and 0.313 ~g/mL peptisle The tubes were ;.~ batfA at 30~C for 1 hour e~cept for the ~Live control tube which was i~ .o-~A for s, then c~ iru~,cd at 3000 rpm for 5 ...;...~-s. The s ~ n~ was Af~ i and the cell pellet was .~ W with 1 mL of 70% EtOH ~en ;.. - --l~t~ for 10 .~ t~s to acl~_ 100% Icill. After the 1 hour ;~ ;01~, all the tubes were ~ ~ ;r~E~rcl at 3000 rpm for 5 ",;""t 5 Su~ were A~ A and the pellets ~ A~d wi~ 1 mL of 80 ~g/mL of pr~pidium iodide (Sigma, St. Louis, MO) in Dulbecco's PBS (DPBS, GIBCO, Grand Island, NY) e~cept the ~u~lluo,..~fn~ control, which was ~ A~l in 10 DPBS alone. The tubes were mi~ced and ;~ PA in the dark at room t ~ ., for at least 20 The FACScan flow ~",~t. ~ (Bec~n Dir~ ~n, M~r~ view, CA) was allowed to warm up for at least S minutes before assay analysis. The ~ttir~ were adjusted apt"~t~ to the followin~
15a~luA ~

A~lifier D~t~
FSC 1.00-2.00 ~i00 SSC 1.00-2.00 200 300 FL1 Log 400 500 FL2 Log 400 500 Cells were analyzed (10,000 cells/tube) and their ~ e nuolc~ r~A~ FA- Inthese~ ;,~e~.toll-~r..~l~controldid not have ~i~nifir~nt llu~ nr~ The population of dead (i.e., propiAinm iodide stained) fimgal cells was det~l",lled by a nu~ n-e threshold ~t~.~;n the neg~ e control and ~siliv~ control. For all ~n~r-,~ n$ of 25 peptiA~, the~ of deadcellswasplottedagainstpeptide co.~r. .~.,.I;.~n and an ICso was APle"";..rA by curve fitting. The results for 1CP1~ ;VG
peptides are sho~-vn in Tables S llllough 8 below.

WO 97/04008 PCT~US96/03845 TAl~ F, S

Ac~y of pep~des on C ~ s SLU#l Fkp~de ICSo ~u~ln~L) P.284 0.31 hlP.353 0.53 P.268 0.55 ~IP.342 0.60 ~P.391 0.64 P.391 0.73 krP.391 0.73 P.366 0.89 ~D~rP.389 0.95 ~D~llP.373 1.13 P.342 1.88 ~llP.342 2.03 ~IlP.465 2.11 ~lP.367 2.37 ~P.406 4.29 hlP.378 13.09 P.407 27.03 t .. ;r.in B 79.36 WO 97/04008 PCT~US96/03845 TART ~ 6 Ac~v~y of pep~dt~ on valious sb~ns of C. olbiGons ICSo ~uglniL) p~i SLU#l 10231 90028 26SSS 140S3 P.284 0.31 1.86 1.08 0.59 0.50 ~D~rP.342 1.88 8.07 3.44 3.19 2.74 ~D~rP.365 2.11 3.75 0.27 0.15 0.13 ~DP.366 0.89 4.53 2.29 0.69 1.35 ~D~nP.367 2.37 ~n~ 0.22 0.21 0.08 ~D~DP.373 1.13 2.92 1.86 1.46 1.64 P.389 0.95 3.12 2.79 0.89 0.95 ~D~rP.391 0.64 2,06 1.29 0.79 1.04 = Not ~

-TABI~E 7 Activ~y of Pep~des on Vnrious ~ cl --Candida Cand~da Cand~a gZ~ ~, k ;~
Pep~de ICso ICso IC50 ~g/mL) ~g/mL) ~g/mL) ~D~IlP.284 6.27 1.20 1.82 ~DP.342 11.00 3.24 NT
~llP.365 15.26 1.25 7.72 ~Y[lP.366 21.00 3.03 ~r ~IlP.367 20.00 1.25 2.32 kD~lP.373 4.96 1.11 3.74 ~lP.389 4.64 2.26 5.36 ~IP.391 2.85 1.69 0.85 NT = Not Tested TAR~ ~ 8 A~h~y of Pep~des on Clytococcus Neofonnons 13690 Pep~de ICSo ~ug~ni~) ~IlP.284 0.11 ~D~fP.342 o gs ~D~rP.353 0.37 ~D~DP.365 0.03 ~DP.366 0.47 P.367 0.05 ~P.373 0.87 P.389 0.25 ~P.391 0.34 CA 02227292 l998-Ol-l9 The effects of cu~l~h;~ ;n~c of peptide and ~mphntPririn B
against C~ndida strain SLU-l were st~ ip~l- For these albicans SLU-l was grown and a~ d in a broth t~ ti-~n assay as df~cç ih~
in P-~mr~ 2, e~cept that peptide alone, ~",l~l,ot ~- ;rin B alone, or 5 c4 --hi~ul;0nc of peptide and ~ ot~ ;n B were im~ with the fungal cells for te~ting.
The results of such an assay using ~ peptide XMP.97, alone or in colllb~lion with ~ nt_ ;rin B, are shown in Figure 3. In Figure 3, the filngjri~ activity of co,.~ ;onc of Xl~P.97 and 10 ~,..pl~nt~ in B are r~.,t~l for the XMP.97 Con~ l;onc shown and nc of ~ Jt~ ;~ ;.. B of 0.047 ~g/ml (open squares); 0.074 ~g/ml (closed tri~nglPc);o.l88 ~g/ml (open t-;-~nglr~ 0.375 ~Lg/ml (closed circlec);
and 0.750 ~Lg/ml (open circles). The activity of XMP.97 alone is by the closed squares. Both XMP.97 and ~ ot ~ ;~ . B are each err~Li~
15 alone at certain cnn~ ~C as anti-fungal agents. The co ~~b;naLon of peptide and ~ h-JtJV~ ;n B does not result in inhibition (as it would if the twodrugs were ~ r)~ but ratner results in dc~;lcas.ng the amount of botn anti-fungal agents l~Ui~A for ~-~ Icilling. In particular, c;oncu~ t ~lminictr~tion of this Domain m derived peptide with an anti-fungal agent, 20 such as ~ hol-~ririn B, achieved an i~ o.~d th~ ir ~rf~~ n~;.
ougll ~A~..'il~ the c~.~r~ ;nn of ~ ho~ B l~uilcd to eradicate or inhibit fungal growth. Rer~n~ the use of ~ .ho!e. ;rin B has been limited by its systemic to~cicity, lo~lillg the conrPnt~tinn of such an anti-fungal agent 1~4uil~d for ~ l;r err~ ~S can reduce to~icity, and thus may allow 25 wider use of this agent.
The anti-fungal activity of Domain m derived pepti~l~s may also be evaluated in viw in animal models for a variety of fungal speri~s inr-lnrling Gy~lo~oridiumpar~ Gyptococcus ne~",-ansandHistoplas7na C'Zrsl'7a~. Animal models for C parl~um, SpO~ d by c~ l ~uices 30 from the N~tion~l T..!J;L~.le of Allergy and Tnfe~tin~l~ Diseases, include severe -d i.. ,.n~i~ on~y (SCID) mouse models and a colostrum-d~
SPF piglet model.
, The anti-fungal activity of Domain m derived pepti~l~s may be evaluated in viw in ~ ;l;m-~l animal mr-lelc, ;..r.l".l;.~, for; ~!e, a S ~n~ ~ic rabbit model of ~ d ~n~ Qic such as d~ cd by Walsh et al., J. Irffect. Dis., 161:755-760 (1990) and Thaler ct al., J. Ir~ect. Dis., 158:80 (1988); a mouse model of ~1;.c.c~n~;,.al~;l Aspergillosis such as d~ ;heA by Arroyo et al., An~imicrob. Agen~s ~ Ch~mo., pp. 21-25 (Ja.,u~ ~, 1977); and a n~ LIu~ iC rat model of tli.c~ ..,inal~ C~n~ ciC such 10 as described by ~,hn~r et al., Am. J. P~siol. ~ung Cell. Mol. P*ysiol.J
10:1-8 (1994) and l.,f~..cl,~s cited therein.

Example 4 IN V~VO ANTI-FUNGAL EFFECT OF ~ll~
IN MICE WlTH SY~1~C C~lDA INFECTION
This; ~1~ a~,s~s the in ~w anti-fungal effects of Domain m derived peptiA~s in miti~ting the total mortality or mortality rate of mice systemi~ ly i,.r~,~d with ~nn~ q a~bic-n~2s. Peptides that had been scl~ned for anti-fungal activity in the rddial ~lirrus;on and broth assays ~ . ;I~A in P.-~m~ '~ 2 were ~.~ and ~ A as de~~libed in F
20 1.
Groups of 15 male DBA/2J mice at age ~8 weeks a~ nn Labclal4l~, Bar Harbor, ME) were in~cll~t~A with 1.24 ~ 105 C. albicans (SLU-l s~in as ~esc~ ;l~A, in P ~mrle 2) by Ullld~ ous injectiQn into the ta~
vein. Cells were plep~l for animal inj~ction as follows. A single colony 25 was ~1P~ led and used tO inocul~te a 5 mL tube of Sabouraud d.,~ ose broth.
Tnr.llh~tinn was at 30~C with ~h~king to allow ~ -.1;. n for a period of 15-18 hours. Four mL of the overnight culture were added to 100 mL of fresh Sabc,u,dud d~,~L.ose broth (1:25 ~ ltinn) and ;--~ ~-h:~t~ for 4 hours. The 100 " mL culture was pPll~t~ at 1,500 X g for S .. ;.. l~ s Cells were washed twice W O 97/04008 PCT~US96/03845 by adding 20 mL D-PBS, vorte~cing and re cellLIirugi~g. Cells were c~?ll~ted in one tube and a sample is diluted 1:10 to be ~ d by OD570 (1 OD unit = 3 ~ 107 CFU/mL). The eells were diluted to the desired dose in D-PBS
and kept at 4~C until used. Doses were c~lr.. ~ by p~lr~Jlll~illg serial ten-S fold ~ ntion~ and plating 50 ~Ll per ~ilntion on S~ho~ d~ use agar.
~olo~i~os were counted the following day after u.~ at 37~C.
A 500 mL culture ,vielded a~lu~ y 1 ~c 109 CFU/mL.
A Candida inocll4tion of a~lo~ ly 1 ~ 105 cells resulted in an LD80 over 28 days in this model. T~ ly after fungal ch~n~n~te~
10 the mice were inl~a~lously inje~te~ via the tail vein with a 0.1 mL ~~olu~lle of 10 mg/kg XMP.36, 5 mg/kg XMP.97, 10 mg/kg XMP.102, 1 mg/kg s~...l.h. ~ in B (Sigma, St. Louis, MO), or ~hn.,~ lrf~d saline (PI~S) as a control. T1L;~ t with the same ~...o~ c of peptid~ ..pholericin B
or PBS was l~pr~t~d at Day 2 and Day 4 (e~ccept that the second dose of 15 XMP.36 was given at a dose of 5 mg/kg). Mice were ...o~ ..cd twice daily for mortality until ~ --l;on of the study at Day 28. The mortality data, displayed in Figure 4, show that 100% of the mice treated with ~ .h. ,t~r . ;rinB s.llvivcd, 53% of mice treated with XMP.97 i.~lVi~ p<O.OS colllp~ud to control), 33% of mice t~eated with XMP.36 S.llvi~.od, 27% of mice treated with XMP.102 ~ d, and 20% of mice trcated wi~ PBS ;.. llvi~d until Day 28. In Figure 4, the symbol ~X~ s survival after L.~ -t with .hotr . ;cin B; open squa~es, ~ " -.1 with XMP.97; open circles, Ll~l ...~ -.l with XMP.36; open ~ n~1c~ nl with XMP. 102; and open tri~nglPs, L,~ ..t with buffer. Sp~ictirql ci~nifir~nr~ was evaluated using 25 ~e Lifetest Survival Curve analysis. [I~wless, 3tnn~ti~n7 Modcls and Methods for Life~ime Data, John Wiley & Sons, New York (1982).] The d~ tion and almost linear decline in survival is ~n~1~ous to human Iu~Slic c~n~
riition~l 3~ose studies, groups of 15 mice were injected with a fungal ch~l1Pnge of 0.5 ~c 105 Candida cells, ~ d for injection as , ;hed above, followed ~ e~t at Day 0, Day 2 and Day 5 with a 0 1 mL volume of 10 mg/kg XMP 127, 5 mg/kg ~MP.13, 5 mglkg XMP 37, 1 ,~ mg/kg ~ hol~ ;rin B, or PBS as a control I~e mortality data arc dispL~3~
in Figure 5; 100% of the mice treated with a ~ho r~ n B ;,~iv~d, 67% of S mice treated with XMP 127 s ll vivvd (p < 0 05 cc, ~ d to control), 33 % of mice treated with XMP 37 s..~ d, 20% of mice treated with XMP 13 s~vi~cd, and 33% of mice treated with PBS S~ ivvd until Day 28 In Figure 5, the symbol "X" ,c~ s survival after L~ nl with ~ l)I lf; ;i B;
open circles, L.~ nt wvith XMP 127; filled tri~nglP-s~ l,e~ wvith buffer;
10 open squares, 1, -l --t witn XMP 37; open t ;~ c, 1,~ t with In these 3-dose studies, ~mrhn~ericin B was completely ~t~livc, as e~ ~d The effect of XMP.102, a control peptide will,uul anti-fungal activity as d~t~ ...inrd by a radial .I;rr~ - assay as df~ in 15 F ~ 2, was no dirr~ om PBS. The data d~ e that ~-h,,;,,i~ .l;on of pepti~les XMP.97 and XMP.127 to mice ch~llf ng syst~mi~ y with C al~ican~ !~ y provided a ci~ rcdllctinn in mortality co--,~d with buffer-treated eo ~LIols.
Further studies to d~t~--.--;nf the err~ti~ ess of anti-fungal 20 pceptides were ~ - r~. ..-f d at an i~ c~d dosing l~illlCII (6 doses rather than 3 doses as ~f~S". ;1~1 above). Groups of 9 week-old male DBA/2J mice were innClll~t~ with cQn~ l ion~ of 2.7 x 105 C'~ 7 cells (~l~uod as ~l_c~-. ;hed above) by il,L.a~ ous inje~tinn in the tail vein. T....--~ lf ly after fungal t~h~ ng~7 the mice were treated with a 0.1 mL volume of 10 mg/lcg XMP.284, 1 mg/kg qmrhotf~ri~in B or PBS as a control at Day 0, Day 2, Day 4, Day 7, Day 9 and Day 11. All ~ll~hot~li. ill B-treated qnimqlc were plo~ ~ The results for XMP.284 (closed circles) and PBS control (oE~en circles) are displayed in Figure 6. The mortality data showed that only one of the PBS-treated qnimqlc su,~ived injection with 2.7 ~ 105 C~ndida at Day 6 IlllUUgll Day 24 (6% survival), however, XMP.284 ~lut~iled 13 qnimqlc (87% survival) at Day 6 and 3 znim~l~ (339~t; survival) at Day 24.
nnzl 6-dose ~ were conAuct~ as ~1~s ~
above, using inocula of 0.5-3.0 ~c 105 C~ndid~ cells and using 0.01, 0.05, 0.1, 0.5, 1.0 or 5.0 mg/kg doses of peptide. The results are s~.. z.;,~1 in S Table 9 below.

~ 8 D 8 O O _ D
,~ D D D D O D D O O O ~}
D D D D o D D ~ ~ o ~

~ ~a, _~~~~~~~~~OO~O

- ~ X ~X X X X X X ~X X X X X ~

~ _ ~ D
~ ~ 8 ,~3 D O ~ .D ~, ~o ~ . D _ D ~ ~
~ o ~ ~ Y ~ ~ ~
~ -- ~ D ~ D 8 ~ ~ -- o D ~ ~

O _ O

O O
v~ ~ ~ ~ ~ V~ o o ~ ~ ~
t:~~~~~~OOOOOOOO
~ O O
O O

WO 97/04008 PCT~US96/03845 _ D ~ ~ô D D D D D O o o OOO~OOOOOOOOOO
~ O

V ~ X X X X X X

PCT~US96/03845 D ~
~ _ o .ô .o o _ o '~

~ A

.3~

~ ~ ~ ~ ~'~

~ D

An in vivo fi~jr~ 1 assay was d~,._lo~l to study the cc ~ ; v~ efficacy of pf~ptitle5 and ~ . . .pho~ B (AmpB) tio reduce fungal load in the l~id~ ;. of mice syst~-mir~lly infr~t,~1 with Condida a~bicans.
~ were ~kci~n~3 to ~:1e~ - -..;..r the e~tent of fungal clP~ from 5 the kidneys following peptide or AmpB L.~ t as follows.
Tn~~ tion of male DBA/2 mice (Charles River Labs) with 6 ~ 104 C. a~bicans and s~lminictr~tinn of saline, AmpB or peptide was p~.r.. ~ on Day O via i~ d~-nous ;.je~;l;nn into ~e tail vein. All groups (n=6) ~ d equal C. albicans rh~ n~e (s~ inoc~ m of 1.0 - 1.5 10 x 105 reduced by half to avoid mortality) and equal total volume of sterile saline or ~ ;r~ agent per ;--je~ . T~ was i~ t. A ;~ P~ t. .1~, after inoc~ tinn All mice were dosed q.d. or q.o.d with saline, peptide or Amp B. At study ~ ;on on Day 4, all z~nim~l~ were o~~rifi~i by C02 ~s~}~ dlion and their ~id~ i. e~ccised for Candida ~ n lS.S~ ;r;r~lly, i~ ]y follow~ng animal ~ifi~, both lcidneys were e-ri~7 and adrenal glands and ~rlhPring tissue ~~ --o._d. Pairs of }i~ were placed i.. P.I;~ly into ~ ;ghed lS mL conical tubes CO~ p S mL sterile ~line plus a 1:100 riilllti~n of a 10 mg/mL stock s)lllticn of pPni-~illin/sl,~",~_i" Tubes were weighed again, and the 20 dirr~ l~ .lc~ l~l.l~d as "kidney gram fresh weight. n Tubes were stored on ice until organ ...~
For Candida re-;~ ;, l- and CFU d~ t - ...;~ ;. n, a glass-on-glass tissue hf~---~;. --;~- - (T~.~luecl~ Tissue Grinder, 15 mL, Wheaton) was washed with soap and water, rins_d, and stPrili7~ for 2 ~ Jt~ 5 with ice-cold 25 70% eth~nf-l Following d~c~ of the eth~nol, ho"-og-rl-;,. ~~ were rinsed with sterile PBS, which was also ~1P~n~. Then S mL of saline/~ntih:oti~-s and kidneys were added to the plGp~d hG~n;J ~ and ground until kidney V c~rslll~s were free of s~rlhPrjn5~ tissue. 2 mL of this ho.. - ~n~l~o was ~n.~f~.rred sterilely to a clean tube on ice. 100 ~LL of ho...~e-.~'~ (serially diluted in sterile PBS) were plated onto Sa~uldud D~LIose Agar ph~les and -Jl~ at 37~C oVcrni~ht Colonies were C."""~ ~~h ~;1 CFU and CFU/GFW c~lr~ ~, and results analyzed by ANOVA and Fisher's PLSD.
The results of assays with ~ peptir~s are shown in Table 10.

PCT~US96/03845 TAR~ ~. 10 Pep~ide Dose (mg/kg) Dose Regimen P~

XMP.366 0.5 single dose 0.0005 0.1 q.d b 0.05 q.d, b.i.d b, b 0.01 q.d, b.i.d 0.008, b XMP.342 5 q.d., q.o.d. b, b q.d b XMP.391 5 q.d, q.o.d. 0.002, b q.d b XMP.373 5 q.d, q.o.d b, b q.d b X~P.353 5 q.d., q.o.d b, b q.d b a P-values vs. saline are derived from Kaplan-Meier survival analysis b not st~ eally better than saline (P ~0.05) Studies were also ~Ir,ll--ed to ~et~ i.. e ~e ~,rr~ ess of Cp~r~ rC anti-fungal p~pt~ Ps in cycl~rin A-;..... ~-o~ ssed mice systemicaUy infe_ted wi~ ~ *7 a7bicans SLU-l. Groups (15 qnimqWgroup) of 9 week-old male DBA/~ mice were i~ o,~ ~l.p~ d by 5 ~ e~ - .t with 10 mg/kg (Day-l) of ~clor~lin A A-h..;..;et -od by ;~I.~.;l.)...~l ;,,jP~ One day later (Day 0), ~e mice were inoc~
with 2 ~c 105 ~ndida cells by inlld~ Jus injection in the tail vein.
T~ t.cly after fungal chqllp-~ge~ the mice we~e treated with a 0.1 mL
volume of 10 mg/kg XMP.284, 10 mg/kg XMP.127, or PBS as a control.
Cycl~).,l~.. ;.- A injeeti~-nc were 1~ at Day 1, Day 3, Day 7, and Day 9.
XMP.284, XMP. 127 or PBS ~ C were l~,~t~d at Day 2, Day 4, Day 6, Day 8 and Day 10. AU ~mrhotericin ~treated qnimqlc were ~ d -1'he results di~l~l in Figure 7 of the mortality data after ~ . n~ with XMP. 127 (closed ~ ngk~), XMP.284 (open squares) and PBS control (open 15 circles) show that the i~ n-o~ ~scd mice are more s~ d;~ to C~ndida ior~l;on as ~ ~t~ , XMP.284 and to a lesser e~tent XMP. 127, provided ~0~ against the infP~ tion as Ill~ul~l by ill~;l~d survival ~ d with PBS CCJ IL.uls.
Further in vivo '~ with or wilhuul ~ o~ ;n A
i... nfi,.,.l,L,les~on are ~rulll~ed to col-r,l.. the in vitro anti-fungal activity of ~i~Ldes as d~ihe~ in E;~ample 3 on strains of ~ndida c~nci~l~ed re-~i~t~nt to other anti-fungal agents: polyene-l~,s;sl~lt C. albicans (ATCC
A~c~ n No. 38247), 5-nuolu~ e ~sist~t C. albicans (ATCC No.
44373), azole-l~is~t C. albicans (ATCC No. 62342), and hotoc~ e-~ ict~nt C. albicans (ATCC No. 64124).

Example S
SERUM STABILlTY ASSAYS
This ~ add,~ses ehe serum seabi1ity of Domain I~l derived pepti~s and the effect of serum d~ AI;~ n using HPLC and S biO~dSS~dy.
For ~ese serum stability ~ , peptides were ~
by solid phase pepeide sy~esis and ~ulirled to 94% or greater pu~ity a~;
dP~;.;l~d in F~ 1. Blood wa c~llPrt~ from ....4~-dl~kanr. anP~I.Pc; .~fl rats by aortic bleed into V~ u~ ~ tubes and allowed to clot at room 0 h."rf.. ~l",~ for a~,;.. At~ly 30 ~ lec, then c~ ;Çu~d at 3000 rpm (about 1000 X g) for 10 .";..utr-s at room ~ J~ and the se~um ~ ;"-t~
In ~ 1iti~n, frozen human serum ~or~ ~ mPir~n r nln~irs~ Inc., Miamis FL, cat. no. 2140, lot no. 94115) was thawed at room 'f".~ ~ and fileered tl~u~l. a 0.45 ~m ...- -..k.~ before use.
A 1 mg/mL snl~tinn of an ~ ~~ ."pl~,~ XMP peptide to be tested was added to an equal vol~ c of either rat or human serum ~ -- ;1~ above and ...;.;..I~;nPd at 37~C. At 0, 1, 2, and 4 hours, 100 ~L were ~ lu.~c~l and ylu~l by solid phase ~ e~;nl~ for HPLC analysis as follows. Serum ~~ '~~ were ~l~ for HPLC using C-18 Se~Pak c~LLidges (1 mL
20 cartridge with 100 mg of soIbent, Waters Corp., ~lford, MA). One l~ul-dl~d L of serum sample were added to an equal volume of 1% TFA and mi~ced for 30 secon~ on a Vorte~ mi~cer. The sample was then applied to a C-18 Sep-Pak car~idge that had been ~ n~d by w~hillg with 1 mL of m-oth:~nnl followed by 1 mL Milli-Q water. Wealdy l. t~led co...l~on~ were 25 eluted by washing with 1 mL of 0.1% TFA. The bound peptide was eluted with two volumes of 250 ~L 80% ~ 0.065% TFA.
The m:-ten~l eluted from the Sep-Palc cartridge was analyzed on a Michrom Ultrafast Micl.,pr~ Analyzer equiy~ed with a 150 mm X 1 WO 97/04008 PCT~US96/03845 mm, S ~ particle, 300 A pore C-8 Zorbax cQlllmn- The column oven was set to 40~C, the flow rate was 100 ~L/min-lt~, and L,je~ Lioll volumes were typically 5-lO ~LL. ~IPLC was p r .~ d using S%: ~ h.. ;l ;lP10.1% TFA in water as mobile phase A, and 80% -~r~ ;1PIO.O65% TFA as mobile phase 5 B. The eluate was ~-~n;t-~,cd s~ l.o~u...~ lly at 214 nm. Peptide standards were dissolved in mobile phase A at 0.1 mg/mL. The g~1iPnt was 25-35% B/10 ...;...,~s followed by a 5 minute wash step of 10û% B and reeqllilihr~tion at 25% B for 10 ~ IJt..C, The pepti,~ entifiP1 and purifi~ after serum ;-~ as 10 d~- ;hCcl above were s~l,;e~l~d to N ~ 1 peptide seqllPnrinE p~r~ ed on an Applied Biosystems Model 477A/120A sc~lu~n~cr and to el~;L,u..~l~
ion~ n mass s~LIu~ (EiSI/MS) ~c.rul..-ed using a VG P;~ ~h Bio-Q
Mass S~;tlu~ . In ~ , the ~ fC i.~ and purified after serum inl"~hAI;on as ~ ;1~ above were also ~cted for ~eir anti-fungal 15 activity in a radial dirrui.;on bioas~y with ~ndida albicans SLU-1 st~ain as des~libed in F-~mrle 2.
For these L 1~ Domain III derived pepti~ XMP.97, XMP.327, XMP.332 and XMP.333 were used. The serum stability of each dirf~,cd s.~l~s~ l1y. For ~ r 1~ XMP.97 was d~P~ led 20 in serum with a half-life of 59 ~;..ul-l, under the ri~ acsay c~ ;l;m~c Two ..,~I,olites of XMP.97 were ~ d and were d~-....n~d to be cleavage products where the cl~ ge at the amino ~r~ IIC yielded peptides ~ U1~.1~l by either one or two amino acids. The ~le~ products and kin-~.ti~.c were similar for co~ ;ally vl~ined human serum or freshly 25 ~cd rat serum. Other ~~Ic~ ic products of XMP.97 were ~lQu" ably present but in c4n~ntr~tion~ below det~tinn limits.
The rhP~ 5 ob~l~d after serum ;r..;~,b~;on of a peptide were ~en~lly acco~ni~l by a loss in activity as det~.-..ined in the radial Jirfus;ol assay with Candida. For ~ '~, XMP.327 was de~.-AFd with a serum half-life of 40 .~ ~s under the ~ -il,ed HE~C as-cay ~ A;l;n~ ~e serum half-life of ~n~P.327 as A~ rA by anti-fungal a.;li~ily in ~e radial ~l;rrl-- rn assay was 43 ..~in.~t~5. Ln o~er cases, there5 may be a dirr~lce l~h~ the rate of di~es- ~~ of anti-fungal activity and the rate of peptide Ai~pp ~ ~ ..n-~, in~ sl ;n~ that cer~in ~ boLtes may have a~livi~
The el~yllles l~,~l,c;l-lr for peptide de~r.qAqtinn were not ;,~. ;r.~lly if~ ~ in these ~ -l ~;-- . nl~ However, ~l~no~p~ qcp~s 10 present in serum are capable of le.lluvi lg one or more residues from the N-f~ ~ .. ;...-c of p~ptille~s [See, e.g., Hooper, N.M., r~lop~pl;AqQps~ in ~i~ l~r~l 1~. . ;. . ~ to Protein Deli~l y, pp.23-50, eds., Audus and Raub, Plenum Press, New York, 19931. ~...;n~ ~ N (EC 3.4.11.2), for ~ Ic, has a broad s~ ~ g the N f~ ;n-1 amino acid from~5 ...~hl~r~ A peptides. Based on sites of ~nl;al hyd~ ~s, ~ $ can be ign~ to ...i..i-..i,. certain ~e~"~ n ~l~ . Serum ~e~q~1q*nn at spe~-ific amino acids within a peptide may be av. 1~ by inc~ n of D-amino acids or other atypical amino acids, and/or by ~ n to ~
~lOt~ 1...... .......~4g~.;1inn In q-l~ii*. nql st~ ips~ pçp*~lP-s were ~le-~ignPd to have i.~cl~
serum stability. For s ~ ptiAcs were i,~ h~ d using one or more D-amino acids. Also, p~*~l~s were ~nll. ~ and then their N t~ ;n~Js was a~lyla~l as ~-;1~ in F~ 1. For ~ '- XMP.333 was srth~-~i7Pd having the same amino acid se~luc"ce as XMP.327, e~cept that the amino t - ---in-l lysine residue used for s~lllll~is was a D-amino acid. When XMP.333 was tested, its serum half-life as ~cl~ ~...in~d in the radial ~lirr..~
assay was 130 ...;n.~t~s (as coll.~dlcd with 43 ",j"..t. s for XMP.327). These results inrli~ t~ that a single D-amino acid at the N t.~....;.-..c ~lc~cn~ some W O 97/04008 PCT~US96/03845 e,~ tinn and increases the half-life of the peptide.
Peptide cor ;,I. u ;~ can be ple~u~d with inclcased half-life, but may not ,..~i..f;~ the same in vitro activity. For e~cample, ~P.327 had a serum half-life of 43 ~ s and activity in radial dirrus;ol~ of 353 pmol (see 5 Table 1). Peptide XMP.331 having the same amino acid ~.,~ of XMP.327 but having an a~lylal~d ~ t ~ .~.;....e, had an illcl~d serum half-life of 280 .ni...-t e as d~t ~,ted by HPLC analysis, but a de~l~;d activity of ~3,493 pmol (see Table 1) as c~ d with the non-ac~lyl~t~d XMP.327.
However, even with dec~ in utro activity-, such a peptide may have 10 increased efficacy in viw due to its inc.~d stability.
Other peptide consL.u~;~ can be ~ d with not only ~e~ nifi~ntly increased stability but also with ",~ r~1 anti-fungal activity in the radial ~I;rr.~ o~- assay. For e~ample, XMP.332 was ~"II,P- ,~ using all D-amino acids and is the inverse s~u~nce of XMP.327. Such a "retro-D"
15 peptide should be ~ I to serum ~y~-cs that l-.C4~ P and hydrolyze the peptide bond ~jd~..cen L-amino acids. In fact, XMP.332 did not show any decl~ in activity or d~;lG~e in peptide C4~ n over a 6 hour period of serum in- ub~l;on. Such a peptide co~sL-u~l, which can ,,,-~ the in utro equivalent molar activity to its L-amino acid peptide ~ul,lc.~ul and 20 shows in~;l~d serum half-life, may have h~ ~d efficacy in vivo. The half-life of the activity in serum as ~ ~l by radial dirruia;on assays and the half-life of peptide in serum as d~ by HPLC analysis are shown in Table 11 for 1G~ I ;VG peptides.

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This; I l- addresses the design and aSS_y of anti-fungal pepti~ies for SLIu~luldl motif and .. ;.~;.. fimAti~m_l sequence analysis.
As shown in F ~ 2, 3, and 4 abave, XMP.97 was A.~..n~A to have ~ignifiA_nt in vitro activity against G albicans and ~ig;AifiA_nt in vivo aclivily in a mouse systemic rA~ AQi~ model. The sf~ was derived from XMP. 13 with a lysine s~ for glycine at .~;I;nn 152 in the BPI s4u~.~ce. As shown in FYAmplA 5, S~.lLiâl N-~f-...;n~l amino acid removal was obs~ when the pe~i~lçs~ in~ ing ~P.97, were in~-ul~l~ with serum. The 13 amino a~id peptide XMP.284 (SKVKWLlQLFHKK-amide; SEQ. ID. NO:117) was s~ d, pllrifiPd (97%) and tested for anti-fungal a~tivity. The in vitro activity WaS
surl~n~in~ly not ~lc7 iably ~l; ~..;..;~hod (see Table 1). A ~IP-lPtinn series of 35 pep~des was ~e~ A from this star~ng s~u_.~ce. All possible N- and C-~ lPtinn 12-mers lluuu,~h ~mers (XMP.285-XMP.319) were srthP~i7l~A as shown in Table 12 below.
Crude peptides were as~d for an initial purity as dec~
in P ;....l~lr 1 and for in vitro activity with the radial ~;rr,.~;O~. filngi~ l assay as ~IP~--- ;1~d in P~, '- 2. The nmol value shown in Table 12 l~ Gse~ a 20 c~lc~ tP~ value (log l;l.,.l;n~ curve) for the number of n allo ~ l~Uil~d to achieve a net 30 mm2 zone in the assay. In ~uliîyill~, XMP.97 and XMP.284, a ~ignifir~nt change was obsel~vd in the pmol value upon pnrifi-~ti~n The m~gnitude of change was larger than ol~s~ d with other crude peptides and was likely due to removal of inactive peptide i~pulilies. Thus, final 25 c4---1~-;~n~ were made using pepti~les purified as d~P~r~ in F~mpl- 1, and pl~ldbly asssdyed on the same day.
The most active crude pepti~i~p~s were purified by HPLC and re-WO 97/04008 PCT~US96/03845 assayed. The results ar~ shown in T, ble 12. From this analysis, as ~ by Table 12, Xl~.293 was ~e smq~ t peptide with an i~lC ~se in molar activity ~cla~i~e to peptide XMP.97. XMP.297 was also equivalent to XMP.284 in activity. Inh.c~L~.gly, XMP.298 was within two-5 fold of XMP.297. Activity was A~mon~trable even with 6 amino acid I;AP5~ such as XMP.315, ho~ r, this level of activity was decl~sed by about 3 orders of m~ Ae col~-paLed with the activity of the star~ng ~~u~.~oe.
These data 7A~ ...t~ that one group of Domain m derived 10 peptides of the invention are desclibed and defined by a structural motif con~icting of a core of 4 to 6, ~l~rc~ably 5 to 6, amino acids where the core co~,l,.in.~ one neutral hydlu~hilic residue in the middle of hyd~ù~hobic an ino acids, and where the core is bounA~A. or flanl~ed at the N- and/or C~ v~
by c~ti~ nic amino acids. ~f~,cd core S~u.,.lCCS inr~lnA~ LlQL, IQLF, 15 WLIQF, LIQLF and WLIQLF. ~rt;ll~d c~tioni~ amino acids in~l..Ae: K
(most ~ ~d), R, H, ~,,.;lh.l.f (ORN) and di~minobutyric acid (DAB).
Peptides with such a motif possess optimal activity. Activity was ol)s~ d, but was s~lllc;~llal Aimini~hl?A when the peptide cc,..l;~;l-rd aU of the c~tionic residues on the C ~....;....c (e.g., XMP.298) or on the N-l~-l..;n.~c (e.g., XMP.300) of the core. P~lides XMP.320 - XMP.368 were Ac~;pi-~A and plc;~vd conci~t~nt with this motif, and provide ~ 1 support for the structuIalmotifand ~ ru.~ lch~"t.;,~ n sequenceofanti-fungal p~ptiAes accol.ling to the invention.

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~ .0 0 WO 97/04008 PCTAUS96/03~45 ~, Example 7 L:PS NEUTRAIIZATION ACIIVITY OF ANTI-FUNGAL ~lll~ES
This ~Y~mpl- addresses ~e in vitro and in vivo LPS n~lltr.q1i7ing a.;livil~ of Domain m derived peE~tides.
S An in vitro LPS n~utr~q-li7-q-tinn SC~l~lg assay for eV~ly-q-tior of Domain m derived ~ s was d~ ,lo~d (as flPd-~ ~ ;kd in c~owned andl co~ g U.S. Patent Ap~ q-tinn Serial No. 08/306,473) which p~ovides both a ~ of efficacy of each peptide (EC~jo) and of the to~icity/grow~
of each p~ptide (IC5~). This s~ ilive ass y for i~ iliul~ of cellular ~lol;r~., l;on in mouse cells treated with LPS can also be ut~ for nl;~ n of LPS levels in human plasma upon de~lop",~ l of a st~u,d~d curve.
In this assay, mouse RAW 264.7 cells (ATCC ~rr~C_ .~n No.
TlB71), ...A;f.~ rA in RPMI 1640 ...~J;I-... (GIBCO), su~ mpntpA with 10 mM H~;.l'~S buffer (pH 7.4), 2 mM L-gl-ll;.. n;i-r, pPnirillin (100 U/mL), SL~ y. lll (100 ~g/mL), 0.075% sodium bic~l~lla~, 0.15M 2-~tl-Anol and 109~ fetal bovine serum (Hyclone, Inc., Logan, IrI~, were first ;~--h~f~A by in. ~ .- in the presence of 50 U/mL ~ ant mouse ~-in~r~.,l, (C~lle, r~ , MA) for 24h prior to assay.
20 ~n-lue~PA cells were then ~e~h~ni~Ally cQll~cted and c~ ;ru,~1 at 500 ~c g at4 C and then ~ ~n~ in 50 mL RPMI 1640 1,-~l;ll-l. (without su~ n~nt~), re~lL,iru~ed and again l~ J~n~led in RPMl 1640 111~
(without suppl~m~ont~). The cells were cc,ul~d and their cQn~-ll-~ n adjusted to 2 ~c 105 cells/mL and 100 ~LL aliquots were added to each well of 25 a 96-well microtitre plate. The cells were then inr-u~t~ for about 15 hours with E. coli 0113 LPS (Control S~d~hd, Assoc. of Cape Cod, Woods Hole, MA), which was added in 100 ~LL/well aliquots at a conl PntT~tion of 1 ng/mL
in serum-free RPMI 1640 mP~ lm (this conr~ntr~tirn being the result of I;l.,.~;m~ e~PrimPnt~ in which LPS con~pntr~tion was varied bel~,.~.l 50 30 pg/mL and 100 ng/mL). This in~.uh~tion was ~lrull,led in the ~h~Pn~ or -~ cn~e of peptides in varying ~n~ t.~linn~ ~t~ 25 ng/mL and 50 ~Lg/mL. Re~...hii-Ant human rBPI21 also de-sign~t~ rBPI21~cys, which is rBPI 1-193, with alanine ~ul.,,t;Lul~d at position 132 for ~ e [see co-owned U.S. Patent No. 5,420,019] was used as a pCi!;iLivG control at a c4n~ l;nn S of 1 ~g/mL. Cell ~ ;r. .~ was .~ .d by the s~ n of 1 ~LCi/well [3E~ y~ e S hours after the time of ;..;l;~l;. n of the assay.
After the 15-hour in~ ;o~ beled cells were }~t~d onto glass fiber filters with a cell ~t~l (Tnot~h Bio~i,h,..ls, INB 384, Sample P~
and Filter Counling System, T ~n~inE~, MI.).
The LPS-.. ~l;~l~ inhihitinn of RAW 264.7 cell prQtifpr~tis n is ~ ul~nl on the ~ Ic~ of LBP, as added to the ~~1ion ~ ul~ either as a c4...~ nl of serum or as .c~o...l.;..-~nl LBP (at a co~ nl~ n of 1 ~g/mL). DiLL~GIl~ of peptide b~havior are ol)s~vGd in the assay.
The Domain m derived anti-fungal pepti~lPs wi~ LPS-nPllt~ali7ins~ a~;livil~
accol~li,lg to the present ill~tion gPnP~lly did not e~chibit an ICso at ~e l;nn~ tested, unlike other XMP pP~ptiflps in~ in~ LPS-nPytr lli7in~
pepti~1Ps that are not anti-fungal, as d~-- ;hed in co-o~-vned and CO-~.ldillg U.S. applic~tinn~ Serial Nos. 08/209,762 and 08/306,473. For e~mple, XMP.5 displayed an ECSo (i.e., the peptide con~ t. ,l;~ n at which the growth inhihitory effect of LPS was l~ ~d by 50%) of 5.3 + 0.6 ~Lg/mL; hu~
an ICSo (i.e., the peptide c~ f~ n at which RAW cell growth was inhibited by 50% f~om the value Wi~ UI added LPS or pPptide) was not obsGl ~ o~ at the con~pntr~tiom tested. The results of a l~ tivG assay of e-~-"~ "~ Domain m derived anti-fungal peptides are shown in Figure 8.
The LPS-n~-utr~li7ing a~livilies of the l,u,irled anti-fungal peptides XMP.327 (open squares), XMP.332 (closed squares), XMP.333 (open tri~lP-s) and XMP.337 (closed tri~nglPs) are shown in Figure 8. Also shown as a po~ e control is the activity of rBPI21. Results from leyl~ ll~live peytides tested wvi~ ~is assay are shown in Table 13.

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CA 02227292 l998-Ol-l9 WO 97/04008 PCTrUS96/03845 Domain m derived peptitlçs are also tested for I~S n.outr,.li7ing efficacy in an in vivo mouse ~ nt_l enllo~ f...;_ model. Groups of 15 mice were _~minict~r~ an illLIdvc~ us iniectinn of enrl~A,tc~in (E. coli Olll:B4, Sigma ~h.omiA-_l Co., St. Louis, MO) at a LDgo dosage of 20 mg/kg. This was followed S by a second illLld~,.wuS injection of the peptide to be tested. Tnjectinnc of saline were used in ne~ VC control mice. The AnimAl~ were obs~lved for 7 days and mortality l~ld~d. The efficacy of ~e peptides was .I.e~~ d by a de~;l~ in ~n-lo~ ~l mortality in peptide-inject~l mice as colll~cd with control mice. X MP.284 iS a rcpfr~nlA~;ve peptide active in this murine model. As 10 shown in Figure 7, ~i~nifiA, nt protection was obs~lved with a 0.5 mg/kg dose of XM P 284, while at a 1 mg/kg dose, 14 of 15 ~nim~lc were ~ ~l, and a 3 mg/kg dose was cL~;livc to protect all treated ~nim_l~ (100% sulvival). No _nim_1~ Vi~d in the saline ciontrol group.

E~ample 8 ~lll~E FORMULATIONS
This eY-mplA addresses peptide formlllAtinnc A l~ ;ve Domain m derived peptide XMP.284 was evaluated for stability in liquid forrnlll-tiOn~ C~ urr~,~d saline srl-.l;. n.c and to ~ At, breakdown mf~r.h~ni~m~, if any, that might be Co.. - n to SUCh p~ptirlP5 The ly~hili7~ peptide was dis~olv~d to a conr~-.l.~l;nl- of 1 mg/mL
in three dirr~ buffers. The three formlll~tion buffers used were (a) 10 mM
sollltinn ~retAfe~ 150 mM sodium rhlnri~lP pH 4, (b) 10 mM sodium _retst~ 150 mM sodium rhlnri-l~ pH S and (c) 10 mM sodium acetate, 150 mM sodium ehlnri~l~ pH 6. The form~ ted peptide ~mpl~- were inr,nhAt~l at 4~C and 37~C.
At eaAch time point, ~ , 'ea were withdrawn from ea~h vial and assayed by C18 reverse phase HPLC, abs~ ce at 280 nm, and SDS-PAGE. The study was con~ ct~ for 50 days.
A 0.46 x 25 cm Vydac C18 column (cat no. 218TP54) was used on a Shim~ l HPLC system. The column was run in binary gr. ~ nt mobile phases:

A = Water + 0.05% TFA, Bi = ~ .;le + ~.05% TFA. Chlu.~ og-~ ic c nrliti~nA~ were as follows: wavelength = 229 nm; flowrate = 1 mL~min;
injection volume = 50 ,~L; run time = 37 Ill;lll~t~ 5; gta~ ont = 20% B to 409~ B
in 20 ",;..~ c; AUFS = 0.1 for XMP.284; c~n~Pn~ti~ n of sample = 3.5 ~g per 5 50 ~L iniectis~n volume. In ~ n for the C18 assay, the ~ wilLLa~lvll from the vials were diluted l~fold with 0.05X TFA in water. All samples were filtered through Acrodisc 4 prior to analysis.
Sa~ l 1 were analyzed by SDS polyacrylamide gel de~LIophol_5ls~
run on Novex 10-20% tricine precast gels (Nove~, La Jolla, CA, EC6625).
S~mpl~A were mi~ced with non-re lu~ ing sample loading buffer (Novex LC1676, 2 c) and heated at 95~C for two ...in.~l~s After cooling, samples were run on the geland the gels were stained with Con...-~- D Blue. In ~ 1diti-~n, ~A~mr'-- we~e analyzed ~ ,p~ lly. For this, samples withdrawn at each time point were diluted 6-fold with Millipore water and abs~ll,ance was ~ d at 280 nm and sc~ inP from 210 nm to 340 nm using a ~him~ W 160 spectrophc"~ . All ~mrl~A~ were filtered prior to absc,ll,ance Ill~ul~lllelll(s).
XMP.284 was soluble in water and unburLl~ saline. XMP.284 was also soluble in 10 mM sodium ~.h~ .h~l~, 150 mM sodium rhlnntle pH 7.
The peptide . ~ i n~ soluble in the ~.h~ buffer at 40~C for 1 hour and then 20 55~C for 1 hour. There was very little pl~lu~il loss, as l-le~ul~d by abs~JllJdncL
at 280 nm, in 0.15 M saline burrt;lLd with 10 mM acetate at pH 4, 5 or 6. The real time stability study at 4~C showed that product cnnr~ntr~ti~ n was unrh~n~
Even the acccl~_ldled stability study at 37~C showed that greater than 95% of product co.-~-n~ ic)n was ~ i--l; in~ and that only low levels (less than 0.5% at 25 50 days) of new HPLC peaks ~rCum~ t~d with time at 37~C in the acetate burr~lt;d saline fnnnnl~tirJn~. Given the s--b~ l stability e~i~d by the Domain m derived peptide dS tested, ~ litinn~l rsriri~ont~ may not be n~S~ry but may be desired to further ~nh~nr~ long-term stability and/or activity. I~ lly pl~r~ d is a formlll~tinn that inrl~l~les lO mM sodium acetate, 150 mM sodium 30 çhlori-lr, pH 5.

CA 02227292 l998-Ol-l9 WO 97/04008 PCT~US96/03845 Nul~lcl~us mnr!ifir~tions and v~ri~tinn~ in the pr~~tir~ of the invcl.lioll are ~ l~ to occur to those slcilled in the art upon con~ o~tinn of the f<Jl~--lg des.,lil~tion on ~e yl~lllly pl~ft;ll~d embo~ thereof. .
Co~ u~nlly the only limit~tinn~ which should be placed upon ~e scope of the S present invention are those that appear in the appended claims.

W O 97/04008 PCTAUS96/03~45 SEQVEN OE LISTING
( 1 ) ~N~T- l~r u_l~ATION:
(i) APPLICANT: Little II, Roger G.
Lim, Edward Fadem, Mitchell B.

(Li) TITLE OF l~v~n~lON: Anti-Fungal Peptides (Lii) NVMBER OF SEQVENCES: 206 (iV) C~'K~-~ WDEN OE AnD~.cS
(Al ~nn~Cc~T Marshall, O'Toole, Ger~tein, ~urray & Borun B, STREET: 6300 Sear~ Tower, 233 South Wacker Drive ~CI CITY: Chi ~-~o (Dl STATE: IllinoLs ,EI ~uun~r: UnLted States of AmerLca ~P~ ZIP: 60606-6402 (V) CCMrU~K ~F~n1~RT-T' FORM:
IAI MEDIVM TYPE: Floppy dL~k B COMPUTER: IBM PC ~ _- ;hle Cl OPERATING SYSTEM: PC-DOS/MS-DOS
,D~ 50.~ : P~t~n~Tn ~le--e ~1.0, Version ~1.25 (vi) ~unK~n~ APPLICATION DATA:
(A) APPLICATION NVMBER:
(B) FILING DATE:
(vii) PRIOR APPLICATION DATA:
(A) APPLICATION NUMBER: 08/372,105 (B) FILING DATE: 13-JAN-95 (vii) PRIOR APPLICATION DATA:
(A) APPLICATION NUMBER: 08/306,473 (B) FILING D~TE: 15-SEP-94 (vii) PRIOR APPLICATION DATA:
(A) APPLICATION NVMBER: 08/273,540 (B) FILING DATE: ll-JVL-94 (vii) PRIOR APPLICATION DATA:
(A) APPLICATION NUMBER: 08/209,762 (B) FILING DATE: ll-MAR-94 (vii) PRIOR APPLICATION DATA:
(A) APPLICATION NUMBER: 08/183,222 (B) FILING DATE: 14-JAN-94 (vii) PRIOR APPLICATION DATA:
(A) APPLICATION NVMBER: 08/093,202 (B) FILING DATE: 15-JVL-93 (viL) PRIOR APPLI QTION DATA:
(A) APPLICATION NUMBER: 08/030,644 (B) FILING DATE: 12-MAR-93 (viii) A~u~n~/AGENT lh~u~ATION:
(A) NAME: Borun, Ml~h~l F.
(B) REGISTRATION NUMBER: 25,447 ( C ) h~r~K~N~ /DOCKET NUMBER: 27129/10040 W O 97/04008 PCT~US96/03845 (ix) T~T~ ~ICATION INFORMATION:
(A) TELEPHONE: 312/474-6300 (B) TELEFAX: 312/474-0448 (C) TELEX: 25-3856 (2) ~ ATION FOR SEQ ID NO:1:
(i) S~yl '~~ CHARACTERISTICS:
(A) T. _~r~: 22 amino acidR
(B) TYPE: amino acid (D) TOPOLOGY: linear (ii) I T~CUT~ TYPE: peptide (ix) FEATURE:
(A) NANE/KEY: mi~c feature (D) OTHER lh~u.~ATION: "XMP.5 (ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: C ~' in.l~
(D) OTHER lN~Oh~ATION: /label- Amidation /note= "The C ~ inun i~ Amidated"
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:
Val Hi~ Val His Ile Ser Lyn Ser Ly~ Val Gly Trp Leu Ile Gln Leu Phe Hi~ Lyu Ly~ Ile Glu (2) lN~uR~ATION FOR SEQ ID NO:2:
(i) SEQUENCE ~UAR~T~RTSTICS:
(A) T- _lr~ 13 nmino ~cid~
(B) TYPE: amino acid (D) TOPOLOGY: lin~ar (ii) ~nT~CuT~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: mi~c feature (D) OTHER lNruF~.TION: ~XMP.11"
(ix) FEATURE:
(A) ~A~E/~EY: Modified-site (B) LOCATION: C i- in--~
(D) OTHER lN~khA~ION: /label= Amidation /note= "The C 1, in-lR i~ Amidated"
(xi) ~yuh~_~ DESCRIPTION: SEQ ID NO:2:
Ly~ Ser Ly~ Val Trp Leu Ile Gln Leu Phe Hia Ly~ Ly~

(2) INFOR~ATION FOR SEQ ID NO:3:
(i) S~yu~._~ CUAR~rTFRT9TICS:
(A) LENGTH: 29 amino acid~
(B) TYPE: ~mino acid (D) TOPOLOGY: linear W O 97/04008 PCTrUS96/03845 125 ' (ii) ~nT-~C~T-~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: mi~c_feature (D) OTHER lN~O__IATION: "XMP.12"
(ix) FEATURF:
(A) NAME/REY: Modified-~ite (B) LOCATION: C ~. inl~
(D) OTHER lN~IATION: /label= Am$dation /note= "The C i. ; n~ t~
~xi) SEQUEN OE D~eCRTPTION: SEQ ID NO:3:
Ser Val Hi~ Val Hi~ Ile Ser Ly~ Ser Ly~ Val Gly Trp Leu Ile Gln Leu Phe Hi~ Ly~ Ly~ Ile Glu Ser Ala Leu Arg A~n Ly~

(2) lN~o~JlATIoN FOR SEQ ID NO:4:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14 amino acidc (8) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MnT-~cilT-~ TYPE: peptide (ix) FEATURE:
(A) NAME/~EY: miuc feature (D) Ol~R INFORMATION: ~XMP.13"
(ix) FEATURE:
(A) NAME/ ~ Y: Modified-nite (B) LOCATION: C-~.- in~
(D) OTHER lN~Ok~ATION: /label= Amidation /notee "The C ,l in~ Amidated"
(xi) SEQUENCE DEqr~TPTIoN: SEQ ID NO:4:
Ly~ Ser Ly~ Val Gly Trp Leu Ile Gln Leu Phe Hi~ Ly~ Ly~
1 5 lO
(2) lNru_~ATION FOR SEQ ID NO:5:
(i) .~u~ CHARACTERISTICS:
(A) LENGTH: 28 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(A) NA~E/~ Y: mi~c feature (D) OTHER INFORMATION: "XMP.29"

(ix) FEATURE:
: (A) NAME/KEY: Modified-~ite (B) LOCATION: C-~. inu~
(D) OTHER lNrOK~ATION: /label= Amidation /note= "The C ~. inlln i~ Amidated"

W O 97/04008 PCT~US96/03845 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:
Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Phe His Lys Lys Lys Ser Ly~ Val Gly Trp LQU Ile Gln Leu Phe His Lys Lys (2) l~r~r~TION FOR SEQ ID NO:6:
(i) ~Qu_._~ CHARACTERISTICS:
(A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) M~T.F~T.T~ TYPE: peptide (ix) FEATURE:
(A) NAME/~ Y: misc_feature (D) OTHER INFORMATION: "XMP.31"
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: C I~ i n--~
(D) OTHER l~r~.~lATION: /l~belz ~ tion /note= "The C i. ~ n--n iS Amidated"
(xi) ~yuL._r; D~S~TPTION: SEQ ID NO:6:
Ala Ser Lys Val Gly Trp Leu Ile Gln LRU Phe His Lys Lys 1 5 lO
(2) lN~or~ATIoN FOR SEQ ID NO:7:
(i) ~yu~r; CHARACTERISTICS:
(A) T _~: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( 1i ) ~T~T!CT~-T~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: misc_feature (D) OTHER l~ru~ATION: ~XMP.32"
(ix) FEATURE:
(A) NAME/KEY: Modified-site (B) LOCATION: C ~. ; n-l~
(D) OTHER l~OR~ATION: /l~bel~ P i~n~l~n /note= "The C ~. inlln is Amidated"
(xi) SEQUEN OE D~-~TPTION: SEQ ID NO:7:
Lys Ala Lys Val Gly Trp Leu Ile Gln Leu Phe His Lys Lys (2) lNrORMATION FOR SEQ ID NO:8:
(i) ~yu ._~ CHARACTERISTICS:
(A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear CA 02227292 l998-0l-l9 ( ii ) ~nT~CuT~ TYPE: pept$de (ix) FEATURE:
(A) NAME/REY: mi~c-fQature (D) OTHER INFORMATION: ~XMP.33"
(ix) FEATURE:
(A) NAME/~EY: ~odified-~ite ~B) LOCATION: C ~, in--~
(D) OTHER lN~ORMATION: /l~bel= Amidation /note= ~The C l~- ;n~r is Amidated~
(xi) SEQUEN OE D~SC~TPTION: SEQ ID NO:8:
Ly~ Ser Ala Val Gly Trp Leu Ile Gln Leu Phe Hi~ Ly~ Lyn (2) l~O~_~TION FOR SEQ ID NO:9:
(i) SEQUEN OE CHARACTERISTICS:
(A) LENGTH: 14 ~mino acids (B) TYPB: amino acid (D) TOPOLOGY: linear ( ii ) ~nT~C~TT-~ TYPE: peptide (ix) FEATURE:
(A) NA~E/XEY: mi~c_foature (D) OTHER l~n~ATION: "XMP.34 (ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: C ~, i n--n (D) OTHER l~r~.TION: /label= Amidation /note= ~The C . i n--n i~ Amidated~
(xi) SEQUEN OE n~-C~RTPTION: SEQ ID NO:9:
Lys Ser Ly~ Ala Gly Trp Leu Ile Gln Leu Phe Hi~ Ly~ Lys (2) l~k~ATION FOR SEQ ID NO:10:
(i) SEQUEN OE ~APA~T~RTSTICS:
(A) LENGTH: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~n~CcT-~ TYPE: peptide (ix) FEATURE:
(A) NA~E/~EY: mi~c_feature (D) OTHER INFORMATION: ~XMP.35 (ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: C i. inl~
(D) OTHER l~vk~ATION: /label= Amidation /note= ~The C I. i n--~ i~ Amidated~
(xi) SEQUEN OE D~SCRTPTION: SEQ ID NO:10:
Ly~ Ser Ly~ Val Ala Trp Leu Ile Gln Leu Phe ~i~ Ly~ Ly~

W O 97/04008 PCT~US96/03845 (2) lNrOhM~.TION FOR SEQ ID NO:ll:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: lin~ar ( ii ) ~nT-~cuT~F TYPE: p~pt;~
(ix) F~ATURE:
(A) NAME/XEY: mi~c feature (D) OTHER lNrOI~IATION: ~XMP.36 (ix) FEATURE:
(A) NAME/~EY: Hodified-~ite (8) LOCATION: C ~, ;n~lq (D) OTHER lhrOh~ATION: /label= Amidation /note= ~The C ~. inlln iq Amidated~
(xi) SEQUEN OE DFR~RTPTION SEQ ID NO:ll:
Ly~ Ser Ly~ Val Gly Ala Leu Ile Gln L u Phe Hi~ LYB Ly~

(2) l~r~ ~U.TION FOR SEQ ID NO:12:
(i) ~yu_.~~ CHARACTERISTICS:
(A) T- _ ~ ~: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linQar ( ii ) - ~~JT-~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: mi~c_feature (D) OTHER lhr OI~.TION: ~XMP.37 (ix) FEATURE:
(A) NAME/KEY: Hodified-site (B) LOCATION: C i. ;n--~
(D) OTHER lh~OIIIATION: /label- Amidation /note= ~The C i, inl-n is Amidated~
(xi) ~r;yu~._r; DESCRIPTION: SEQ ID NO:12:
Lys Ser LYB Val Gly Trp Ala I1Q Gln Leu Phe Hi~ Ly~ LYB

(2) lNrO~ATION FOR SEQ ID NO:13:
(i) ~yu~-..~E CHARACTERISTICS:
(A) LENGTH: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT~CuT-~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: misc_feature (D) OTHER lNr-OR~ATION: "XMP.38"

CA 02227292 l998-0l-l9 Wo 97/04008 PCTAUS96/03845 (ix) FEATURE:
- (A) NAME/KEY: Modified-site (B) LOCATION: C-Te inll8 ~D) OTHER lN~O~ATION: /label= Amidation /notez ~The C .,- inl~ is AmidatQd~
(Xi) ~ _ ~ D~Sr~TPTION: SEQ ID NO:13:
Lys Ser Lys Val Gly Trp Leu Ala Gln Leu Phe Hiq Lys Lys (2) lN~U ~L!TION FOR SEQ ID NO:14:
(i) 5~ ~ CHARACTERISTICS:
(A) T- _ A 14 amino ~cid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT-~CuT-T~ TYPE: peptide (ix) FEATURE:
(A) NAME/~EY: misc feature (D) OTHER 1~ ~TION: "xMP.39"
(ix) FEATURE:
(A) NAMF/~EY: NodLfied-site (B) LOCATION: C . i nl~ ~
(D) O~ALR lh~u~ TIoN: /label= ~ ;~ati~n /note= "The C ., inlln is ~ te~"
(xi) ~1 n~.c~TPTIoN: SEQ ID NO:14:
Lys Ser Lys Val Gly Trp Leu Ile Ala Leu Phe His LYB Lys (2) lN~RMATION FOR SEQ ID NO:15:
(i) SEQUEN OE CHARACTERISTICS:
(A) LENGTH: 14 amino acids (B) TYPE: ~mino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "XMP.40"
(ix) FEATURE:
(A) NAME/~EY: ModL$ied-sLte (B) LOCATION: C ~- i nll B
(D) OTHER INFORMATION: /labQl= ~ id~ti~n /note= ~The C-T~ ;nll~ Ls Amidated"
(xi) ~L~U~-.. ~ DFSr~TPTION: SEQ ID NO:15:

Lys Ser Lys Val Gly Trp Leu Ile Gln A a Phe Hin Lys Lys (2) l~rukMATION FOR SEQ ID NO:16:
( i ) ~UL.. _~ CHARACTERISTICS:
(A) T- _.A: 14 amino acLds CA 02227292 l998-0l-l9 (B) TYPE: amino as:id (D) TOPOLOGY: linear nr-~C~Tr-F TYPE: peptide (ix) FEATURE:
(A) NAME/~CEY: mi~c_feature (D) OTHER lN~ v~ATION: "XI~P.41"
(ix) FEATURE:
(A) NA21E/KEY: Modified-~ite (B) LOCATION: C i n~
(D) OTHER lN~ vAl F.TION: /label~ Amidation /note= "The C ~, tnlln iEI Amidated"
(x$) ~c.~B~ ~ m~S~TPTION: SEQ ID NO:16:
Ly~ Ser Ly~ Val Gly Trp Leu Ile Gln Leu Ala Hi~ LyE~ Ly0 (2) lN~vF~ATION FOR SEQ ID NO:17:
(i) SEQVENCE CHARACTERISTICS:
(A) LENGTH: 14 amino acid~
(B) TYPE: amino acLd (D) TOPOLOGY: linear (L$) ~nT-T~ l l -~ TYPE: pept$de (ix) FEATURE:
(A) NAME/KEY: mi~c_feature (D) OTHER lN~v_~5ATION: "XI~P.42"
(ix) FEATURE:
(A) NAME/~EY: Modified--~ite (B) LOCATION: C i, ; n--n (D) OTHER lr~O~l~.TION: /labnl~ ~ tion /note-- "The C ~ inll~ i~ r i~lAted"
(Xi) ~h~UI~ nFq~TPTION: SEQ ID NO:17:
Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Phe Ala Lys Ly~

(2) lN~F~ATION FOR SEQ ID NO:18:
( i ) ~QUL ._~ CHARACTERISTICS:
(A) LENGTH: 14 amino acidn (B) TYPE: amino acid (D) TOPOLOGY: linaar (ii) ~ ~~cYr~F. TYPE: peptide (ix) FEATURE:
(A) NAME/XEY: miElc feature (D) OTHER lNrvR~ATION: ~XHP.43"

(ix) PE ATURE:
(A) NAME/REY: Modified--nite (B) LOCATION: C i. inll~
(D) OTHER lN~v~5ATION: /label= Amidation /note= ~The C i. inlln i~ Amidated"

CA 02227292 l998-0l-l9 WO 97/04008 PCT~US96/03845 (xi) SBQUEN OE D~-C~RTPTION SEQ ID NO:18:
Lys Ser Lyn Val Gly Trp Leu Ile Gln Leu Phe Hin Ala Ly~

(2) lNr~MATION FOR SEQ ID NO:19:
(i) SEQUENCE CHARACT~RISTICS:
(A) T- _ ~ A 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MOT~FC ~ ~ ~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: misc_feature (D) OTHER lNr~-laATIoN: ~XMP.44 (ix) FBATURE:
(A) NA~ /REY: Modified-~ite (B) LOCATION: C 1~ in-~
(D) OTHER lNrO~nATION: /label= Amidation /noto= "The C l. ; n--n i~ ~ t~
(xi) ~L~U__. ~ D~-C~RTPTION: SEQ ID NO:l9:
Ly~ Ser Ly~ Val Gly Trp Leu Ile Gln Leu Phe Hi~ Ly~ Ala (2) INFORMATION FOR SEQ ID NO:20:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) M~T~cuT~ TYPE: peptide (ix) FEATUE~E:
(A) NAME/KEY: mi~c_feature (D) OTHER lN ~P~TION: ~XMP.55 (ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: C - Te ; n-- ~
(D) OTHER lNr~E~5ATION: /label= Amidation /note= ~The C-T~ i n--n iS Amidated~
(xi) sr;yuL. ~ D~S~RTPTION: SEQ ID NO:20:
Gly Trp Leu Ile Gln Leu Phe His Ly~ Lyn Ile Glu Ser Ala Leu Arg A~n Ly~ Met Ann Ser (2) INFORMATION FOR SEQ ID NO:21:
: ( i ) S~UL_. - r; CHARACTERISTICS:
(A) LENGTH: 14 amino acidn (B) TYPE: amino acid (D) TOPOLOGY: linear CA 02227292 l998-0l-l9 (i$) ~ P!cv~ ~ TYPE: peptide (ix) FEATURE:
(A) NAME/XEY: misc_feature (D) OTHER INFOR~SATION: "XMP.82"
(ix) F15ATURE:
(A) NAME/~tEY: Modified--~ite (B) LOCATION: C i. inlln (D) OTHER lNru.~ATION: /label= Amidation /note= "The C ;~.- inll~ Amidated"
(Xi) :ik.~l F ~.C~'DTPTION: SEQ ID NO:21:
Ly~ Ser Lys Val Gly Trp Leu Ile Gln Leu Trp Hi~ Ly~ Lys (2) lN~OR~ATION FOR SEQ ID NO:22:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MnT-T!~ T-F~ TYPE: peptLde (Lx) FE ATURE:
(A) NAME/~Y: mi~c_feature (D) OTHER lN~5ATION: "X~5P.83"
(ix) FEATURE:
(A) NAME/XEY: Modified--Elite (B) LOGATION: 10..12 (D) OTHER lNru.~ATION: /labelz Substituted--Ala /note= "Position 6 is beta-l-naphthyl-Elub~tituted"
(Lx) FEATURE:
(A) NAME/XEY: ModifLed--~ite (B) LOCATION: C i. i n~l ~
(D) OTHER lNruE~SATION: /label= Amidation /note= "The C ~. inll~ i~ Amidated"
(xi) S~syuk~~ DF~-CC~TPTION: SEQ ID NO:22:
Ly~ Ser Lyff Val Gly Ala Leu Ile Gln Leu Phe His Ly~ Lyn (2) lN~R~5ATION FOR SEQ ID NO:23:
(i) SEQUEN~ CHARACTERISTICS:
(A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT.P!~T.F TYPE peptide (ix) FlSAT~JRE:
(A) NAME/REY: mi~c_feature (D) OTHER INFORMATION: "XMP.85"
(Lx) FEATURE:
(A) NAME/REY: Modified--~ite (B) LOCATION: C 1,- inllQ

-(D) OTHER INFORMATlON: /label= Amidation - /note= ~The C~ nl-~ in Amidated"
~xi) ~ul ._r. DT~S~RTPTION: SEQ ID NO:23:
Lys Ser Ly~ Val Leu Trp Leu Ile Gln Leu Phe His Ly~ Ly~

(2) lNru.~TION FOR SEQ ID NO:24:
(i) SFQUEN OE r~ARAcT~RTsTIcs (A) LENGTH: 14 amino acid~
(B) TYPE: amino acid (D) TopoLoGr: linear ( ii ) ~nT-~C~T-T~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: misc feature (D) OTHER l~r~_J~ATION: ~XHP.86 (ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: C .. i n--~
(D) OTHER lNr~kdATION: /label= P ;~~t;~n /notQ= ~The C ~_ ;nl~n i~ ~ t~
(xi) SEQUEN OE nT~Cr~TPTION: SEQ ID NO:24:
Ly~ Ser Ly~ Val Gly Trp Leu Ile Leu Leu Phe Hi~ Lys Ly~

(2) l~ ~TION FOR SEQ ID NO:25:
(i) sr;yu~ rUARArT~RT.CTICS
(A) LENGTH: 14 amino ncid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT-T'!CuT~T~ TYPE: peptide (ix) FEATURE:
(A) NAHE/REY: mi~c ~eature (D) OTHER lNr ~fic~.TION: ~XMP.87 (ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: C ,. i n--~
(D) OTHER INFORMATION: /label= Amidation /note= "The C ~. inl~ is r i~At (xi) SEQUENCE D~CCRTPTION: SEQ ID NO:25:

Ly~ Ser Ly~ Val Gly Trp Leu Ile Gln Leu Phe Leu Ly~ Ly~

(2) lN~ORMATION FOR SEQ ID NO:26:
(i) SEQUEN OE CHARACTERISTICS:
(A) T- _~: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) T.TCC~T.TC TYPE: pepti.de (ix) FEATURE:
(A) NA~L/REY: miElc_feature (D) OTHER lNl~l~IATION: "XISP.91"
(ix) FLATURE:
(A) NAME/XEY: Modified--E~ite (B) LOCATION: C i. in~l~
(D) OTHER lNr~a~SATION: /label= Amidation /note= "The C 1. inlln iu Amidated"
(xi) ~ y~ DT~-C~-PTPTION: SEQ ID NO:26:
Lyl~ Ser Ly~ Val Gly Trp LQU Ile Phe Leu Phe HiE~ Ly~ Ly~

(2) lN~J_~ATION FOR SEQ ID NO:27:
(i) SEQUENOE CHARACTERISTICS:
(A) LENGTH: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear (ii) M~T-TcCUTT~ TYPE: peptide (ix) FlZATURE:
(A) NAME/REY: mi~c_feature (D) OTHER ~ Ofi~L~.TION: "~LMP.92 (ix) P'E:ATURE:
(A) NAME/REY: Modified--~ite (B) LOCATION: C ~. inll~
(D) OTHER lr~l~O~ATION: /label= Amidation /note= "The C ~. inll~ iB Amidated"
(xi) ~c.yu~iN~;ri DESCRIPTION: SEQ ID NO:27:
Ly~ Ser Lys Val Gly Trp Leu Ile Lyn Leu Phe EIin Ly~ Ly~

(2) lNr-~J~.TION FOR SEQ ID NO:28:
(i) SEQUENOE CHARACTERISTICS:
(A) LENGTH: 14 amino acidn (B) TYPE: amino acid (D) TOPOLOGY: line~lr (ii) ~nTF~CUTTC TYPE: peptide (ix) FEATURE:
(A) NAME/REY: mi~c_feature (D) OTHER INFORMATION: "a~Mp.94"
(ix) FEATURE:
(A) NAME/REY: Modified--~ite (B) LOCATION: C ~. inlln (D) OTHER IN~0~5ATION: /label= AmLdation /note= "The C ~, in~7~ i~ Amidated"
(Xi) :j~!iyUL.._ri DESCRIPTION: SEQ ID NO:28:
Ly~ Ser Lyn Val Gly Trp Leu Ile Gln Leu Phe Phe Ly~ Lyl3 CA 02227292 l998-0l-l9 W O 97/04008 PCT~US96/03845 1 5 lO
(2) ln~v~.TION FOR SEQ ID NO:29:
(i) -~ ;L ~ CHARACTERISTICS:
(A) LENGTA: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~T~T'CuT~T~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: miuc feature (D) O~l~A~R lNr~.TION: ~XMP.95"
(ix) F~ATURE:
(A) NAME/ ~ Y: Modified-~ite (B) LOCATION: C .. ; n~n (D) OTAER lN~o~JlATIoN: /label= r i~Ation /note= "The C i, i n~ Amidated"
(xi) ~J~-~CE D~erRTPTION: SEQ ID NO:29:
Ly~ Ser Ly~ Val Phe Trp Leu Ile Gln Leu Phe Hi8 Ly~ Ly~

(2) lnr~ATIoN FOR SEQ ID NO:30:
(i) SEQUEN OE CAARACTERISTICS:
(A) T- _.A: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~T ~CuT-T~ TYPE: peptide (ix) FEATURE:
(A) NA~E/ ~ Y: mi~c_feature (D) O~HER lN~OR~ATION: ~XMP.96"
(ix) FEATURE:
(A) NAME/ ~ Y: ~odified-~ite (B) LOCATION: C-.. i n~
(D) OTHER lN~L~TION: /label= ~ i~Ation /note= "The C ., i n--~ t~
(xi) SEQUEN OE D~e~TPTION: SEQ ID No:30:
Ly~ Ser Ly~ Val Gly Trp Leu Ile Gln Leu Phe Hi~ Ly~ Phe (2) INFORMATION FOR SEQ ID NO:31:
(i) ~ ~ CHARACTERISTICS:
(A) LENGTH: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT.T'~TT.T~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: minc_feature (D) OI~AER INFORMATION: "X~P.97"

W O 97/04008 PCT~US96/03845 (ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: C ~. inl~
(D) OT~ER lNr~.TION: /label= Amidation /note= "The C . i n--n i~ Amidated"
(xi) SEQUEN ~ DFS~TPTION: SEQ ID NO:31:
Lys Ser Ly~ Val Lys Trp Leu Ile Gln Leu Phe His Lys Lys (2) lN~O~r~TION FOR SEQ ID NO:32:
(i) SEQUEN OE CHARACTERISTICS:
(A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~T~T~CuT-F TYPE: peptide (ix) FEATURE:
(A) NAME/REY: misc_feature (D) Oln~R lNrO~ATION: "XMP.100"
(ix) FEATURE:
(A) NAME/~EY: Modified-~ite (B) LOCATION: C i,- in--~
(D) OTHER lhr~.~3ATION: /label~ ~ tinn /note= "The C ~. inl-n i~ Amidated"
(xi) SEQUEN OE nF-CC~TPTION: SEQ ID NO:32:
Ly~ Ser Lys Val Lys Trp Leu Ile Lys Leu Phe His Ly~ Lys 1 5 lO
(2) lNrO~L~TION FOR S~Q ID NO:33:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 28 amino acid3 (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~T.T~CUT.T! TYPE: peptide (ix) FEATURE:
(A) NAME/REY: misc_feature (D) OTHER INFORMATION: "XMP.101"
(ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: C 1. inll~
~D) OTHER lNrvK~ATION: /label= Amidation /note= "The C ~. in-ln i~ Amidated"
(xi) ~r;yuL._r; DT~!C~TpTIoN: SEQ ID NO:33:

Lys Ser Lys V~l Lyn Trp Leu Ile Lys Leu Phe Phe Lys Phe Lys Ser 1 5 lO 15 Ly~ Val Lyn Trp Leu Ile Ly~ Leu Phe Phe Lys Phe (2) lNr~k~ATION FOR SEQ ID NO:34:

CA 02227292 l998-0l-l9 WO 97/0400~ PCTtUS96t03845 (i) s~u- . ~ CHARACTER.STICS:
(A) LENGTH: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear (ii) M~T-~C~ITT! TYPE: p~ptide (ix) FEATURE:
(A) NAME/ ~ Y: mi~c_feature (D) OTHER ~ 5ATION: ~XMP.104"
(ix) FEATURE:
(A) NAME/REY: Modified-~ite ~B) LOCATION: C ~ ;nl~
(D) OTHER INFORMATION: /label= Amidation /note= "The C I. in--R i~ Amidated"
(xi) Sh~Ur,._r; DT~'C~TPTION: SEQ ID NO:34:
LYR Ser Lys Val Gly Trp Leu Ile Ser Leu Phe Hi~ Ly~ LYR

(2) lNrO}~.TION FOR SEQ ID NO:35:
(i) S~ ~ CHARACTERISTICS:
(A) LENGTH: 14 amino acids (B) TYPE: ~mino acid (D) TOPOLOGY: linear (ii) ~nT.T.!~IT.T~ TYPE peptide (ix) FEATURE:
(A) NAME/REY: mi~c_feature (D) OTHER INFORMATION: "XMP.106"
(ix) FEATURE:
(A) NAME/~ Y: Modified-~ite (B) LOCATION: C I. i n-- R
(D) OTHER l~Oh~.TION: /labelz Amidation /note~ "The C ~ ~ n--~ is Amidated"
(xi) SEQUENCE DESCRIPTION: SEQ ID No:35:
Ly~ Ser Lys Val Gly Trp Leu Ile Thr Leu Phe Hin LYB Ly~

(2) lhrORMATION FOR SEQ ID NO:36:
(i) s~u~ ~ CHARACTERISTICS:
(A) T- _ ~ ~: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MnT-T~'CUT-T~' TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: mi~c_feature (D) OTHER lhpo~ATIoN: "XMP.107"
(ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: C .. in--n (D) OTHER INFORMATION: /label= Amidation W O 97/04008 PCT~US96/03845 /note= "The C ~.- ;nll~ is Amidated"
(xi) SEQUEN OE D~C~RTPTION: SEQ ID NO:36:
Ly~ Ser Lys Val Gly Trp LQU Ile Gln Leu Phe Trp Lyn Lys (2) ~N~O.~.TION FOR SEQ ID NO:37:
(i) SEQUEN OE CHARACTERISTICS:
(A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: lin~ar (ii) MOT~CU~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: miQc_feature (D) OTHER lNrv~.TION: "XMP.108"
(ix) FeATURE:
(A) NAME/~EY: ~odified-nite (B) LOCATION: C ,, in~Q
(D) OTHER l~v.l~ATION: /label= ~ ti~n /notes "The C ~, i n--a is Amidated"
(xi) SEQUEN OE DFC~TPTION: SEQ ID NO:37:
Lys 8er Ly~ Val Gly Trp Leu Ile Gln Leu Phe Hi~ Lys Trp (2) l~ru~ATION FOR SEQ ID NO:38:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14 amino acids (8) TYPE: umino acid ~D) TOPOLOGY: linear ( ii ) ~T~C~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: mi~c_feature (D) OTHER lNru.~ATION: "XMP.109"
(ix) FEATURE:
(A) NAM~/~EY: Modified-Qite (8) LOCATION: 11 (C) OTHER lN~v~nATION: /label= Sub~tituted-Ala /note= ~Po~ition 11 is beta-l-nnphthyl-sub3tituted."
(ix) FEATURE:
(A) NAME/~EY: Modified-sitR
(B) LOGATION: C ~. ; n--~
(D) OTHER INFORMATION: /label= Amidation /note= "The C . inllQ i~ Amidated~

(xi) ~r;yuk~ D~eCRTPTION: SEQ ID NO:38:
Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Ala His Lys Lys (2) lNrvl~.TION FOR SEQ ID No:39:

W O 97/04008 PCT~US96/03845 ~ C~ARA~'~ZRTsTIcs ~A) T- _ ~ ~: 14 amLno acid~
(8) TYPE: amino acid (D) TOPOLOGY: linear (ii) MnT ~TT-T! TYPE: p~pt;~
(ix) FEATURLE:
(A) NAME/XEY: miQc feature (D) OT~ER lN~.~TION: "XMP.llO"
(ix) F~ATURE:
(A) NAME/ ~ Y: Modified-site (B) ~OCATION: 12 (C) OTHER lhro~lfATIoN: /label= Sub~tituted-Ala /note= "Po_ition 12 i~ beta-l-naphthyl-~ub~tituted."
(ix) FEATURE:
(A) NAME/REY: Modified-nite (B) LOCATION: C i~ iml~
(D) OTHER l~.~3ATION: /label= Amidation /note= ~The C ~. ; n--~ in Amidated"
(xi) SEQUENCE n~QC~TPTION: SEQ ID NO:39:
Ly_ Ser Ly_ Val Gly Trp Leu Ile Gln Leu Phe Ala Lyn Ly_ (2) lNr~KMATION FOR SEQ ID NO:40:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~ .TccuT~T~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: misc_feature (D) OTHER lhr~K~ATIoN: ~XMP.lll"
(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: 14 (C) OTHER INFORMATION: /label= Sub~tituted-Ala /note= "Po~ition 14 iB beta-l-naphthyl-sub~tituted."
(ix) FEATURE:
(A) NAME/ ~ Y: Modified-~ite (B) LOCATION: C ~_ ;n~Q
(D) OTHER l~OKMATION: /label~ Amidation /note= "The C i~ ;n--Q iQ Amidated"
(xi) ~yu~_~ DESCRIPTION: SEQ ID NO:40:
Ly_ Ser LYQ Val Gly Trp Leu Ile Gln Leu Phe Hi~ Ly~ Ala (2) l~rOkdATION FOR SEQ ID NO:41:
( i ) ~UL_. CE CHARACTERISTICS:
(A) T- _~: 14 amino acid~
(B) TYPE: amino acid -(D) TOPOLOGY: line~r ( ii ) MnT-T!C~TT-T~ TYPE peptide (ix) FEATURE:
(A) NAME/KEY: misc_feature (D) OTHER lN~ATION: "XMP.113"
(ix) F~ATURE:
(A) NAME/~EY: Modified-~ite (B) LOCATION: C ~- i n--n (D) OTHER lN~O~.TION: /label= Amidation /notes ~The C i n--n iS Amidated"
(xi) ~u~.~F DT2.S~TPTION: SEQ ID NO:41:
Lys Ser Lys Val Gly Trp Leu Ile Gln Phe Phe His Lys Ly~

(2) lN~ATION FOR SEQ ID NO:42:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: lincar ( ii ) MnT~cTJT~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: misc_feature (D) OTHER lh~OR~ATION: "XMP.116 (ix) FEATURE:
(A) NAME/KEY: Modified-site (B) LOCATION: 6 (C) OTHER lh~ATION: /label= Substituted-Ala /note~ "Po~ition 6 i~ bnta-1-naphthyl-substituted."
~ix) FEATURE:
(A) NAME/KEY: Modified-site (B) LOCATION: C ~. ; n~n (D) OTHER lN~I~.TION: /label= ~ tion /note= ~The C ~. inl-~ is Amidated"
(xi) SEQUENCE DT~.SCT2TPTION: SEQ ID NO:42:
Lys Ser Lys Val Lys Ala Leu Ile Gln Leu Phe His Lys Ly~

( 2 ) lN ~OkMATION FOR SEQ ID NO:43:
( i ) S~U~N~K CHARACTERISTICS:
(A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT~CuT~T~ TYPE: peptide (ix) FEATURE:
(A) NAME/ ~ Y: misc_feature (D) OTHER INFORMATION: "XMP.123"
(ix) FEATURE:

CA 02227292 l998-0l-l9 WO 97/04008 PCT~US96~3845 (A) NAME/REY: Modified-site ~ (B) LOCATION: g (C) OTHER l~rOhMATION: /l~bel= Su~stituted-Phe note= "The phenyl~lAnin~ at position 9 i~
~, ~ i no--substituted~ "
(ix) FEATURE:
(A) NANE/REY: Modified-site (B) LOCATION: C ~ in~n (D) OTHER l~nMATION: /label= Amidstion /not~ "The C ; n~ iS Amidated"
(xi) SEQUENCE DFS~RTPTION: SEQ ID NO:43:
Lys Ser Lys Val Gly Trp Leu Ile Phe Leu Phe His Ly~ Lys (2) lr.~RMATION FOR SEQ ID NO:44:
(i) ~r.~UL.._r; CHARACTERISTICS:
(A) LENGTH: 14 smino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~r-~c~TT-~ TYPE: pepti~
(ix) FEATURE:
(A) NAME/REY: misc_feature (D) OTHER INFORMATION: "XMP.124"
(ix) FEATURE:
(A) NAME/REY: Modified-nite (B) LOCATION: C ~.- i n--~
(D) OTHER lNru~hATION: /label= Amidation /note= "The C i. ; n--n ie r ;~ate~
(xi) S~ul- -E DT~'CCRTPTIoN: SEQ ID NO:44:
Lys Ser Ly~ VB1 Lys Trp Leu Ile Gln Leu Trp His Lyn Lys l 5 10 (2) lNrv~ATION FOR SEQ ID NO:45:
(i) SEQUEN OE CHARACTERISTICS:
(A) LENGTH: 14 amino acids (8) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~T-T'CuT~T! TYPE: peptide (ix) FEATURE:
(A) NAME/~EY: misc_feature (D) OTHER lNrO~SATION: ~XMP.125"
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: C i. inll~
(D) OTHER l~rORMATION: /lnbel- Amidation /note= "The C ~. ;n~s is Amidated"
(Xi) ~h~UL..-~ DESCRIPTION: SEQ ID NO:4S:
Lys Ser Lys Val Gly Trp Leu Ile Tyr Leu Phe His Lys Lys CA 02227292 l998-0l-l9 (2) lNrukdATION FOR SEQ ID NO:46:
Qur;~r; CHARACTERISTICS:
(A) T- _ ~ ~: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT.TCCTJT.TC TYPE: peptLde (ix) FEATURE:
(A) NAME/REY: mi~c_feature (D) OT B R lNr-u l~ATION: "XMP.126"
(ix) FEATURE:
(A) NAME/KEY: Modified-site (B) LOCATION: 6 (C) OTHER lNrOk~ATION: /label= D-Trp /note= "Ponition 6 i~ D-tryptophan."
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: C i. ; n--v (D) OT B R ll.ru.~ATION: /label= Amidation /note= ~The C i~ ~ n-~ L~ Amidated"
(xi) SEQULN OE D~-C~TPTION SEQ ID NO:46:
Ly~ Ser Lys Val Gly Trp Leu Ile Gln Leu Phe Hi~ Lys Lys (2) lNr~n~aTION FOR SEQ ID NO:47:
(i) ~ur.~ CHARACTERISTICS:
(A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) M~T~TCCUT~TZ TYPE: p~pt;~
(Lx) FEATURE:
(A) NAME/KEY: misc_feature (D) OTHER lNruX~ATION: "XMP.127"
(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: C I, ;nll~
(D) OT B R lNrO~ATION: /label= Amidation /note= ~The C ~. inll~ is Amidated~
(xi) ~h~uh~ur; DT~-CrRTPTION: SEQ ID NO:47:
Lys Ser Lys Val Gly Phe Leu Ile Gln Leu Phe His Lys Lys (2) lNruR~ATION FOR SEQ ID NO:48:
~u~._r; CHARACTERISTICS:
(A) LENGTH: 14 amino acidn (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii) ~nT,~Jr-~ TYPE: pep'ide (ix) FEATURE:
(A) NAME/ ~ Y: misc feature (D) OTHER lN~O~ ~TION: "XMP.12~"
(ix) FEATURE:
(A) NAME/~EY: Modified-~ite (B) LOCATION: 6 (C) OTHER lNru~NATIoN: /label= D-Phe /note= "Po~7ition 6 is D ~h~nyl a 1 An; n~, (ix) FEATURE:
(A) NAME/ ~ Y: Modified-~ite (B) LOCATION: C i, ;n-7~
(D) OTHER lNrO~ ~TION: /label= Amidation /not~s "The C ~. ; n--n is ~ ted~
(xi) SEQUEN OE D~C~RTpTIoN: SEQ ID NO:48:
Ly~7 Ser Lys Val Gly Phe Leu Ile Gln Leu Phe Hi~7 Lys Lys (2) l~r~_l ~TION FOR SEQ ID NO:49:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTHz 14 amino acid~
(B) TYPE: ~mino acid (D) TOPOLOGY: lin~ar ( ii ) ~T ~CU~ TYPE: pept;~
(ix) FEATUR~:
(A) NAME/KEY: misc_feature (D) Oln~R INr~R~ATION: ~XMP.129"
(ix) FEATURE:
(A) NAME/~EY: Modified-~ite (B) LOCATION: 6 (C) OTHER lNru.~lATION: /label= Sub~tituted-Ala /note= "Position 6 i~ D-l-beta-l-naphthyl-substituted."
(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: C-T~ ; n--~
(D) OTHER lhru.~.TION: /label= P ;d~t;~n /note= "The C ~ ; n--n i~ P ; dAted~
(xi) Xh~uL _r; D~C~TpTIoN: SEQ ID NO:49:
Lys Ser Lys Val Gly Ala Leu Ile Gln Leu Phe His Lys Lys (2) l~.r~.~.TION FOR SEQ ID NO:50:
(i) SEQUEN OE CHARACTERISTICS:
(A) LENGTH: 14 ~mino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~ r.Fc~rr.~ TYPE: peptide (ix) FEATURE:

(A) NAME/REY: misc_feature (D) Ol~R Ih~OkdATION: "XMP.130"
(ix) F~ATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: 6 (C) OTHER lh~h~ATION: /labele Substituted-Ala /note= ~Po~ition 6 i~ beta-2-naphthyl-sub~tituted."
(ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: C ~ ; n--~
(D) OTHER l~r~ATION: /label- Amidation /note= "The C i- i n--n i~ teA~
(xi) SEQUEN OE DF-C~DTPTION: SEQ ID NO:50:
Ly~ Ser Ly~ Val Gly Ala LQU Ile Gln Leu Phe His Lyn Lyn (2) lN~ I~ATION FOR SEQ ID NO:51:
(i) SEQUEN OE CHARACTERISTICS:
(A) LENGTH: 14 amino acidn (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) M~T-~-~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: mi~c_feature (D) OTHER lNrO1~4ATION: "XMP.131"
(ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: 6 (C) OTHER lN~h~ATION: /label= Sub~tituted-Ala /note- "Po~ition 6 i~ D-~eta-2-naphthyl-~ubctituted. n (ix) FEATURE:
(A) NAME/REY: ModifiHd-~ite (B) LOCATION: C i. ;n--~
(D) OTHER lN~ ATION: /label~ r ;~at;o~
/note~ ~The C-~- ; n--n i~ Amidated"
(xi) ~yu~._~ D~c~TpTIoN: SEQ ID NO:51:
Ly~ Ser Ly~ Val Gly Ala Leu Ile Gln Leu Phe Hia Lyn Ly~
1 5 lO
(2) INFORMATION FOR SEQ ID NO:52:
(i) ~u~._~ CHARACTERISTICS:
(A) LENGTH: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~T ~C~-~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: mi~c feature (D) OTHER lN~u~ATION: "X~P.132"

W O 97/04008 PCTnUS96~384s (ix) FEATURE:
(A) NAME/ ~ Y: Modified-site (8) LOCATION: 6 (C) OTHER lN~ ATION: /label= Sub~tituted-Ala /notez "The alPnin~ at position 6 i~
pyridyl-~ubstituted."
(Lx) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: C-T~ i n~ ~
(D) O~n~R lN~v~ATION: /label= Amid~tion /note= "The C ~. in~lQ in Amidated"
(xi) SEQUEN OE D~-CCPTPTION: SEQ ID NO:52:
Ly_ Ser Ly~ Val Gly Ala LQU Ile Gln Leu Phe His Ly~ Ly~

(2) l~rv_~TION FOR SEQ ID NO:53:
(i) SEQUEN OE C~A~T~RTeTIcs:
(A) LENGTH: 14 amino acid~
(B) TYPE: ~ nino ~cid (D) TOPOLOGY: linear ( ii ) MOT~CUT-T~' TYPE: peptide (ix) FEATURE:
(A) NANE/REY: misc fQature (D) OTHER INFOR~ATION: "XMP.133"
(ix) FEATURE:
(A) NAME/~EY: Modified-_ite (B) LOCATION: 6 (C) OTHER l~v_~ATION: /label- Sub3tituted-Phe /note= "Po_ition 6 i~ para . in~-~ub~tituted."
(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: C-T~ in-. n (D) OTHER lN~v_~QTION: /label- Amidation /note= ~The C-Te in~Q is Amidated"
(xi) ~u~- ~E D~e~RTpTIoN: SEQ ID NO:53:
Ly~ Ser LyQ Val Gly Phe L~u Ile Gln Leu Phe Hi_ Ly~ Ly~

(2) lNrv_~TION FOR SEQ ID NO:54:
( i ) ~UL_. S'E ~UAR~t~Tl;!~TsTIcs (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: lin~ar ( ii ) MOT.~JT.~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: mi_c_feature (D) OTHER lh~ORMATION: "XMP.134"
(ix) FEATURE:
(A) NAME/REY: Modified-~ite W O 97/04008 PCT~US96/03845 (B) LOCATION: 5 (C) OTHER lN~ vR~ATION: /label r Substituted-Phe /note= "Position 5 i~ para-amino-~ubntituted. n (ix) F~ATURE:
(A) NAME/~Y: Modified-~ite (B) LOCATION: C .~ inl-n (D) OTHER lh~n~ATION: /label= Amidation /note= "The C ., inl-~ is r i~ated"
(xi) SEQUENCE D~RTPTION: SEQ ID NO:54:
Lyu Ser LYB Val Phe Trp Leu Ile Gln Leu Phe Hi3 Lyu Ly~

( 2 ) lN ~OR~ATION FOR SEQ ID NO:55:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14 ~mino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~T-T~T-T! TYPE: peptide (ix) FEATURE:
(A) NAME/REY: mi~c feature (D) OTHER lhr~__ L~TION: "XMP.135"
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: C-.. ;n-~~
(D) OTHER lNFu.~.TION: /label= Amidation /note= "The C 1- inll~ is ~ ted"
(xi) SEQUENCE DFSrRTPTION: SEQ ID NO:55:
Ly~ Ser Ly~ Val Gly Ly~ Leu Ile Gln Leu Phe His Ly~ Ly~

(2) lNrOK~ATION FOR SEQ ID NO:56:
( i ) ~FyUL ._F CHARACTERISTICS:
(A) LENGTH: 16 amino acid~
(B) TYPE: ~mino acid (D) TOPOLOGY: circular ( ii ) ~nT~T''CTTT~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: misc_feature (D) OTHER lN~II~ATION: "XMP.137"
(ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: C ~- inl~n (D) OTHER INFORMATION: /label= Amidation /note= "The C ., inl-~ is Amidated~
(xi) ~yu~.~~ DESCRIPTION: SEQ ID NO:56:
Cy~ Lys Ser Ly~ Val Gly Trp Leu Ile Gln Leu Phe Hi~ Ly~ Ly~ Cy~

W O 97/04008 PCT~US96/03845 (2) ~ ~TION FOR SEQ ID ~0:57:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14 amino acid8 (B) TYPE: amino acLd (D) TOPOLOGY: linear (ii) ~T~c~r~ TYPE: pepti~
(Lx) F~ATURE:
(A) NAME/~EY: mi~c_feature (D) OTHER l~O~.TION: "XMP.138"
(Lx) FEATURE:
(A) NAME/KEY: Modified-site (B) LOCATION: C-Te in-~
(D) OTHER l~O~ATION: /label= Amidation /note= "The C- , ; n--~ i ~'te~"
(Xi) ~UL..~E D~Cr~TpTIoN: SEQ ID NO:57:
Ly~ Ser Lyc Val Lys Phe Lnu Ile Gln Leu Phe Hi~ Ly~ Ly~

(2) l~TION FOR SEQ ID NO:58:
(i) SEQUEN OE C~ARACTERISTICS:
(A) T, _ A 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~n~Cur-~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: mi~c_feature (D) OTHBR I~r ~dATION: "XMP.139"
(Lx) FEATURE:
(A) NAMB/~EY: Modified-~ite (B) LOCATION: C ~ i n-- n (D) OTHER INFORMATION: /label= Amidation /note= "The C-~. i n--n i~ Amidated"
(xi) ~u~_~: DESCRIPTION: SEQ ID NO:58:
Lys Ser Ly~ Val Gly Tyr Leu Ile Gln Leu Phe His Ly~ Lys (2) INFORMATION FOR SEQ ID NO:59:
(i) SEQUEN OE CHARACTERISTICS:
(A) LENGTA: 14 amino acid~
(8) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) I' r-~Jr-~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: mi~c_feature (D) OTAER INFORMATION: "XMP.142"
(Lx) FEATURE:
(A) NAME/KEY: Modified-~ite W O 97/04008 PCTnJS96/03845 (B) LOCATION: C ~ in~
(D) OTHER lN~u-l~ATIoN: /label= Amidation /note= "The C .~ in~ Amidated"
(xi) SEQUENCE D~C~PTPTION: SEQ ID NO:59:
Lyu 8er LYB Val Gly Trp Leu Ile Gln Trp Phe His Ly~ Ly~

(2) lN~O~ATION FOR SEQ ID NO:60:
(i) SEQUEN OE CHARACTERISTICS:
(A) T- _ A 14 ~ino ncid~
(B) TYPE: amino acid (D) TOPOLOGY: lin~ar ( ii ) M~T-~CUT-~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: miuc feature (D) OTHER 1N~ L~TION: "XMP.143 (ix) P~ATURE:
(A) NAME/KEY: Modified-site (8) LOCATION: lO
(C) OTHER lNrOr~TION: /label= Substituted-Ala /note= "Position 10 i~ beta-l-naphthyl-substituted."
(ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: C i~ ;n--~
(D) OT~AER lN~Oh~.TION: /label= Amidation /note= ~The C ~ nl~n i~ P i~ated~
(xi) SEQUENCE D~S~RTPTION: SEQ ID NO:60:
Ly~ SQ~ Ly~ Val Gly Trp LQU I1Q Gln A a Phe Hi~ Ly~ Ly~

(2) lN~.~L~TION FOR SEQ ID NO:61:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTA: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linoar ( ii ) MnT~U I ~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: misc feature (D) OTHER lN~ ~R~ATION: "XMP.144"
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: 6 (C) OTHER lN~knATION: /label~ Sub~tituted-Ala /note= ~The A 1 ~n i n~ at poaition 6 i~
cyclohexyl-substituted."
(ix) FEATURE:
(A) NAME/REY: Modified-nite (B) LOCATION: C-T~ ; n~ ~
(D) OTHER INFORMATION: /label= Amidation /note= "The C-~. in~ Amidated"
(Xi) ~h~U~-_.'~ D~C~TPTION: SEQ ID NO:61:
Ly~ Ser Ly~ Val Gly Ala Leu Ile Gln Leu Phe Hi~ Ly~ Lys (2) lNrvh~ATIoN FOR SEQ ID NO:62:
r CHARACTERISTICS:
(A) LENGTH: 14 amino ~cid~
(B) TYPE: amino acid (D) TOPOLOGY: linear (ii) ~nTr~C~T~ TYPE: peptide (ix) FEATURE:
(A) NAHE/~EY: mi~c feature (D) OTHER INFORHATION: "XMP.146"
(ix) F~ATURE:
(A) NAHE/KEY: Modified-~ite (8) LOCATION: 12 (C) OTHER lN~dATION: /label= Sub~tituted-Ala /note= "Position 12 is beta-1-naphthyl-Gub~tituted."
(ix) FEATURE:
(A) NAME/R~Y: Modified-~ite (B) LOCATION: 14 (C) OTHER INFORMATION: /label= Substituted-Ala /note= "Position 14 i~ beta-1-naphthyl-~ub~tituted."
(ix) FEATURE:
(A) NAME/KBY: Modified-nite (B) LO Q TION: C-,. ; n--~
(D) OTHER ~r~.llATION: /label~ Amidation /note- ~The C 1. inl-n i~ Amidated"
(xi) SEQUEN OE DESCRIPTION: SEQ ID NO:62:
Ly~ Ser Lys Val Gly Trp Leu Ile Gln Leu Phe Ala Lys Ala (2) I~O~MATION FOR SEQ ID NO:63:
(i) SEQUEN OE CHARACTERISTICS:
(A) LENGTH: 14 amino acids (B) TYPE: nmino acid (D) TOPOLOGY: linear (ii) 1- ~C~ TYPE: p~ptide (ix) FEATURE:
(A) NAHE/KEY: mi~c feature (D) OTHER lN~vKMATION: ~XMP.148"

(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: 6 (C) Ol~R INFORNATION: /label= Sub~tituted-Ala /note= "Position 6 is beta-l-naphthyl-~ubstituted."
(ix) FEATURE:

W O 97/04008 PCT~US96/03845 (A) NAME/REY: Mod'fied-~ite (B) LOCATION: 12 (C) OTHER lN~ ATION: /label= Sub~tituted-Ala /note= "Position 12 is beta-l-naphthyl-~ubstituted."
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: C . i n--~
(D) OTHER lN~ TION: /label= Amidation /note= "The C I. i n--n i~ Amidated"
(xi) SEQUEN OE DT~'CC~TPTIoN: SEQ ID NO:63:
Lys Ser Ly~ Val Gly Ala Leu Il~ Gln Leu Phe Ala Lys Lys (2) lNrv~.TION FOR SEQ ID NO:64:
~u~- ~ CHARACTERISTICS:
(A) LENGTH: 14 amino acidq (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) M~T-~C~TT~T~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: miffc_feature (D) OTHER l~rO~L~TION: "XMP.161"
(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: C ~. i n--~
(D) OTHER lNr~.llATION: /label- Amidation /note- "The C ~. i nu~ is Amidated"
(xi) SEQUENCE ~Cr~TPTION: SEQ ID NO:64:
Ly~ Ser Lyff Val Lys Ala Leu Ile Gln Leu Phe His LYB LYB

(2) INFORMATION FOR SEQ ID NO:65:
(i) SEQUEN OE CHARACTERISTICS:
(A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~T-~-T! TYPE: peptide (ix) FEATURE:
(A) NAME/~ Y: minc_feature (D) OTHER lN~kMATION: "XMP.166"
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: C ~. i n--n (D) OTHER INFORMATION: /label= Amidation /note= ~The C ~. i n~ Amidated~
(xi) ~yuL.._r, D~CCRTPTION: SEQ ID NO:65:
Lyn Ser Ly~ Val Gly Val Leu Ile Gln Leu Phe His Ly~ Lys CA 02227292 l998-0l-l9 ( 2 ) Ih ~ ~SATION FOR SEQ ID E~0:66:
($) ~u~ . ~ CHARACTERISTICS:
(A) LENGTH: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT T~CrJT ~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: mi~c feature (D) OTHER lN~_~SATION: "XMP.222 (ix) FEATURE:
(A) NAME/~EY: ModLfied-~ite (B) LOCATION: 6 & 14 (C) OTHER lN~o~ATIoN: /label= Sub~tituted-Ala /note= "Po~ition~ 6 and 14 are beta-l-naphthyl-nub~tituted."
(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: C ~, i n--~
(D) Ol~R lN~O~SATION: /label= Amidation /note= "The C ~. ;n~ P i~nted"
(xi) SEQUEN OE n~RTPTION: SEQ ID NO:66:
Lyn Ser Lys Val Cly Ala LQU Ile Gln Leu Phe Hi~ Ly~ Ala (2) lNr~L~TION FOR SEQ ID NO:67:
(i) c~ CHARACTERISTICS:
(A) T _ ~: 14 smino ~cid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT~T~Cu~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: mi~c_feature (D) OTHER lN~ ATIoN: "XMP.223"
(ix) F~ATURE:
(A) NAME/~EY: Modified-~ite (B) LOCATION: 6 & 10 (C) OTHER lN~KNATION: /label= Sub~tituted-Ala /note= "Po~ition~ 6 & 10 are beta-1-naphthyl-~u~tituted."
(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: C ~. ;~.-~
(D) Ol~R INFORMATION: /label~ Amidation /note- "The C i.- i n-~ Amidated"
(Xi) Sr.~UL_.~~ D~S~RTPTION: SEQ ID NO:67:

Ly~ Ser Lyn Val Gly Ala Leu Ile Gln Ala Phe Hi~ Lyn Lyn (2) INFORNATION FOR SEQ ID No:68:
( i ) ~DL.. ~ CHARACTERISTICS:

CA 02227292 l998-0l-l9 (A) T- _L~ 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT~T'!CnT~T~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: mi~c_feature (D) OTHER lN~ATION: "XMP.224"
(ix) F~ATURE:
(A) NAME/~EY: Modified-nite (8) LOCATION: 6 (C) OTHER lN~O~MATION: /label= Substituted-Ala /note= "Po~Ltion 6 i~ beta-l-naphthyl-substituted."
(ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: 9 (C) OTHER lh~OA~ATION: /label= Substituted-Phe /note= "Po~ition 9 i~ para-amino-subntituted."
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: C ~- in--P
(D) OTXER lN~O~.TION: /label= Amidation /not~ ~Th~ C ~ ; n--P i~ ~ t~"
(xi) SEQUEN OE n~CrRTPTION: SEQ ID NO:68:
Ly~ Ser Ly~ Val Gly Ala Leu Ile Phe Leu Phe His Ly~ Ly~

(2) lN~ORMATION FOR SEQ ID NO:69:
(i) ~ ~ CHARACTERISTICS:
(A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MnT-T!~JT-T' TYPE p~ptide (ix) FEATURE:
(A) NAME/REY: minc_feature (D) OTHER lNrOR~ATION: "XMP.225"
(ix) FEATURE:
(A) NAME/ ~ Y: Modified-~ite (B) LOCATION: 6 (C) Ol~R INFORNATION: /label= Substituted-Ala /note= "Po~ition 6 i~ beta-l-naphthyl-~ub~tituted."
(ix) FEATURE:
(A) NANE/~ Y: Modified-~ite (B) LOCATION: 5 (C) Ol~R lNru.~ATION: /label= Substituted-Phe /note= "Ponition 5 in para-amino-nubntituted."
(ix) FEATURE:
(A) NAME/~EY: Modified--ffite (B) LOCATION: C-Te i nU ~
(D) OTHER lNr~KMATION: /label= Amidation /note= "The C-T~ lnus is Amidated~

WO 97/04008 PCT~US96/03845 (xi) S~QUEN OE D~S~TPTION: SEQ ID NO:69:
Ly~ Ser Ly~ Val Phe Ala Leu Ile Gln Leu Phe Hi~ Ly~ Ly~

(2) IN~O~ ~TION FOR SEQ ID NO:70:
(i) ~u~._~ CHARACTERISTICS:
(A) r- _.~: 14 amino acid~
(8) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOT~CCr-~ TYPE: peptide (Lx) FEATURE:
(A) NAME/~EY: mi~c feature (D) OTHER lN~ TION: ~XMP.226 (ix) FEATURE:
(A) NAME/~EY: Modified-~ite (B) LOCATION: 6 (C) OTHER lN~u ~.TION: /label~ Sub~tituted-Ala /note- "Po~ition 6 i~ beta-l-naphthyl-~ub~titutod."
(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: C ~, in--~
(D) OTHER lN~O_~L~TION: /label- P ;~-t;nn /note- "The C ~. ; n--n i~ A~idated~
(xi) SEQUEN OE D~-CC~TPTION: SEQ ID NO:70:
Ly~ Ser Ly~ Val Gly Ala Leu Ile Gln Leu Trp His Ly~ Ly~

(2) lN~Ok~ATION FOR SEQ ID NO:71:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear (ii) ~nr-~C~r-~ TYPE: peptide (ix) FEATURE:
(A) NAME/~ Y: mi~c feature (D) OTHER lN~O~ATION: "XMP.227"
(ix) FEATURE:
(A) NAME/~EY: Modified-nite (B) LOCATION: 10 & 14 (C) OTHER INFORMATION: /label= Substituted-Ala /note= "Ponitionn 10 & 14 are beta-1-naphthyl-~ub~tituted. n (ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: C i. ; n--~
(D) OTHER lN~O~MATION: /label= Amidation /note= "The C ~, ;nt-ft i~ P ;~At~An (xi) SEQUENCE DESCRIPTION: SEQ ID NO:71:
Ly~ Ser Ly~ Val Gly Trp Leu Ile Gln Ala Phe Hi~ Ly~ Ala CA 02227292 l998-0l-l9 WO 97/04008 PCT~US96/03845 1 5 lO
(2) lN~A~ATION FOR SEQ ID NO:72:
(i) SEQUENNCE CHARACTkRISTICS:
(A) LENGTH: 14 amLno acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MnT~CUT~ TYPE: peptide (ix) FEATURE:
(A) NAME/AREY: misc feature (D) OTHER lN~A~AF.TION: "AYMP.228"
(ix) FEATURE:
(A) NAME/~EY: Modified-rite (B) LOCATION: 9 (C) OTHER lN~ J~aTION: /label- Subntituted-Phe /note= "Position 9 i8 para - amino - sub8tituted. "
(ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: 14 (C) OTHER lN~u~l~ATIoN: /label= Sub~tituted-Ala /note= ~Position 14 is beta-l-naphthyl-~ubstituted."
(ix) FEATU~E:
(A) NAME/~EY: Modified-rite (B) A'A~CATION: C ~. i n--~
(D) OTA~FR lNA~.~aTION: /label= P i~-t-i~n /note= "The C ; n--n iB Amidated"
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:72:
Lys Ser Ly~ VA1 Gly Trp Leu Ile Phe Leu Phe His Ly~ Ala l 5 10 (2) lN~ufi~ATIoN FOR SEQ ID NO:73:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) M~T~cl~.~ TYPE: peptide (ix) FA~.ATURE:
(A) NAME/REY: misc_feature (D) Ol~R INFORMATION: "AYMP.229"
(ix) FEATURE:
(A) NAME/KEY: Modified-rite (B) LOCATION: 5 (C) OTHER lN~Ofi~ATION: /label= Sub3tituted-Ala /note= "Po~ition 5 i~ para-amino-~ub~tituted."

(ix) FEATURE:
(A) NAME/KEY: ~odified-~ite (B) LOCATION: 14 (C) OTHER INFORMATION: /label- Subrtituted-Ala /note= "Po~ition 14 i8 beta-l-naphthyl-~ubntituted."

~5 (ix) FEATURE:
(A) NAME/~EY: Mod$fied-site (B) LOCATION: C i- i n~l~
(D) OTHER lN~ ~ATION: /label= P i~Ation /note= "The C i-- inll~ in Amidated~
(xi) s~ D~SrRTPTION: SEQ ID NO:73:
Ly~ Ser Ly~ Val Phe Trp Leu Ile Gln Leu Phe His Lyn Ala (2) lh~Rr~.TION FOR SEQ ID NO:74:
(i) SEQUEN ~ ~A~T~TeTICS:
(A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linoar ( ii ) ~ ~T~C~-~ TYPE: peptide (ix) FEATURE:
(A) NAME/XEY: misc feature (D) OTHER lhr ~hATION: ~XMP.230"
(ix) FEATURE:
(A) NAME/~ Y: Modified-site (B) LOCATION: 14 (C) OTHER lhro~ TIoN: /labels Sub~t$tuted-Ala /notQ= "Po~ition 14 i~ beta-l-naphthyl-substituted."
(ix) FEATURE:
(A) NAME/~EY: Modified-sito (B) LOCATION: C ~. i n~ ~
(D) OTHER lN~ L~TION: /l~bel~ Amidation /note- ~The C ~. i n~ P i ~tod"
(xi) sh~u~ r; nT!er~TPTION SEQ ID NO:74:
Ly~ Ser Ly~ Val Gly Trp Leu Ile Gln Leu Trp Hi~ LYR Ala (2) l~r~F~ATION FOR SEQ ID NO:75:
( i ) Sh~U ~ ~ CHARACTERISTICS:
(A) LENGTH: 14 amino acidR
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) YnT-~cu~-F TYPE: peptide (ix) F~ATURE:
(A) NAME/REY: misc_feature (D) OTHER lNrO~ ~TION: "XMP.231"
(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: lO & 12 (C) OTHER lhrohr~TIoN: /label-- SubRtituted--Ala /note= "PositionR 10 & 12 are betn-l-naphthyl-~ubRtituted."
(ix) FEATURE:
(A) NAME/XEY: Modified-site (B) LOCATION: C ~. inllR

W O 97/04008 PCT~US96/03845 (D) OTHER lN~ATlON: /labels Amidation /note= ~The C i. in-7n i~ Amidated"
(xi) SEQULNCE DTCQ~TPTION: SEQ ID NO:7S:
Ly~ Ser Ly~ Val Gly Trp Leu Ile Gln Ala Phe Ala Lys Ly~
l 5 lO
(2) lNru-~lATIoN FOR SEQ ID NO:76:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MnT~CT~TT~T~' TYPE: peptide (ix) FEATURE:
(A) NAME/XEY: mi~c_feature (D) OTHER lh~_~lATION: ~XMP.232"
(ix) FEATURE:
(A) NAME/KEY: Modified-uite (B) LOCATION: 9 (C) O'l~R lN~O~ATION: /label- Sub~tituted-Phe /note= "Po~ition 9 i8 para in~-~ub~tituted."
(ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: 12 (C) OTHER l~O~MATION: /label= Substituted-Ala /note= "Po~ition 12 i~ beta-l-naphthyl-nub~tituted."
(ix) FEATURE:
(A) NAME/XEY: Modified-~ite (B) LOCATION: C ~. in--~
(D) OTHER lN~O~ TION: /labels Amidation /note= ~The C-~ i n--n i~ Amidated~
(Xi) ~UL_._r; DESCRIPTION: SEQ ID NO:76:
Ly~ Ser Ly~ Val Gly Trp Leu Ile Phe Leu Phe Ala Lys Ly~
l 5 lO
(2) lN~n~ATION FOR SEQ ID NO:77:
(i) SEQUBN OE CHARACTERISTICS:
(A) LENGTH: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT~T~cuT~T~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: mi~c feature (D) OTHER lNrO~ATION: "XMP.233"

(ix) FEATURE:
(A) NAME/REY: Modified-nite (B) LOCATION: 5 (C) OTHER INFORMATION: /label2 Sub~tituted-Phe /notes "Pouition 5 i~ para-amino-~ub~tituted."
-CA 02227292 l998-0l-l9 (ix) FEATURE:
~ (A) NAME/REY: Modified-~ite (B) LOCATION: 12 (C) OTHER l~O~MATION: /I~bel2 Substituted-Ala /note= nPosition 12 i~ beta-l-naphthyl-nubstituted."
(ix) FEATURE:
(A) NAME/ ~ Y: Modified-site (B) LOCATION: C ,- ;n--Q
(D) OTHER lNr~RMATIoN: /label= Amidation /note= "The C . i n--a is Amidated"
(xi) ~u~..~E DESCRIPTION: SEQ ID NO:77:
Lys Ser Lys Val Phe Trp Leu Ile Gln Leu Phe Ala Ly~ Ly~

(2) lNr~.TION FOR SEQ ID NO:78:
(i) ~ ~ CHARACTERISTICS:
(A) LENGTH: 14 amino acidn (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~T ~CU~ ~ TYPE: p~ptidQ
(ix) FEATURE:
(A) NAM~/~Ey: misc feature (D) OTHER lh~_ L~TION: ~XMP.234 (ix) FEATURE:
(A) NAME/KEY: Modified-site (B) LOCATION: 12 (C) OTHER INFORMATION: /label= Substituted-Ala /note= ~Position 12 is beta-l-naphthyl-substituted."
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: C ~ i n-l~
(D) OTHER INFORMATION: /label= Amidation /note= ~The C '. i n--n iS Amidated"
(xi) ~QD~N~ D~CCRTPTION: SEQ ID NO:78:
Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Trp Ala Lys Lys (2) lh~ SATION FOR SEQ ID NO:79:
(i) SEQUEN OE CHARACTERISTICS:
(A) LENGTH: 14 ~mino acids (8) TYPE: amino ncid (D) TOPOLOGY: linear (ii) MnT~CULE TYPE: peptide (ix) FEATURE:
(A) NAME/REY: mi~c_fQature - (D) OTHER INFORMATION: "XMP.235"
(ix) FEATURE:
(A) NAME/REY: Modified-nite (B) LOCATION: 9 CA 02227292 l998-0l-l9 (C) OTHER lN~ OR~ATION: /label- Substituted-Phe /note= "Position 9 is para-amino-substituted."
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: 10 L
(c) OTHER lN ~ ATION: /label= Subntituted-Ala /not~= "Po~ition lO is bet~-l-naphthyl-~ubstitutod."
(ix) F~ATURE:
(A) NAME/~Er: Modified-~ite (B) LOCATION: C ~, i nl~ R
(D) OTHER lN~ ATIoN: /label= ~ t,ion /note= "The C .- inlln is Amidated"
(xi) SEQUENCE D~R~RTPTION: SEQ ID NO:79:
LYB Ser Ly~ Val Gly Trp Leu Ile Phe Ala Phe His LYB LYB

(2) lNr~R~ATION FOR SEQ ID NO:80:
(i) SEQUEN OE CHARACTERISTICS:
(A) LENGTH: 14 amino acid~
(B) TYPE: ino acid (D) TOPOLOGY: linear ( ii ) MnT~CYT~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: mi~c feature (D) OTHER lNr~ATION: "XMP.236"
(ix) FEATURE:
(A) NAME/~EY: Modified-site (B) LOCATION: 5 (C) OTHER lN~OFr~TION: /label= Sub_tituted-Phe /note= "Position 5 i~ para - in~-~ubstituted."
(ix) FEATURE:
(A) NAME/REY: Modifiad-~ite (B) LOCATION: lO
(C) OTHER lNr~k~ATION: /label= Substituted-Ala /note= ~Position 10 is beta-l-naphthyl-substituted."
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: C ,. ; n~l~
(D) OTHER lhrO~ATION: /label~ Amidation /note= "The C . inll~ in Amidated"
(Xi) ~UL_.-~ D~S~TPTION: SEQ ID NO:80:
LYB Ser LYB Val Phe Trp Leu Ile Gln Ala Phe His Ly~ Ly~

(2) INFORMATION FOR SEQ ID NO:81:
( i ) ~UL.._~: CH~RACTERISTICS:
(A) LENGTH: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear CA 02227292 l998-0l-l9 (ii) ~~rTccuTrC TYPE: peptide (ix) E'EATURE:
(A) NA~5E/~Y: mi~c feature (D) OTE~CR INFORMATION: "XMP.237"
(ix) FEATURE:
(A) NAME/KEY: Modified--~ite (B) LOCATION: 10 (C) OTHER lN~O~lATION: /label= Substituted--Ala /note= "Po~ition 10 i~ beta-1-naphthyl-~ubE~tituted. n (ix) FLATURE:
(A) NAME/~~Y: Modified--~ite (B) LOCATION: C .. inn~
(D) OTHER lNruK~ATIoN: /label= Amidation /note= "The C .. i n--n i~ Amidated"
(xi) :ik~UL_--Tc D~C~!RTPTION SEQ ID NO:81:
Ly~ Ser Lyr~ Val Gly Trp Leu Ile Gln Ala Trp Hi~ LyE~ Lys (2) lr.~ .~L~TION FOR SEQ ID NO:82:
(i) SlSQUENOE CHARACTERISTICS:
(A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) M~T~TccuT~F TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: misc_feature (D) OTHER lr~uk~lATION: "XMP.238"
(ix) FEATURE:
(A) NAME/KEY: Modified--~ite (B) LOCATION: 5 (C) OTHER lN~vR~ATION: /lnbel~ Substituted-Phe /note= "Po~ition 5 i~ para inn-sub~tituted."
(ix) FEATURE:
(A) NAME/KEY: Modifi~d--~ite (B) LOCATION: 9 (C) OTHER lN~ATION: /label= SubE~tituted--Phe /note= "Poaition 9 in para in~ ubstituted."
(ix) FEATURE:
(A) NAME/l~EY: Modified--r~ite (B) LOCATION: C i'~ i n-- ~
(D) OTHER INFORMATION: /label= Amidation /note= "The C .. in~ Amidated"
(Xi) :i~;yUL.._I!; DESCRIPTION: SEQ ID NO:82:

Lys Ser Ly~ Val Phe Trp Leu Ile Phe Leu Phe HiQ Ly~ Lyç

(2) lN~u~sATION FOR SEQ ID NO:83:
(i) SEQUEN~ CHARACTERISTICS:
(A) LENGTH: 14 amino acid~

WO 97/04008 PCT~US96/0384S

(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT~T~CuT~T~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: misc_feature (D) OTHER INFORMATION: "XMP.239"
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: 9 (C) OTHER lhrO~ATION: /label= Substituted-Phe /note= ~Po~ition 9 ia para-amino-substituted."
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: C i. i n--~
(D) OTHER lNr~k~ATION: /label= Amidation /note= "The C i. i n-~n is Amidated~
(xi) SEQUEN OE DESCRIPTION: SEQ ID NO:83:
Ly_ Ser Lyn Val Gly Trp Leu Ile Phe Leu Trp Hia Lys Lys (2) lN~Or_~.TION FOR SEQ ID NO:84:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGT~: 14 amino acida (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT-T'CTTT~T~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: misc_feature (D) OTHER lNrOR~ATION: ~XMP.240 (ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: 5 (C) OTHER lNr~.~.TION: /label~ Substituted-Phe /note= "Pouition 5 i~ para-amino-~ub3tituted."
(ix) FEATURE:
(A) NAME/REY: Modified-_ite (B) LOCATION: C i.- i n--a (D) OTHER lNrv~ATION: /label= Amidation /note= ~The C ~, ; n--~ is P ; ~a~
(xi) SEQUEN OE DESCRIPTION: SEQ ID NO:84:
Ly~ Ser Lys Val Phe Trp Leu Ile Gln Leu Trp Hin Ly~ Lys (2) lNrOR~ATION FOR SEQ ID NO:85:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear CA 02227292 l998-0l-l9 W O 97/04008 PCT~US96/03845 ( ii ) 1 r-T~JT-T~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: mi~c feature (D) OTHER IN~Ok~ATION: ~XMP.241"
,.
(ix) FEATURE:
(A) NAME/~EY: Modifi~d-site (B) LOCATION: C-~. ;n--~
(D) OTHER INr-OR~ATION: /label= AmidatLon /note= "The C ~. inn~ is Amidated"
(xi) SEQUENCE n~-~PTPTION: SEQ ID NO:85:
Lyu Ser Ly~ Val Gly Trp Leu Ile Leu Leu Trp Hi~ Lys Ly~

(2) lhrv~TIoN FOR SEQ ID NO:86:
(i) L __ ~ CHARACTERISTICS:
(A) T- _1~: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linQar (ii) - ~C~T~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: mi~c feature (D) OTHER lNrvR~U.TION: "XMP.242"
(ix) FEATURE:
(A) NAME/~EY: Modified-~ite (B) LOCATION: 6 (C) OTHER IN~vRMATIoN: /label= Sub~tituted-Ala /note= "Po~ition 6 is D-beta-2-naphthyl-~ub~tituted. n (ix) FEATURE:
(A) NAME/KEY: Modified-~itQ
(B) LOCATION: C ~ i n-- ~
(D) OTHER ~rv~ATION: /labQl~ Amidation /note= ~The C ~, ~ n--~ i~ Amid~ted~
(xi) Sr.~ur._~ D~RTPTION: SEQ ID NO:86:
Ly~ Ser Lys Val Gly Ala Leu Ile Leu Leu Phe Hi~ Ly~ Ly~

(2) lNru__J~TION FOR SEQ ID NO:87:
(i) SEQUEN OE C~ARArTT~!RTSTICS:
(A) LENGTH: 14 amino aCids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~T-~CvT-~ TYPE: peptide (ix) F~ATURE:
(A) NAME/ ~ Y: mi~c_feature (D) OTHER lNkv~l~ATIoN: "XMP.243"
(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: 6 CA 02227292 l998-0l-l9 W O 97/04008 PCT~US96/0384 (C) OTHER INFORMATION: /label= Sub~tituted-Ala /note= "Poaition 6 i~ D-beta-2-naphthyl-sub~tituted."
(ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: C ~ ; nl- S
(D) OTHER lhru,~ATION: /label= Amidation /note= "The C .~ inllQ in Amidated"
(xi) SEQUENCE D~-C~TPTIoN: SEQ ID NO:87:
Ly~ Scr Lyn Val Gly Ala Leu Ile Gln Leu Trp His Lys Lys (2) lNru~ATION FOR SEQ ID NO:88:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) M~T~cuT~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: mi~c_foature (D) OTHER lNrùRMATION: "XMP.244"
(ix) FEATURE:
(A) NAME/REY: Modified-nite (B) LOCATION: 6 (C) OTHER lNPu.W.TION: /label= Sub~tituted-Ala /note= "Po~ition 6 in D-beta-2-naphthyl-~ubstituted."
(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: C ~. in~q (D) OTHER l~r~nMATION: /label- Amidation /note= "The C I~- ; n--n is Amidated"
(xi) Sr;yur...~E D~Cr~TPTION: SEQ ID NO:88:
LYQ Ser Ly~ Val Gly Ala Leu Ile Leu Leu Trp Hiq Ly~ Ly~
l 5 l0 (2) lNr~n~ATION FOR SEQ ID NO:89:
(i) ~ryuL.._r; CHARACTERISTICS:
(A) LENGTH: 14 amino acid3 (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(A) NAME/REY: miQc_feature (D) OTHER lNru~NATION: "XMP.249 (ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: C .. inll~
(D) OTHER INFORMATION: /label= Amidation /note= "The C-Terminun i~ Amidated"

W O 97/04008 . PCT~US96/03845 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:89:
Ly~ Ser Ly~ Val Gly Gly Leu Ile Gln Leu Phe Hi~ Ly~ Ly~

(2) lNrOk~ATION FOR SEQ ID NO:90:
(i) ~QUr''-~ CHARACTERISTICS:
(A) LENGTH: 14 amino acide (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(A) NAME/REY: minc_feature ~D) OTHER INFORMATION: "XMP.250"
(ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: C- I ~ i n-~ ~
(D) OTHER lNruK~ATION: /label= Amidation /note= "The C 1. inll~ in Amidated~
(xi) SEQUENCE D~RCRTPTION: SEQ ID NO:90:
Lyn Ser Ly~ Val Gly Leu Leu Ile Gln Leu Phe Hi~ Ly~ Ly~

(2) lNr~MATION FOR SEQ ID NO:91:
( i ) ShQUL_._~ CHARACTERISTICS:
(A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptLde (ix) FEATURE:
(A) NAME/REY: minc_feature (D) OT B R lN~O~.TION: "XMP.251"
(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: C .. i nll ~
(D) OTHER l~ruKMaTION: /label= Amidation /note= "The C-T~ i nll~ i8 Amidated"
(xi) SEQUEN OE DFRrRTPTIoN: SEQ ID NO:91:
Ly~ Ser Lyn Val Gly Ile Leu Ile Gln Leu Phe Hi~ Lyn Ly~

(2) INFORMATION FOR SEQ ID NO:92:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MnT~cuT~ TYPE: peptide (ix) FEATURE:

CA 02227292 l998-0l-l9 W O 97/04008 PCTrUS96/03845 (A) NAME/KEY: misc_feature (D) OTHER lN~khATION: "XMP.252"
(ix) FEATURE:
(A) NAME/XEY: Modified-~ite (B) LOCATION: 6 (D) OTHER lh~ Gr-~ATIoN: /label- D-Ala /note= "Po~ition 6 i_ D-Alanin~
(ix) FEATURE:
(A) NAME/REY: Modified-Rite (B) LOCATION: C ~. inlln (D) OTHER INFOR~ATION: /label~ Amidation /not~ The C-T~ i n--~ iR Amidat~d"
(Xi) Sh~Ur..._L DT~'Q~TPTION: SEQ ID NO:92:
Lyn Ser LYR Val Gly Ala Leu Ile Gln Leu Phe Hi_ Lys Ly_ (2) INFORMATION FOR SEQ ID NO:93:
(i) Sh~UL_ - T! CHARACTERISTICS:
(A) LENGTH: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MnT~CUTT~ TYPE: peptide (ix) FEATURE:
(A) NAME/ ~ Y: mi~c_feature (D) OTHER lNr ~ATION: ~XMP.253"
(ix) FEATURE:
(A) NAME/REY: Modified-Rite (B) LOCATION: 6 (D) OTHER INFOR~ATION: /label- D-Val /notQs ~Position 6 iR D-valine~
(ix) FEATURE:
(A) NAME/KEY: Modified-_ite (B) LOCATION: C .. in-3R
(D) OTHER lN~un~ATION: /label= Amidation /note= "The C ~, inl~R i_ P i~ateA"
(Xi) Sh~U~UL D~S~-~TPTION: SEQ ID NO:93:
Lyu Ser Ly~ Val Gly Val Leu Ile Gln Leu Phe Hi~ Ly~ Ly~

(2) lNru~ATION FOR SEQ ID NO:94:
( i ) Sh~U~N~ CHARACTERISTICS:
(A) T _~ 14 amino acidR
(B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MnTT~'CUTT~' TYPE: peptide (ix) FEATURE:
(A) NANE/KEY: mi~c_feature (D) OTHER INFORMATION: "XMP.254"

CA 02227292 l998-0l-l9 WO 97/0~008 PCTrUS96/03845 (ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: 6 (D) Oln~R lh~u~MATION: /label= beta-Ala /note= nPo~ition 6 i8 beta-AlAnin~"
(ix) FEATURE:
(A) NAME/REY: Modified-site (8) LOCATION: C i~ in--~
(D) OTn~R lN~O~ATION: /label= A~idation /note= ~The C ~l- i n~ iU Amidated"
(Xi) Sh~U~ D~c~RTpTIoN: SEQ ID NO:94:
Lyn Ser Ly~ Val Gly Ala Leu Ile Gln Leu Phe Hi~ Ly~ Ly~

(2) Ih~.~.TION FOR SEQ ID NO:95:
(i) SEQUEN OE CHARACTERISTICS:
(A) LENGTH: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) M~T.~CUT.~ TYPE: peptide (ix) FEATURE:
(A) NAME/~EY: mi~c_feature (D) OTHER lN~vn~ATION: "XMP.255"
(ix) FEATURE:
(A) NAME/ ~ Y: Modified-site (B) LO Q TION: 6 (D) OTHER lN~vkMATION: /label= alpha-aba /note= "Po~ition 6 i~ alpha ~ inob~Lylic acid"
(ix) FEATURE:
(A) NAME/~EY: Modified-~ite (B) LOCATION: C-~. inl~
(D) OTHER lN~v.~ATION: /label= Amidation /note= nThe C i~ innn i~ Amidated~
(xi) s~u~.._~ DFc~TpTIoN: SEQ ID NO:95:
Lys Ser Ly~ Val Gly Xaa Leu Ile Gln Leu Phe Hi~ Lys Ly~

(2) INFORMATION FOR SEQ ID NO:96:
( i ) S~ '' Ct7~RA~TFUTSTICS:
(A) LENGT~: 14 amino acidn (B) TYPE: nmino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(A) NA~E/KEY: mi~c_feature (D) OTHER lN~uF~IATION: "XMP.256"
(ix) FEATURE:
(A) NAMoe/KEY: Modified-~ite (B) LOCATION: 6 WO 97/04008 PCT~US96/03845 (D) OTHER INFORMATION: /label~ gaba /note~ "Position 6 is gamma i n~uLy ic acid"
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: C-l. in..g (D) OTHER INFORMATION: /label= Amidation /note= ~The C i. inlln is Amidated"
(xi) ~u~ ~ DESCRIPTION: SEQ ID NO:96:
Lys Ser Ly~ Val Gly Xaa Leu Ile Gln Leu Phe His Ly~ Lyn (2) lhr-O~ATION FOR SEQ ID No:97:
(i) S~U _, - T~ CHARACTERISTICS:
(A) T- _~A: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT~T~CuT~T~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: mi~c_feature ~D) OTHER lNr-O~ ATION: "XMP.257"
(ix) FEATURE:
(A) NAME/XEY: Modified-site (B) LOCATION: 6 (D) OTHER INFORMATION: /label= a-methyl-A
/noto~ "Po~ition 6 in alpha-~ethyl- a l An; n~
(ix) FEATURE:
(A) NAME/XEY: Modified-site (B) LOCATION: C I. inll~
(D) OTHER lN~uh~ATION: /label- Amidation /note- ~The C ~. inllp is ~ ted"
(xi) SEQUENCE DT~C~RTpTIoN: SEQ ID NO:97:
Lys Ser Ly3 Val Gly Ala Leu Ile Gln Leu Phe His Lys Lys (2) lNrohhATIoN FOR SEQ ID NO:98:
(i) s~u~. ~ CAARACTERISTICS:
(A) T- _ LA: 14 amino ~cidu (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: minc feature (D) OTHER INFORMATION: "XMP.258"

(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: 6 (D) OT'AER INFORMATION: /label= t-butyl-G
/note= "Po~ition 6 is tert-butyl-glycine"

CA 02227292 l998-0l-l9 (ix) FEATURE:
(A) NAME/ ~ Y: Modified-site (B) LOCATION: C-T~ i nl- n (D) OTHER l~K~ATION: /label= Amidation /note= ~The C-~.- inl~Q is Amidated~
(xi) -~u~. nFR~RTPTIoN: SEQ ID NO:98:
Lys Ser Lys Val Gly Gly Leu Ile Gln Leu Phe His Lys Lys (2) lhr~L!TION FOR SEQ ID NO:99:
(i) SEQUEN OE CHARACTERISTICS:
(A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MnT-~cuT-~ TYPE: peptide (ix) FEATURE:
(A) NAM~/REY: mi~c feature (D) OTHER INFORMATION: ~XMP.259 (ix) FEATURE:
(A) NAME/ ~ Y: Modified-site (B) LOCATION: 6 (D) OTHER IN~RMATION: /lnbel= N-methyl-G
/note= "Pocition 6 i~ N-~ethyl-glycine~
(ix) FEATURE:
(A) NAME/ ~ Y: ~odified-~ite (B) LOCATION: C - T~ i n-l Q
(D) OTHER lN~OKMATION: /label= Amidation /note= ~The C ~. in~ Amidated"
(xi) SEQUENCE D~SCRTPTION: SEQ ID NO:99:
Lys Ser Lyn Val Gly Gly Leu Ile Gln Leu Phe Hi~ Lys Ly~
l 5 10 (2) IN~K~ATION FOR SEQ ID NO:100:
( i ) ~L~L_. '~ CHARACTERISTICS:
(A) LENGTH: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MnT.~CI~.~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: mi~c feature (D) OTHER lN~ORMATION: "XMP.260 (ix) FEATURE:
(A) NAME/ ~ Y: Modified-~ite (8) LOCATION: 6 (D) OTHER INFORMATION: /label= N-methyl-V
/note= "Position 6 is N-Methyl-valine"
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: C-l. inl~n CA 02227292 l998-0l-l9 (D) OTHER lNI~u~r5P~ION: /label= Amidation /note= "The C-- . inlln i~ Amidated"
(Xi) :j~yUL..-~ DT~SCRTPTION: SEQ ID NO:lOO:
Lys Ser Lyf~ Val Gly Val Leu Ile Gln Leu Phe Hi~ LyEI Ly ~2) lNr uK~SATION FOR SEQ ID NO:101:
(i) S15QUENOE CHaRACTERISTICS:
(A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) M~TT'CUTT~' TYPE: pepti~le ($x) FEATURE:
(A) NAME/ICEY: miE~c_feature (D) OTHER lNr-u~lATION: "~MP.261"
(ix) FEATURE:
(A) NAME/KEY: Modified--nite ~B) LOCATION: 6 (D) OTHER lNrOR~ATION: /label= N--methyl--L
/nOtQ-- "Po~ition 6 in N--Methyl--l~ucine"
($x) FEATURE:
(A) N~ME/l~EY: Modified--~ite (8) LOCATION: C ., in--n (D) OTHER lNrOR~ATION: /label= Amidation /note= "The C--.- inll~ ate~l"
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:101:
Lys Ser Lys Val Gly Leu Leu Ile Gln Leu Phe His Lys Ly~

(2) lNrOR~ATION FOR SEQ ID NO:102:
(i) SEQUENCE CHARACTERISTICS:
(A) T. _~A: 14 amino acids (8) TYPE: amino acid (D) TOPOLOGY: linear (ii) M~T-T'C~JT-~ TYPE: peptide (ix) FEATURE:
(A) NAM~ /REY: misc_feature (D) OTHER lNru~MATION: "X}SP.262"
(ix) FEATURE:
(A) NAME/ICEY: Modified--site (8) LOCATION: C--T~ i n--~
(D) OTHER lNru~ATION: /label= Amidation /note= "The C---~ inll~ is Amidated"

(xi) ~;riyulsN~;~ DESCRIPTION: SEQ ID NO:102:
Ly~ Ser Lys VM1 Gly Trp Leu Ile A~n Leu Phe His Ly~a Lyu (2) INFOR~TION FOR SEQ ID NO:103:

CA 02227292 l998-0l-l9 WO 97/04008 PCT~US96/03845 (i) Sr;yUL.._r; CHARACTERISTICS:
- (A) LENGTH: 14 amino acidq (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MnT~T'C~T-~ TYPE: peptide (Lx) F~ATURE:
(A) NAME/~EY: misc feature (D) OTHER l~rv~ATION: ~XMP.263"
(ix) FEATURE:
(A) NAME/REY: ~;fi~-site (B) LOCATION: C ..- i n-l ~
(D) OTHER INFORMATION: /l~bel~ Amidation /note= "The C-~. ; n~ Amidated~
(xi) ~:r.~Uh~_~ D~-CC~TPTION: SEQ ID NO:lû3:
LYB Ser Lyn Val Gly Trp Leu Ile Glu Leu Phe His LYB Lyn (2) l~rO~L~TION FOR SEQ ID NO:104:
(i) SEQUENCE ~Ra~A~T~TSTIcs (A) T- _~: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~OT.T'~IT.~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "XMP.264"
(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: C i. in--~
(D) OTHER IN~ATION: /label~ Amidation /note= ~The C .. ; n~ Amidated~
(xi) Sh~Uh~_~ D~scRTpTIoN: SEQ ID NO:104:
LYB Ser LYB Val Gly Trp Leu Ile A~p Leu Phe His Lyn LYB

(2) lhru.~ATION FOR SEQ ID NO:105:
(i) s~uh~-r; CHARACTERISTICS:
(A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MOT.T'CUT.~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: misc feature (D) OTHER INFORMATION: "XMP.265 ~.
(ix) FEATURE:
(A) NAME/KEY: Modified-site (8) LOCATION: C-T~ i nu~
(D) OTHER INrOKMATION: /label= Amidation CA 02227292 l998-0l-l9 W O 97/04008 PCT~US96/03845 /note= "The C-T~ inl7n is Amidated"
(xi) ~u~ DESCRIPTION: SEQ ID NO:105:
Lys Ser Ly~ Val Gly Trp Leu Ile Arg Leu Phe Hi~ Lys Lys ( 2 ) lN ~OXMATION FOR SEQ ID NO:106:
(i) SEQUENCE CHARACTERISTICS:
(A) T ~ 14 amino acid~
(B) TYPE: amino acid (D) TOPOLûGY: linear (ii) ~nT~CUT~ TYPE: peptLde (ix) FEATURE:
(A) NAME/ ~ Y: mi~c_feature (D) OTHER lN~uKMATION: "XMP.266"
(ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: C-Te i nll ~
(D) OTHER lN~MATION: /label= Amidation /note= "The C ~. inl~ Amidated"
(xi) SEQUENCE ~-c~RTPTIoN SEQ ID NO:106:
Lys Ser Ly~ Val Lys Val Leu Ile Gln Leu Phe His Lys Lyn l 5 10 (2) INFORMATION FOR SEQ ID NO:107:
(i) SEQUENCE CHARACTERISTICS:
(A) T, _.~: 14 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT~T~CUT ~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: mi~c_feature (D) OTHER lNruKMATION: "XMP.267"
(ix) FEATURE:
(A) NAME/KEY: Modified-site (B) LOCATION: C-T~ 1 nll ~
(D) OTHER lN~Ok~ATION: /label= Amidation /note= "The C--e~ inll~ i~ Amidated"
(xi) S~yU~l._~ DESCRIPTION: SEQ ID NO:107:
Lys Ser Lys Val Lys Trp Ala Ile Gln Leu Phe His Lys Lyn ( 2 ) lN~uKMATION FOR SEQ ID NO:108:

( i ) S~yU~N~ CHARACTERISTICS:
(A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MnT~CT~ ~ TYPE: peptide (Lx) FEATURE 5 (A) NA~E/~EY: minc_feature (D) OTHER INFORMATION: "XMP.268"
(ix) FEATURE:
(A) NANE/~EY: Modified-site (B) LOCATION: C i. inlln (D) OTHER INFORMATION: /label= ~ i~atj~n /note= "The C ,, inl~ in r l~ated"
(xi) ~UL.._ri D~gr~TPTION: SEQ ID NO:108:
Ly~ Ser LyQ Val Gly Val Ala Ile Gln Leu Phe His LYQ LYQ
l 5 lO
(2) INFORNATION FOR SEQ ID NO:lO9:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14 amLno acidn (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~T-T!~lT-T' TYPE: peptide (ix) FEATUR~:
(A) NAME/~EY: mi~c feature (D) OTHER lh ~u~QTION: ~XMP.269"
(ix) FEATURE:
(A) NANE/REY: Modified-_ite (B) LOCATION: C i. inll~
(D) OTHER INFORMATION: /label= Amidation /note= "The C ~. inuQ iQ Amidated"
(xi) ~ur ._~ D~CC~TPTION: SEQ ID NO:lO9:
Ly_ Ser Ly_ Val LyQ Val Ala Ile Gln Leu Phe Hin Lyff LyQ

(2) lNru_~.TION FOR SEQ ID NO:llO:
(i) SEQUEN OE CHARACTERISTICS:
(A) LENGTH: 28 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MnT-~CUT-~ TYPE: peptide (ix) FEATURE:
(A) NANE/KEY: miuc_feature (D) OTHER lNrOk~ATION: "X~P.270"
(ix) FEATURE:
(A) NAME/~EY: Modified-~ite (B) LOCATION: C ~- inl-Q
(D) OTHER lNrO~ATION: /label- Amidation /note= "The C-~. in~Q i~ Amidated"
(xi) ~u~_ri DESCRIPTION: SEQ ID NO:llO:
Ly~ Ser LYQ Val Gly Trp Leu Ile Leu Leu Phe ~iQ LyQ Lys LYQ Ser l 5 lO 15 CA 02227292 l998-0l-l9 W O 97/04008 PCT~US96/03845 Ly~ Val Gly Trp Leu Ile Gln Leu Phe Hi~ Ly~ Ly~

(2) lN~u~ATION POR SEQ ID NO:111:
(i) ~u~NCE CHARACTERISTICS:
(A) LENGTH: 28 umino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT~T~CuT~T~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: mi~c_feature (D) OTHER ll.~ORdATION: "XMP.271"
(ix) FEATURE:
(A) NAME/~ Y: Modified-~ite (B) LOCATION: C-'l~ inlln (D) OTHER lN~OR~ATION: /label= Amidation /note= ~The C ~, i n~ Amidated"
(xi) SEQUENCE DT~-Cr.~TPTION: SEQ ID NO:111:
Lyc Ser Ly~ Val Gly Trp Leu Ile Gln Leu Phe Hi~ Ly~ Ly~ Lyu Ser Ly~ Val Gly Trp Leu Ile Leu Leu Phe Hi~ Ly~ Ly~

(2) lN~O~L~TION FOR SEQ ID NO:112:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 28 amino acidn (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) M~T~T~cuT-T~ TYPE: peptide (ix) PEATURE:
(A) NAME/REY: mi~c_feature (D) OTHER lN~uK~ATION: "XMP.272"
(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: C ~. i n--~
(D) OTHER l~Ok~ATION: /label= Amidation /note= ~The C ~. inu~ i~ Amidated~
(Xi) ~h~U~ DESCRIPTION: SEQ ID NO:112:
Ly~ Ser Ly~ Val Gly Trp Leu Ile Leu Leu Phe Hi~ Ly~ Lys Lyn Ser Ly~ Val Gly Trp Leu Ile Leu Leu Phe Hi~ Ly~ Lyn (2) lN~ATION FOR SEQ ID NO:113:
( i ) ~yUL.. - ~ CHARACTERISTICS:
(A) LENGTH: 28 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT ~CUT-T~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: misc_feature (D) OT~ER INFORMATION: "XMP.273"
(ix) FEATURE:
(A) NAME/REY: Modified-site ~B) LOCATION: C i. 1 n~n (D) OTHER lNr~k~ATION: /label= Amidation /note= "The C ~ ;n~7~ i~ Amidated"

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:113:
Lyn Ser Lys Val Gly Trp Leu Ile Phe Leu Phe His Lys Lys Ly~ Ser Lys Val Gly Trp Leu Ile Gln Leu Phe Hi~ Lys Lyn (2) lN~O~.TION FOR SEQ ID NO:114:
(i) ~UL CE ~UARA~T~T~CTICS:
(A) LENGTH: 28 amino ncid~
(B) TYPE: amino acid (D) TOPOLOGY: linoar ( ii ) ~nT-~C~T-~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: mi~c feature (D) OTHER lNr~K~ATION: "XMP.274"
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: C ~. i n-~
(D) OTHER lr~ ATION: /l~bel~ Amidation /note= ~The C . in-7n in r i~ted"
(xi) SEQUENCE D~C~TPTION: SEQ ID NO:114:
Lys Ser Lys Val Gly Trp Leu Ile Gln Leu Phe His Lyn Ly~ Lys Ser Ly~ Val Gly Trp Leu Ile Phe Leu Phe His Lys Ly~

(2) lNrok~ATIoN FOR SEQ ID NO:115:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 28 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MnT.F~JT.T~' TYPE: peptide (ix) FEATURE:
(A) NAME/REY: mi~c_feature (D) OTHER lN~MaTION: "XMP.275"
(ix) FEATURE:
(A) NAME/REY: Modified-site W O 97/04008 PCTAUS96/038~5 (B) LOCATION: C-T~rr; n (D) OTHER INFORMATION: /label= Amidation /note= "The C . inll~ is Amidated"
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:115:
Ly~ Ser Lyn Val Gly Trp Leu Ile Phe Leu Phe His Ly~ Lyn Lyn Ser Ly~ VA1 Gly Trp Leu Ile Phe Leu Phe Hi~ Ly~ Ly~

(2) lN~ ~.TION FOR SEQ ID NO:116:
(i) ~yuL.~E CHARACTERISTICS:
(A) LENGTH: 14 amino acid~
(B) TYPE: ino acid (D) TOPOLOGY: linear ( ii ) ~T~T~CUT~T~' TYPE: peptide (ix) FEATURE:
(A) NAME/REY: miac feature (D) OTHER lN~OkMATION: "XMP.283"
(ix) FEATURE:
(A) NAME/~EY: Modified-~ite (B) LOCATION: C .~ i nl- R
(D) OTHER lNr~k~ATIoN: /label- Amidation /note= ~The C-T~ i nll~ i8 Amidated~

(xi) ~yu~ nT~'C~TPTION: SEQ ID NO:116:
Ly~ Ser Ly~ Val Lys Phe Leu Ile Ly~ Leu Phe Hi~ Ly~ Ly~

(2) INFORMATION FOR SEQ ID NO:117:
(i) SEQUENCE CHARACTERISTICS:
(A) T- _'~A 13 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "XMP.284 (ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION C--~ inlln (D) OTHER INFORMATION: /label= Amidation /note= "The C i~ i nU~ i~ Amidated"

(xi) ~yuL.._~: D~S~RTPTION: SEQ ID NO:117:
Ser Ly~ Val LYB Trp Leu Ile Gln Leu Phe Hi~ Ly~ Ly~

(2) lNrOk~ATION FOR SEQ ID NO:118:

W O 97/04008 PCT~US96/03845 ( i ) ~15QU~ 1!; ~ARArT~:~ rsTIcs (A) LENGTH: 12 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT-T~'ctlT-T~' TYPE: peptide (ix) FEATURE:
(A) NAME/REY: misc feature (ix) FEATURE:
(A~ NAME/REY: Modified-site (B) LOCATION: C-T~ i n..~
(D) OTHER lNr~K~ATION: /label- P idat~on /note= "The C i. i n--n i~ Amidated~
(D) O-l~R lN~v~ATION: ~XMP.285~

(xi) ~yu~ ~ D~S~RTPTION: SEQ ID NO:118:
Ser Ly~ Val Lys Trp Leu Ile Gln Leu Phe His Ly~

(2) ~ ~.TION FOR SEQ ID NO:ll9:
( i ) ~kUUk.. ~E CHARACTERISTICS:
(A) LENGTH: 12 ~nino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MnT~CVT~T~ TYPE: peptide (ix) FEATURE:
(A) NAME/REr: misc_feature (D) OTHER INFORMATION: "XMP.286"
(ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: C ~. i nl- n (D) OTHER l~.l~.TION: /label= P i~tion /note= "The C . i n--~ is Amidated"
(xi) ~g~ ~ D~-e~RTPTlON: SEQ ID NO:ll9:
Lyn Val Lyn Trp Leu Ile Gln Leu Phe Hi~ Ly~ Ly~
1 5 lO
(2) INFORMATION FOR SEQ ID NO:120:
(i) ~u~ CHARACTERISTICS:
(A) LENGTH: 11 amino acidn (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) M~-~-~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: mi~c_feature (D) OTHER INFORMATION: "X~P.287"
(ix) FEATURE:
(A) NAME/REY: Modified-site (B~ LOCATION: C--T, ; n~
(D) OTHER lN~ laTION: /l_bel= Amidation /note= "The C ~, in~ Amidated"
(xi) SEQUENCE DT~SCRTPTION: SEQ ID NO:120:
Ser Lys Val Ly~ Trp Leu Ile Gln Leu Phe Hi (2) lNrORriATION FOR SEQ ID NO:121:
~gu~ CHARACTERISTICS:
(A) LENGTH: 11 _mino _cidEi (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nl'.T~'CTJT.Ti! TYPE: p~ptid~
(ix) FEATURE:
(A) NAME/REY: mi~c_feature (D) OTHER INFORMATION: "XMP.288"
(ix) FEATURE:
(A) NAME/REY: ~lodified-~ite (B) LOCATION: C 1. in..~
(D) OTH13R lN~ATION: /label= P ;r3at;~n /note= nThe C i. ;n--R in Amidated"
(xi) SEQUEN~ DT~!QCRTPTION: SEQ ID NO:121:
Ly~ Val LyE~ Trp Leu Ile Gln Leu Phe His Ly (2) lNru_~ATION FOR SEQ ID NO:122:
(i) ~urr~u~ CHARACTERISTICS:
(A) LENGTH: 11 amino acid (8) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MnT.~CTIT.T;~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: misc_fe_ture (D) OTHER lNru.~TION: "XMP.289"
(ix) FEATURE:
(A) NAME/REY: Modified--~ite (B) LOCATION: C .. ;nl~n (D) OTHER lNrO~ATION: /label-- Amidation /note= "The C il~ ;n-~ 3 Amidated"
(xi) :jr;S~u~ ri DESCRIPTION: SEQ ID NO:122:
Val LYR Trp Leu Ile Gln Leu Phe Hi~ Ly~ Ly~

(2) ~ OR~SATION FOR SEQ ID NO:123:
(i) ~Ul..._r. CHARACTERISTICS:
(A) T~ 0 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear W O 97/04008 PCT~US96/03845 (ii) MOLECULE TYPE: p~ptide (ix) FEATURE:
(A) NAME/~EY: misc_feature (D) OT~R lNrORMATION: "XMP.290"
(ix) FEATURE:
(A) NAME/REY: Modified-site (8) LOCATION: C i~ inll~
(D) OTHER l~u~oATIoN: /label= Amidation /note= "The C ~. inll~ i~ Amidated"
(xi) ~yu~ ~ DESCRIPTION: SEQ ID NO:123:
Ser Lys Val Lys Trp Leu Ile Gln Leu Phe 1 5 lO
(2) lNrOR~ATION FOR SEQ ID NO:124:
(i) ~u_._~ CHARACTERISTICS:
(A) LENGTH: 10 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linuar ( ii ) ~nr~CuT-F TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: misc feature (D) OTHER ~ ORMATION: ~XMP.291 (ix) FEATURE:
(A) NAME/KEY: Modified-site (B) LOCATION: C .. in--n (D) OTHER INrOk~ATION: /label= Amidation /note= "The C . i n~ Amidated"
(xi) ~yu~N~ D~Cr~TpTIoN: SEQ ID NO:124:
Lyu Val Lys Trp Leu Ile Gln Leu Phe His 1 5 lO
(2) lNru.~TION FOR SEQ ID NO:125:
( i ) ~hyUr,~ CHARACTERISTICS:
(A) LENGTH: 10 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT-~C~T ~ TYPE: peptide (ix) FEATURE:
(A) NAME/ ~ Y: minc feature (D) OTHER lN~-u~MATION: "XMP.292"
(ix) FEATURE:
(A) NAME/ ~ Y: Modified-site (B) LOCATION: C-l. in--~
(D) OTHER lNrOR~ATION: /label= Amidation /note= "The C .. i n-~ Amidated"
(xi) ~yu~N~ DESCRIPTION: SEQ ID NO:125:
Val Lys Trp Leu Ile Gln Leu Phe His Lys CA 02227292 l998-0l-l9 WO 97/04008 PCT~US96/03845 (2) INFORMATION FOR SEQ ID NO:126:
( i ) ~UL.._~ CHARACTERISTICS:
(A) T- _lA: 10 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT.T~crlT~T~! TYPE: pepti~
(ix) FEATURE:
(A) NAME/~EY: misc feature (D) OTAER lNr~.l5ATION: ~XMP.293"
(ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: C l- inllQ
(D) OTHER lhr~R~ATION: /label- Amidation /note= "The C-T~ i n--~ is Amidated~
(xi) S~u~-._r, DT~qCRTPTION: SEQ ID NO:126:
Lys Trp Leu Ile Gln Leu Phe His Ly~ Lys (2) lNr OR~ATION FOR SEQ ID NO:127:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 9 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~T T'C~Tr-T' TYPE: peptide (ix) FEATURE:
(A) NANE/~EY: mi~c_feature (D) O-lA~R lN~ .TION: ~XMP.294 (ix) FEATURE:
(A) NAME/ ~ Y: Modified-site (B) LOCATION: C ~, inllQ
(D) OTHER lNr~.~ATION: /label= Amidation /note= ~The C i. in..Q is P i~ted~
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:127:
Ser Ly_ Val Lys Trp Leu Ile Gln Leu (2) lNrOk~ATION FOR SEQ ID NO:128:
(i) ~u~.. ~ CHARACTERISTICS:
(A) LENGTA: 9 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOT.T~!C~JT.T~. TYPE: peptide (ix) FEATURE:
(A) NAME/REY: mi~c_feature (D) OTA~ER lN~oRMATIoN: "XMP.295~ ,-CA 02227292 l998-0l-l9 (ix) FEA.TURi:
(A) NAME/~EY: Modified-site (B) LOCATION: C I.- in~
(D) OTHLR INFORMATION: /label= Amidation /note= "The C-~. ;n~ Amidated"
(xi) ~uL..~T~ DT~ TPTION: SEQ ID NO:128:
Lys Val Lys Trp Leu Ile Gln LQU Phe (2) l~v~.TION FOR SEQ ID NO:129:
( i ) ~UL_. - T~ CHARACTERISTICS:
(A) LENGTH: 9 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) M~T~T'!CUT~ TYPE: peptide (ix) FEATURE:
(A) NA~E/KEY: minc feature (D) Ol~R INFORMATION: ~XMP.296"
(ix) FEATURL:
(A) NAME/~EY: Modified-nite (B) LOCATION: C ~ in--n (D) u~R ll.~v,~,TION: /label= Amidation /note= ~The C ~ ; n--~ iS Amidated~
(Xi) S~y~_.~T! DT!~r~TPTION: SEQ ID NO:129:
Val Lyu Trp Leu Ile Gln Leu Phe His (2) INFORMATION FOR SEQ ID NO:130:
(i) S~U~N~ CHA~ACTERISTICS:
(A) LENGTH: 9 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MnTTCcuTT~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: mi~c feature (D) OTHER lN~Okr~.~.TION: "XMP.297"
(ix) FLATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: C i-- ; nun (D) OTHER lh~vR~ATION: /label= Amidation /note= "The C 1- ; n--n i~ Amidated"
(Xi) Sh~U~N~ DESCRIPTION: SEQ ID NO:130:

Ly~ Trp Leu Ile Gln Leu Phe His Lys (2) INFORMATION FOR SEQ ID NO:131:
( i ) Sh~U~-._~ CHARACTERISTICS:
(A) LENGTH: 9 amino acid~

(8) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MnT~T~cuT~T~ TYPE: peptide (ix) FEATURE:
(A) NAME/ICEY: miE~c_feature (D) OTHER INFORMATION: "XMP.298"
(ix) FE ATURE:
(A) NAME/~Y: Modified-~ite (B) LOCATION: C--T-? i n~l R
(D) OTHER INFORMATION: /label= Amidation /note= "Th~ C--~ R if Amidat~d"
(xi) ~lu~ DESCRIPTION: SEQ ID NO:131:
Trp Leu Ile Gln Leu Phe His LyE~ Lyn (2) lNruEi~ATION FOR SEQ ID NO:132:
(i) S~u~ CHARACTERISTICS:
(A) LENGTH: 8 nmino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT.T~!c~yT~T~' TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: miElc_feature (D) OTHER INFORMATION: "XMP.299"
(ix) FEATURE:
(A) NAME/KEY: Modified--cite (B) LOCATION: C--T~ inu8 (D) OTHER INFORMATION: /label= Amidation /not~= "The C--l, in~ln i8 ~ iflated"
(xi) ~U~._15 I!T'!cf~T~TpTIoN: SEQ ID NO:132:
Ser Lyf~ Val Ly~s Trp Leu Ile Gln (2) lN~uWATION FOR SEQ ID NO:133:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 8 amino acidn (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) M~T~T~cuT~T~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: miE~c_feature (D) OTHER INFORMATION: "XMP.300"

(ix) FEATURE:
(A) NAME/2~EY: Modified-~ite (B) LOCATION: C--T~ - R
(D) OTHER INFORMATION: /label= Amidation /note= "The C-l. i n~ Amidated"

, -CA 02227292 l998-0l-l9 W O 97/04008 PCT~US96/03845 (xi) ~-~u~. ~ DESCRIPTION: SEQ ID NO:133:
Lys Val Lys Trp Leu Ile Gln Leu (2) lN~ATIoN FOR SEQ ID NO:134:
( i ) ~r ~U~ CHARACTERISTICS:
(A) LENGTH: 8 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear T-~ TYPE: peptide (ix) FEATURE:
(A) NAME/~EY: mi~c_feature (D) OTHER INFORMATION: ~XMP.301 (ix) FEATURE:
(A) NAME/KEY: Modified-site (B) LOCATION: C-~
(D) OTHER lN~K~ATION: /label= Amidation /note= "The C-l. i n~ Amidated~
(xi) SEQUENCE DP!-cr~TpTIoN: SEQ ID NO:134:
Val Lys Trp Leu Ile Gln Leu Phe (2) INFORMATION FOR SEQ ID NO:135:
(i) SEQUEN OE CHARACTERISTICS:
(A) T- _ ~ ~: 8 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MnT~T~cuT~ TYPE: peptide (ix) FEATURE:
(A) NAME/~EY: misc feature (D) OTHER l~OR~ATION: "XMP.302"
(ix) FEATURE:
(A) NAME/~EY: Modified-uite (B) LOCATION: C rl~ i n~n (D) OLn~R l~u.~ATION: /label= Amidation /note= "The C i. imln i~ Amidated"
(xi) S~u~ ~ D~Cr~TpTIoN: SEQ ID NO:135:
Lys Trp Leu Ile Gln Leu Phe Hin (2) lN~Rr~TIoN FOR SEQ ID NO:136:
( i ) ~UL~._~ CHARACTERISTICS:
(A) LENGTH: 8 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE:

W O 97/04008 PCT~US96/03845 (A) NAME/REY: mi~c feature (D) OTHER ~Nr~n~ATION: "XMP.303"
(ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: C 1. i n--n (D) OTHER lNrORdATION: /label= Amidation /note= "The C 1. inlln i~ Amidated"
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:136:
Trp Leu Ile Gln Leu Phe His Ly~

(2) lhrO~L~TION FOR SEQ ID NO:137:
(i) ~ ~ CHARACTERISTICS:
(A) LENGTH: 8 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MnT.~CTJT.~ TYPE: peptide (ix) FEATURE:
(A) NAME/~EY: misc f~ature (D) OTHER lNr~,~YATION: ~XMP.304"
(ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: C 1. in-lP
(D) OTHER lh~OR~ATION: /label= Amidation /note- ~The C i.- i n-~ Amidated"
(xi) ~ur..~~ D~CrRTpTIoN: SEQ ID NO:137:
Leu Ile Gln Leu Phe HiD Lys Ly~

(2) lN~uK~ATIoN FOR SEQ ID NO:138:
(i) &~u~ ~ CHARACTERISTICS:
(A) LENGTH: 7 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT.T'C~TT.~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: miuc_feature (D) OTHER l~r-un~ATION: "XMP 305"
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: C 1. in-ln (D) OTHER INFORMATION: /labels Amidation /note= ~The C ~. in--P in Amidated"

(xi) ~uriN~ri DESCRIPTION: SEQ ID NO:138:
Ser Lys Val Lys Trp Leu Ile (2) lN~oRMATIoN FOR SEQ ID NO:139:

-. ~ CHARACTER~STICS:
~- (A) LENGTH: 7 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ~ ii ) M~T ~CUT-~ TYPE: p~ptide (ix) FEATURE:
(A) NAME/KEY: mi~c_feature (D) OTHER INFORMATION: ~XMP.306"
(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: C-Te ; n~l ~
(D) OTHER lhrvk~ATION: /l~bel- Amida.tion /note= ~The C ~. i n~ Amidated~
(xi) SEQUENCE DT~CCRTPTION: SEQ ID NO:139:
Ly~ Val Ly~ Trp Leu Ile Gln (2) INrO.~ ~TION FOR SEQ ID NO:140:
( i) :ilSy~ rT7~Rl~rl~FRTsTIcs (A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) I ~P~Cu~-~ TYPE: peptide (ix) FEATURE:
(A) NAME/~ Y: misc_feature (D) OTHER INFORMATION: "XNLP.307"
(ix) FEATURE:
(A) NAME/ ~ Y: Modified-~ite (B) LOCATION: C ~ ;n--n (D) OTHER lN~ L~TION: /label= Amidation /note= ~The C ~. in~ P ;~Ated"
(xi) SEQUEN OE DESCRIPTION: SEQ ID NO:140:
Val Ly~ Trp Leu Ile Gln LQU

(2) lNrv~lATION FOR SEQ ID NO:141:
(i) ~u~ ~ CHURACTERISTICS:
(A) LENGTH: 7 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~ ~T~CuT ~ TYPE: peptide (ix) FEATURE:
(A) NAME/ ~ Y: mi~c_feature (D) OTHER INFORHATION: ~XMP.308"
(ix) FEATURE:
(A) NAME/ ~ Y: Modified-~ite (B) LOCATION: C - T~ i nt~ ~
(D) OTHER lN~OkMATION: /label- Amidation CA 02227292 l998-0l-l9 W O 97/04008 PCT~US96/03845 /note= "The C- ~ ~ i nll~ i8 Amidated"
(xi) SEQUENCE DTcS~RTPTION: SEQ ID NO:141:
Ly~ Trp Leu Ile Gln Leu Phe (2) lNru~ATION FOR SEQ ID NO:142:
(i) ~yu~. ~ CHaRACTERISTICS:
(A) LENGTH: 7 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nJ.T~OUT.T~ TYPE: peptide (ix) FEATURE:
(A) NA~E/REY: misc_fQ~ture (D) OTHER INFORMATION: "XMP.309"
(ix) FEATURE:
(A) NAME/KEY: Modified-site (B) LOCATION: C I. inll~
(D) OTHER lN~ukdATIoN: /label= Amidation /note= "The C I~ inllo i~ P i~Ated"
(xi) SEQUEN ~ DTCc~RTpTIoN: SEQ ID NO:142:
Trp Leu Ile Gln Leu Phe Hi~

(2) IN~ukMATION FOR SEQ ID NO:143:
( i ) ~yUL . ~TC CHARACTERISTICS:
(A) LENGTH: 7 amino acid~
(8) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT~T''OUT T~! TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: mi~c feature (D) OTHER lh~OR~ATION: "XMP 310"
(ix) FEATURE:
(A) NAME/KIY: Modified-nite (B) LOCATION: C ~- inlln (D) OTHER INFORMATION: /label= Amidation /note= "The C-T~ i nl~ P i ~ted"
(xi) ~yu~_~ DTCcrRTpTIoN: SEQ ID NO:143:
Leu Ile Gln Leu Phe Hi~ Lyn (2) INFORMATION FOR SEQ ID NO:144:

(i) ~:yu~._~ CHARACTERISTICS:
(A) T. _.~: 7 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~T~FCuT rc TYPE: peptide W O 97/04008 PCT~US96/03845 (ix) FEATURE:
(A) NAME/REY: misc_feature (D) OTA~R lNrORMATION: ~XMP.311"
(ix) FEATURE:
(A) NAME/REY: Nodified-site (B) LOC~TION: C ., in~R
(D) OTHBR l~r~__~.TION: /label- Amidation /note= nThe C .~ in..R is Amidated~
(xi) ~u~_~ D~erRTPTION: SEQ ID NO:144:
Ile Gln Leu Phe His Lys Lys (2) lNr~.~ATION FOR SEQ ID NO:145:
(i) S~uLNCE CHARACTERISTICS:
(A) T- _-A: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT~CuT ~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: misc feature (D) OT~ER l~r~.TION: ~XMP.312 (ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: C ~ ; n--~
(D) OTHER l~r~MATION: /labul ! Amidation /note= ~The C ~ i n--~ is Amidated"
(xi) ~r;yur.~_r; DESCRIPTION: SEQ ID NO:145:
Ser Lys Val Ly~ Trp Leu l 5 (2) lNb~.TION FOR SEQ ID NO:146:
(i) ~r;yur.~_r; CAARACTERISTICS:
(A) LENGTA: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) ~ ~CUT.~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: miRc_feature (D) OTAER INFORMATION: "XMP.313"
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: C-Terminus (D) OTHER lNrORMATION: /label= Amidation /note= ~The C-Te in~lR in Amidated"
(xi) ~yu~CE DESCRIPTION: SEQ ID NO:146:
Lys Val Lys Trp Leu Ile ~ 1 5 CA 02227292 l998-0l-l9 (2) lN~ATION FOR SEQ ID NO:147: .
(i) ~-yl ~ CHARACTERISTICS:
(A) LENGTH: 6 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: lin~ar ~ ii ) Mnr-T'~JT-~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: mi~c_feature (D) OTHER Ihru.llATION: "XMP.314"
(ix) FEATURE:
(A) NANE/KEY: Modified-~ite (B) LOCATION: C-T~ inl~
(D) OTHER INFORMATION: /label= Amidation /note= "The C . inll~ in Amidated"
(xi) SEQUENCE D~C~TPTION: SEQ ID NO:147:
Val Ly~ Trp Leu Ile Gln (2) l~rOR~ATION FOR SEQ ID NO:148:
(i) SEQUEN OE CHARACTERISTICS:
(A) T- _ ~ A 6 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT~T''CyT~T~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: misc_feature (D) OTHER lN~RhATION: ~XMP.315"
(ix) FEATURE:
(A) NAME/~EY: Modified-site (B) LOCATION: C i. inlln (D) OTHER lN~ATION: /label= Amidation /note= "The C I- in-lQ in Amidated"
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:148:
Ly~ Trp Leu Ile Gln Leu (2) lN~kMATION FOR SEQ ID NO:149:
(i) ~y~ CHARACTERISTICS:
(A) T- _ ~: 6 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~T~T~cyT~F TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: mi~c_feature (D) OTHER INFORMATION: "XMP.316"
(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: C ~,~ inUR
- (D) OTHER lNrO~MATION: /label= Amidation /note= "The C-T~ inun i~ Amidated"
(Xi) ~yU~N~ D~RTPTIoN: SEQ ID NO:149:
Trp Leu Ile Gln Leu Phe (2) lN~hATION FOR SEQ ID NO:150:
(i) ~u~_~ CHARACTERISTICS:
(A) LENGTH: 6 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nr-~crTT~T~! TYPE: p~pt;~
(ix) FBATURE:
(A) NAME/KEY: misc feature (D) OTHER lN~O~ATION: ~XMP.317n (ix) FEATURE:
(A) NAME/ ~ Y: Modified-uite (B) LOCATION: C ~e ;nt~t (D) OTHER lN~O~IATION: /label- Amidation /note= ~The C , i~ i8 r i~Ate~"
(xi) ~u~ ~ D~-~CRTPTION: SEQ ID NO:150:
Leu Ile Gln Leu Phe Hi~

(2) l~O~ ~.TION FOR SEQ ID NO:151:
( i ) S~Q~L . CE CHARACTERISTICS:
(A) LENGTH: 6 amino acid~
(B) TYPE: u~ino acid (D) TOPOLOGY: linear ( ii ) ~T~CuT T~ TYPE: p¢ptide (ix) FEATURE:
(A) NAME/REY: mi~c_feature (D) OTHER lN~OR~.TION: "XMP.318"
(ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: C-T~ i n-- R
(D) OTHER INFORMATION: /label- Amidation /note= ~The C-~. i n--n i~ Amidated"
(Xi) ~UL_._~: DESCRIPTION: SEQ ID NO:151:
Ile Gln Leu Phe His Lyn (2) lN~ATION FOR SEQ ID NO:152:
(i) ~D~_~- CHARACTERISTICS:
(A) LENGTH: 6 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MnT.~CuTr2 TYPE: peptide (ix) FEATURE:
(A) NAME/REY: misc_feature (D) OTHER INFORMATION: "XMP.319"
(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: C ~. inl~
(D) OTHER lNrOFrL~TION: /label= Amidation /note= ~The C ~. in~n is Amidated"
(xi) SEQUEN OE Dr2cr-~TpTIoN: SEQ ID NO:152:
Gln Leu Phe His Lys Lys (2) lNruR~ATION FOR SEQ ID NO:153:
( i ) -~h~Uh~Uh CHARACTERISTICS:
(A) LENGTH: 5 amino ~cids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) ~nT-~crJT-~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: misc feAture (D) OTHER INFORMATION: "XMP.320"
(ix) FEATURE:
(A) NAME/XEY: Modified-site (B) LOCATION: C-l~ inll~
(D) OTHER lNru~ATIoN: /label= Amidation /note= "The C ~- inll~ is Amidated"
(xi) ~:yu~ -~P. DFCr~TpTIoN SEQ ID NO:153:
Trp Leu Ile Gln Leu (2) lNru.~l~TION FOR SEQ ID NO:154:
( i ) ~hUU~ ~ CHARACTERISTICS:
(A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) ~nn~CUT.~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: misc_feature (D) OTHER lhru~ATION: "XMP.321"
(ix) FEATURE:
(A) NAME/~EY: Modified-site (8) LOCATION: C-Te in~
(D) OTHER lNruKMATION: /label= Amidation /note= "The C-~ inll~ in Amidated"
(xi) ~-~u~ D~CrRTpTIoN: SEQ ID NO:154:
Trp Leu Ile Gln Leu Lys (2) lNruk~ATION FOR SEQ ID NO:155:
i ) ~UL_._~ CHARACTERISTICS:
(A) LENGTH: 7 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT-TCcuT~T~ TYPE: p8ptide (ix) FEATURE:
(A) NAME/KEY: misc_feature (D) OT B R lN~OR~ATION: "X~P.322"
(ix) FEATURE:
(A) NAME/REY: Modified-nite (B) LOCATION: C i. innn (D) OTHER INFORMATION: /label= Amidation /note= "The C ~, ; n'-n is Amidated"
(Xi) S~UL.._L r~TCS~RTPTION SEQ ID NO:155:
Trp Leu Ile Gln Leu Lyu Lys (2) l~FuR L~TION FOR SEQ ID NO:156:
(i) SEQUEN OE CRAR~T~CTICS
(A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) M~T~TCC~TT ~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: mi~c feature (D) OTHER lh~k~ATION: "XMP.323"
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: C ., ; n-- n (D) OTHER lN~u.l~ATION: /labsl= Amidation /note= "The C . ;nu~ is Amid~ted"
(xi) ~LyuL.~Tc nFS~TPTION: SEQ ID NO:156:
Ly~ Trp Leu Ile Gln Leu Lys (2) lN~u~JATION FOR SEQ ID NO:157:
( i ) ~UUL_._~: CHARACTERISTICS:
(A) LENGTH: 8 Hmino acidn (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~T.~CUT.~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: misc_feature (D) Ol~R lN~un~ATION: "XMP.324"

CA 02227292 l998-0l-l9 W O 97/04008 PCT~US96/03845 (ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: C .. inl,~
(D) OTHER lNrvn~ATION: /label= Amidation /note= "The C ..- inl-R is Amidated"
(xi) ~r;yu~._r; DFCr~TpTIoN SEQ ID NO:157:
Ly~ Trp Leu Ile Gln Leu LYB Lyu (2) lNr~L~TION FOR SEQ ID NO:158:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 7 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linQ~r (li) MnT~C7JT~ TYPE: peptide (ix) FEATURE:
(A) NAME/~EY: mi~c_feature (D) OTHER INFORMATION: "XMP.325"
(ix) FEATURE:
(A) NAME/~EY: Modified-~ite (B) LOCATION: C i. inl~
(D) OTHER lN~O~L~TION: /label= Amidation /note= "The C .. i n--R i~ Amidated"
(xi) ~u~.~~ D~QrRTPTIoN: SEQ ID NO:158:
Ly~ LYL7 Trp Leu Ile Gln Leu (2) lNrO~ATION FOR SEQ ID NO:159:
(i) SEQUENCE CHaRACTERISTICS:
(A) LENGTH: 8 amino acids (B) TYPE: ~mino acid (D) TOPOLOGY: linear (ii) ~nTP~cuT~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: mi~c feature (D) OTHER INFORMATION: "XMP.326"
(ix) FEATURE:
(A) NAME/KEY: Modified-site (B) LOCATION: C-,~ in77B
(D) OTHER INFORMATION: /label= Amidation /note= "The C .. 1nllR in P i~7-~te~"
(xi) ~U~N~r; DESCRIPTION: SEQ ID NO:159:

Ly~ Ly~ Trp Leu Ile Gln Leu Ly~

(2) lNrOk~ATION FOR SEQ ID NO:160:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 9 amino acid~

(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) YnT.FCrJT.F TYPE: peptide ,, (ix) FEATURE:
(A) NAME/KEY: misc feature (D) OTAER lNr-OE~rlATION: "XMP.327"
(ix) FEATURE:
(A) NAME/~Y: ~Sodified--~ite (B) LOCATION: C--.. in~
(D) OTAER INFORUATION: /label= Amidation /noteS nThe C i. in~ln in ~ t~"
(Xi) S~ J . nFC~RTPTION SEQ ID NO:160:
Lys Ly~ Trp Leu Ile Gln Leu Ly~i Lyq (2) lh~OE~MATION FOR SEQ ID NO:161:
c, CAARACTERISTICS:
(A) T- _.A: 4 amino acid (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) YnT.~lT,F TYPE: p~ptide (ix) FBATIJRE:
(A) NAME/~15Y: mi~c feature (D) OTAER INrOR~ATION: "XMP.330"
(ix) FEAT~JRE:
(A) NAME/ICEY: Modified--3ite (B) LOCATION: C-- . inl-n (D) OTAER lNru.~t.TION: /label= P i~la~inn /note-- "The C ~, i n--~ i~ Amidated"
(xi) ~ D~S~RTPTION: SEQ ID NO:161:
Trp Leu Ile Gln (2) INFORMATION FOR SEQ ID NO:162:
r;yu _._r. cAaRAcTERIsTIcs:
(A) T- _.A: 9 amino acid (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~r ~CuT T~! TYPE: peptide (ix) FEATURE:
(A) NAME/}CEY: mi~c feature (D) OlA~iR lNr-O~SATION: "XMP.331"
(ix) FEATVRE:
(A) NAME~lCEY: Modified--~ite (B) LOCATION:
(D) OTAER INFORMATION: /label= Acetylated /note= "Po~ition 1 i~ acetylated"

(ix) FEATURE:
~A) NAME/REY: Modified--E~ite (B) LOCATION: C I~- ; n~
(D) OTHER INFORMATION: /label= Amidation /note= "The C ~, 1n~ln i~ Amidated"
(xi) ~gu --T' DESCRIPTION: SEQ ID NO:162:
LYR Ly_ Trp Leu Ile Gln Leu LYB Ly~

(2) lN~ O~L~TION FOR SEQ ID NO:163:
(i) SlSQUENOE CHARACTERISTICS:
(A) LENGTH: 9 amino acid (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MnT-T2CTrr.T~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "XMP.332"
(ix) FEATURL:
(A) NAME/KEY: Modified--~ite (B) LOCATION: 1--9 (D) OTHER lN~RIL~TION: /label~ D ~ ino Acid~
/note= "Pol~ition~ 1--9are D . ; no acid~"
(ix) FEATURE:
(A) NAME/~EY: Modified--site (B) LOCATION: C 1~ inlln (D) OTHER lr~O~lATION: /label= Amidation /note= "The C ~ i n--~ iB Amidated"
(Xi) :j~UL.._15 DESCRIPTION: SEQ ID NO:163:
Ly~ LyE~ Leu Gln Ile Leu Trp Ly~ Ly~

(2) lNrOR~ATION FOR SEQ ID NO:164:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 9 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MnT.T2cuT.T2 TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: milsc_fenture (D) OTHER INFORMATION: "XMP.333"
(ix) FEATURE:
(A) NAME/KEY: Modified--~ite (B) LOCATION:
(D) OTHER lN~krSATION: /label= D--Ly~
/note= "Position 1 iB D-lyE~ine"
(ix) PE ATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: C--Te in--R

(D) OTHER lN~ TION: /label~ Amidation ~ /note= ~The C ~. inl7n i~ Amidated~
(xi) ~ur.~_r,- D~-CrRTPTION: SEQ ID NO:164:
Lys Ly~ Trp Leu Ile Gln Leu Lys Lyn (2) lNrOkdATION FOR SEQ ID NO:165:
(i) SEQUENCE CHARACTERISTICS:
(A) T- _ ~: 9 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) YnT-~ T-T! TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: mi3c_feature (D) OTHER lNrukMATION: "X~P.334"
(ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: 1 (D) OTHER I~rO~SATION: /label- D-Pro /note= "Po~ition 1 i~ D-proline"
(ix) FEATURE:
(A) NAME/~EY: ModLfied-site (B) LOCATION: C ~. ;nll~
(D) OTHER lN~OkhATION: /label= Amidation /note= "The C .. in~ Amidated"
(xi) s~uh~-r; D~c~RTpTIoN: SEQ ID NO:165:
Pro Ly~ Trp Leu Ile Gln Leu Lys LYB

(2) lN~ORdATION FOR SEQ ID NO:166:
(i) ~u-.~~ CHARACTERISTICS:
(A) LENGTH: 9 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: mi~c feature (D) OTHER INFORMATION: "XMP.335"
(ix) FEATURE:
(A) NAME/ ~ Y: Modified-~ite (B) LOCATION: C ~el i n~n (D) OTHER INFORMATION: /labels Amidation /note= "The C ~ inun in Amidated"

(xi) sh~u~N~ri DESCRIPTION: SEQ ID NO:166:
Pro Ly~ Trp Leu Ile Gln Leu Ly~ Ly~

(2) INFORMATION FOR SEQ ID NO:167:

r;yuL~ ; CHARACTERISTICS:
(A) LENGTH: 9 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: lincar ( ii ) ~T T~ Cr~T~: TYPE: peptide (ix) PEATURE:
(A) NAME/REY: misc_feature (D) OTHER lNrOE~lATION: "XMP.336"
(ix) FEATURE:
(A) NAME/KEY: Modified--~ite (B) LOCATION: C ~. inl~
(D) OTHER lN~ ATIoN: /label= Amidation /note= "The C i- inl~n i~ Amidated"
(Xi) ~-,,ZUk.._~; DESCRIPTION: SEQ ID NO:167:
Arg Arg Trp LQU Ile Gln Leu Arg Arg (2) lN~u.~.TION FOR SEQ ID NO:168:
(i) SEQVENCE CHARACTERISTICS:
(A) LENGTH: 9 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( 1i ) ~OT~T~CrTT.~ TYPE: peptide (ix) EEATURE:
(A) NAME/REY: mi~c_feature (D) OTHER lhru~ATIoN: "XMP.337"
(ix) FEATURE:
(A) NAME/REY: Modified--uite (B) LOCATION: C .. i n~l~
(D) OTHER INFORMATION: /l~bel= Amidation /note= "The C 1. i n--~ is Amidated"
(xi) .~;r~u~ DT~!g~'PTPTION: SEQ ID NO:168:
Hi~ Hin Trp Leu Ile Gln Leu His His ( 2 ) lNl~ Ok~ATION FOR SEQ ID NO:169:
(i) SEQUENOE CHARACTERISTICS:
(A) LENGTH: 9 amino acidn (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(A) NANE/REY: minc_feature (D) OTHER INFORMATION: "XMP.338"
(ix) FEATURE:
(A) NAME/REY: Modified--~ite (8) LOCATION: 1, 2, 8 & 9 (D) OTBR INFORMATION: /label= Orn , CA 02227292 l998-0l-l9 WO 97/04008 PCT~US96/03845 /note= "Po~ition~ 1, 2, 8 & 9 are Ornithine"
(ix) FEATURE:
(A) NAME/~EY: Modified-site (B) LOCATION: C ~. i nnn (D) OTHER lN~.TION: /label= Amidation /note= ~The C .. ;n~ Amidated~
(xi) SEQUEN OE Drc-c~RTpTIoN: SEQ ID NO:169:
Xaa Xaa Trp Leu Ile Gln Leu Xaa Xaa (2) lN~u.JLATION FOR SEQ ID NO:170:
( i ) S~QUL.~_~ CHARACTERISTICS:
(A) LENGTH: 9 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) M~T-TC~TT-T' TYPE: peptide (ix) FEATURE:
(A) NAME/ ~ Y: mi~c_feature (D) OTHLR INFORMATION: "XMP.339"
(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: 1, 2, 8 & 9 (D) OTHER ~N~o~ATIoN: /label= Dbu /note= "Po~ition~ 1, 2, 8 & 9 are Di~ uLy ic acid"
(ix) FEATURE:
(A) NAME/~ Y: Modified-~ite (B) LOCATION: C-T~ inl~
(D) OTHER lN~n~ATION: /l~bel= Amidation /note= "The C ., i nlln iB Amidated"
(Xi) ~U~NU~: DT~Cr~TpTIoN SEQ ID NO:170:
Xaa Xaa Trp Leu Ile Gln Leu Xaa Xaa (2) IN~R~ATION FOR SEQ ID NO:171:
( i ) ~yU~hu~ CHARACTERISTICS:
(A) LENGTH: 9 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MnT.T~CUT.T~ TYPE: peptide (ix) FEATURE:
(A) NAME/~LY: mi~c_feature - (D) OTHER lN~-OR~ATION: "XMP.340"

(ix) FEATURE:
(A) NAME/KEY: Modified-nite (B) LOCATION: 1, 2, 8 & 9 (C) Ol~n~R lN~Ok~ATION: /label= Sub~tituted-Phe /note= "Po~ition~ 1, 2, 8 & 9 are para-amino-nubntituted."
(ix) FEATURE:

CA 02227292 l998-0l-l9 W O 97/04008 PCT~US96/03845 (A) NAME/~EY: Modified-site (B) LOCATION: C-T~r~i n--n (D) OTHER lN~OR~ATION: /label= Amidation /note= "The C ~,- i n--n is Amidated"
(xi) SEQUENCE DTCcr~TpTIoN SEQ ID NO:171:
Phe Phe Trp Leu Ile Gln Leu Phe Phe (2) lNrORMATION FOR SEQ ID NO:172:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 9 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) Mnr~CUT-~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: misc_feature (D) OTHER lN~u~ TION: "xMp~34l"
(ix) FEATURE:
(A) NAME/~EY: Modified-~ite (B) LOCATION: l, 2, 8 & 9 (C) OTHER l~r~.~L~TION: /label= Substituted-Ala /note= "The al~nin~ at positions 1, 2, 8 & 9 i8 pyridyl-substituted."
(ix) FEATURE:
(A) NAME/~EY: Modified-site (B) LOCATION: C ~. i n--~
(D) OTHER lN~ATION: /label= Amidation /note= "The C ., i n--~ is Amidated"
(xi) SEQUENCE DT~'.SrRTPTION: SEQ ID NO:172:
Ala Ala Trp Leu Ile Gln LQU Ala Ala (2) lN~ YATION FOR SEQ ID NO:173:
( i ) ~Uk~ CHARACTERISTICS:
(A) T- _ ~: 9 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT~CuT~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: misc_feature (D) OTHER lN~vKMATION: "XMP.342"
(ix) FEATURE:
(A) NAME/~EY: Modified-site (B) LOCATION: 1, 2, 8 & 9 (D) OTHER lN~vKhATION: /label= D-Lyn /note= "Ponitions l, 2, 8 & 9 are D-ly~ine"
(ix) FEATURE:
(A) NAME/KEY: Modified-nite (B) LOCATION: C .- inu~

CA 02227292 l998-0l-l9 (D) OTAER lNrO~hATION: /label= Amidation - /note= "The C i. lnl~n i~ Amidated"
(xi) s~uL.CE DESCRIPTION: SEQ ID NO:173:
Ly~ Ly~ Trp Leu Ile Gln Leu Lys Lys (2) INFORMATION FOR SEQ ID NO:174:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTA~: 9 amino acidu (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MnT-T"CTTT~T~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: mi~c_fQature (D) OTHER INFORMATION: "XMP.343"
(ix) F~ATURE:
(A) NAME/R~Y: Modified-3ite (B) LOCATION: C l- ;n--~
(D) O~Ar;R lN~u_~ATION: /label= Amidation /note= "The C ~ ;n--~ iB ~ i~at~"
(xi) ~QDL.._r; DFSC~TPTION: SEQ ID NO:174:
Ly~ LYB Val Leu Ile Gln Leu Ly~ Lyn (2) INFORMATION FOR SEQ ID NO:175:
(i) SEQUENCE CAARACTERISTICS:
(A) T- _.A: 9 ~mino acids (B) TYPE: ~mino ac~d (D) TOPOLOGY: linear (ii) MOTTtCUTT~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: mi~c_f~ature (D) OTHER INFORMATION: "XMP.344"
(ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: C i. in--~
(D) OTAER lNru~l*ATIoN: /label= Amidation /note= "T~e C l~ ; n--n i~ Amidated"
(xi) s~ur..._~- DT~CrRTpTIoN: SEQ ID NO:175:
Ly~ Ly~ Trp Ala Ile Gln Leu Ly~ Ly~

(2) INFOR~ATION FOR SEQ ID NO:176:
(i) sr;Uu~-._r; CHARACTERISTICS:
(A) LENGTH: 9 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT~T''CuT~ TYPE: peptide r (ix) FEATURE:
(A) NAME/REY: misc_feature (D) OTBR lNrORr~ATION: "XMP.345"
(ix) FEATURE:
(A) NAME/REY: Modified--site ~B) LOCATION: C .~ i n--n (D) OTHER INFORMATION: /label= Amidation /note= "The C i. i n--~ is Amidated"
(xi) ~ur;NCE DT~'CrRTPTION: SEQ ID NO:176:
Lyn Lyn Trp Leu Ile Gln Ala Ly~ Ly~

(2) lr~r~J ~ATION FOR SEQ ID NO:177:
(i) ~r;yurr._r; CHARACTERISTICS:
(A) LENGTH: 9 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MnT~TeCUT~T~' TYPE: p~ptide (ix) Fl~ATURE:
(A) NAME/I~EY: miE~c_feature (D) OTHER lr~ruknATIoN: "XMP.346"
(ix) FEATURE:
(A) NAME/REY: Modified--site (8) LOCATION: 3 (C) OTHER lNr~l~ATION: /label= Subutituted--Phe /note= "The phenyl~l ~n i n~ at po~ition 3 i~
~, , in~--gubstituted."
(ix) FEATURE:
(A) NAME/REY: Modified--~ite (B) LOCATION: C i. in--n (D) OTHER lrr~rSATION: /label= Amid~tion /note-- "The C ~, i n--~ i~ Amidated"
(xi) ~r~uL~-ri DF~C~TPTION: SEQ ID NO:177:
Lys Lys Phe Leu Ile Gln Leu Lyn Lyn (2) 1rirOR~5ATION FOR SEQ ID NO:178:
( i ) ~h~UI -._r; CHARACTERISTICS:
(A) LENGTH: 9 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOTT'CrTTT~' TYPE: peptide (ix) FEATURE:
(A) NAME/REY: miE~c_feature (D) OT~;R INFORMATION: "XMP.347"
(ix) FEATURE:
(A) NAME/REY: Modified-~ite CA 02227292 l998-0l-l9 (B) LOCATION: 3 (c) OTHER INFORMATION: /label= Sub~tituted-Ala /note= "Po~ition 3 i~ D-beta-2-naphthyl-sub~tituted."
(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: c ~. i n--~
(D) OTHER l~r~n~ATION: /label- Amidation /note= "The C .l inl.R i~ Amidated~
(xi) SEQUENCE DT~erRTPTIoN: SEQ ID NO:178:
LYB LY~ Ala Leu Ile Leu Leu Lyn Ly~

(2) lN~ ATIoN FOR SEQ ID NO:179:
( i ) ~UL_. -T' CHARACTERISTICS:
(A) LENGTH: 10 amino acidn (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) I .F~JT.F TYPE: peptide (ix) FEATURE:
(A) NAME/~EY: mi~c feature (D) OTHER lN ~_~,TION: ~XMP.348 (ix) FEATURE:
(A) NAME/~EY: Modified-~ite (B) LOCATION: C ~ ; n--~
(D) OTHER l~ORhATION: /la~els Amidation /note= "The C-.-~ inuR i~ Amidated"
(xi) ~:yu~ DF-e~TPTION: SEQ ID NO:179:
LY~ Lyff Ly~ Trp Leu Ile Gln Leu Lya Ly~
1 5 lO
(2) lNruR~ATION FOR SEQ ID NO:180:
( i ) -~UL_. ~E CHARACTERISTICS:
(A) LENGTH: 10 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MnT.FCUT.T~' TYPE: peptide (ix) FEATURE:
(A) NA~E/~EY: mi_c_feature (D) OTHER l~-~K~ATION: "XMP.349"
(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: C-T~ i n~ ~
(D) OTHER l~ORdATION: /l~bel= Amidation /note= "The C-Te inuR iR Amidated~
(xi) ~U~.~L DESCRIPTION: SEQ ID NO:180:
Ly~ Ly~ Trp Leu Ile Gln Leu Ly~ Ly~ LYR

(2) INFORMATION FOR SEQ ID NO:181:
(i) ~u~-.'~ OE PRACTERISTICS:
(A) LENGTH: 11 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) M~T-T~CUT~ TYPE: peptide (ix) FEATURE:
(A) NAME/ ~ Y: minc fQatur~
(D) OTHER INFORMATION: "XMP.350"
(ix) FEATURE:
(A) NAME/XEY: Modified-site (8) LOCATION: C-Te in..n (D) OT B R INFORMATION: /label= Amidation /note= "The C-T~ in~q iq Amidated"
(xi) ~yuL.~T~' DT~'S~RTPTION: SEQ ID NO:181:
Lys Lyu Ly~ Trp Leu Ile Gln Leu Ly~ Ly~ Ly~

(2) lNru ~.TION FOR SEQ ID NO:182:
(i) SEQUENCE CHARACTERISTICSs (A) T, _~: 10 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MnT~T'!~UT~T'! TYPE: peptide (ix) FEATURE:
(A) NAME/ ~ Y: misc_feature (D) OTHER INFORMATION: "XMP.351"
(ix) FEATURE:
(A) NAME/XEY: Modified-nite (B) LOCATION: C ~, inl~n (D) OT B R lN~vk~ATIoN: /label= ~ i~ati~
/note= "The C ~. in~ln i~ Amidated"
(xi) ~u~ DP'SrRTPTION: SEQ ID NO:182:
Lyu Lyn Trp Leu Ile Gln Leu Phe Lys Lys (2) INFORMATION FOR SEQ ID NO:183:
( i) ~!iyU~ rARA~T~RTsTIcs (A) LENGTH: 11 amino acidu (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT ~CUT~ TYPE: peptide (ix) FEATURE:
(A) NAMEtREY: misc feature (D) OTHER INFORMATION: "XMP.352"
(ix) FEATURE:
(A) NAME/REY: Modified-uite W ~ 97/04008 PCTAJS96/03845 (B) LOCATION: c ~
(D) OTHER lN~nMATION: /label= Amidation /note= "The C-.~ i nun i~ Amidated"
( Xi ) SLyUL.. _~ DESCRIPTION: SEQ ID NO:183:
Lyn Lys Trp Leu Ile Gln Leu Phe Hi~ Lyn Ly~

(2) lN~_~IATION FOR SEQ ID NO:184:
( i ) Sh~U~ r, CHARACTERISTICS:
(A) LENGTH: 10 nmino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear (ii) ~ ~~CU~-~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: mi~c_feature (D) OTHER lN~ ATION: "XMP.353"
(xi) SEQUENCE D~cr~TpTIoN: SEQ ID NO:184:
Pro Trp Leu Ile Gln Leu Phe Hi~ Ly~ Ly~

( 2 ) lNr O~.TION FOR SEQ ID NO:185:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 10 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: line~r (ii) M~T-~CUT~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: misc_feature (D) OTHER lNr~ATION: "XMP.354"
(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: 1 (D) OTHER l~h~ATION: /label= Acetylated /note= "Po~ition 1 i~ acetylated"
(xi) ~yuL,.CE D~s~RTpTIoN: SEQ ID NO:185:
Pro Trp Leu Ile Gln Leu Phe Hi~ Ly~ Ly~

(2) lNr~fiMATION FOR SEQ ID NO:186:
;yUL . 'l;! ~ARAr~?TSTICS:
~ (A) T. ~ 0 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: line~r (ii) MnT~CUT~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: mi~c_feature (D) OTHER lN~uR~ATION: "XMP,355"

(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: C ..- in~Q
(D) OTHER lNrOR~ATION: /label= Amidation /note= "The C i. in~ln in Amidated"
(xi) ~uL..~E DT~eC~TPTION: SEQ ID NO:186:
Pro Trp Leu Ile Gln Leu Phe His LYB LYB

(2) l~h~ATION FOR SEQ ID NO:187:
(i) ~ur.._~ CHARACTERISTICS:
(A) LENGTH: 10 amino acids (B) TYPE: amino ac~d (D) TOPOLOGY: linear ( ii ) ~nT~T''CuT~T~' TYPE: peptide (ix) FEATURE:
(A) NAME/REY: miuc_feature (D) OTHER lNrORMATION: "XMP.356"
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: 1 (D) O~R lNr~_~ATION: /label~ Ac~tylated /note- "Po~ition 1 i~ acetylated"
(ix) FEATURE:
(A) NAME/ ~ Y: Modified-~ite (B) LOCATION: C ~. inll~
(D) OTHER INFORMATION: /label= Amidation /note= "The C . inlln is Amidated"
(xi) ~ DT~'eruTPTIoN: SEQ ID NO:187:
Pro Trp Leu Ile Gln Leu Phe Hin Ly~ LYB

(2) lNrOR~ATION FOR SEQ ID NO:188:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: lO amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~T.T'CUT.T' TYPE: peptide (ix) FEATURE:
(A) NAME/REY: misc_feature (D) OTHER lNru~MATION: "XMP.357"
(ix) FEATURE:
(A) NAME/KEY: Modified-Rite (B) LOCATION: C-T~ i nl~ ~
(D) OTHER INFORMATION: /label= Amidation /note= "The C ~, inlln is Amidated~
(xi) SEQUENCE DT~S~TPTION: SEQ ID NO:188:
LYB Trp Leu Ile Gln Leu Phe His LYB Pro W O 97/04008 PCTrUS96/03845 1 5 lO
(2) ~ TION FOR S~Q ID NO:189:
(i) ~u~ . ~ CHARACTERISTICS:
(A) LENGTH: 11 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT-TrCYT~ TYPE: peptide (ix) F~ATURE:
(A) NAME/ ~ Y: mi~c_feature (D) OTHER lN~ok~ATIoN: ~XMP.358 (ix) FEATTJRE:
(A) NAME/ ~ Y: Modified-~ite (B) LO Q TION: C ~, inl~
(D) OTHER INFOR~ATION: /label= Amidation /note= ~The C-~. inl-n i~ ated~
(xi) 9~UL.._~ DT2~rRTPTION: SEQ ID NO:189:
Ly~ Ly~ Trp Leu Ile Gln Lcu Phe His Lys Pro 1 5 lO
(2) lN~ TION FOR SEQ ID NO:19O:
(i) SEQUEN OE CHARACTERISTICS:
(A) LENGTH: 10 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MQT-~UT-F TYPE: peptide (ix) FEATURE:
(A) NAME/ ~ Y: minc_fenture (D) OTHER lhroR~ATIoN: ~XMP.359"
(ix) FEATTJRE:
(A) NAME/ ~ Y: Modifi~d-sitQ
(B) LOCATION: 1 (C) OTHER INFORMATION: /label~ D-Cys /note= ~Position 1 is D-cysteine.
(ix) FEATURE:
(A) NAME/KEY: Modified-site (B) LOCATION: C 1~ in--o (D) OTHER INFORMATION: /label= F i~-tio~
/note= "The C i'~ i n--~ in Amidated~
(xi) ~u~_E D~S~RTPTION: SEQ ID NO:19O:
Cys Trp Leu Ile Gln Leu Phe His Lys Lys - 1 5 lû

(2) lN~ORdATION FOR SEQ ID NO:191:
(i) SEQUEN OE CHARACTERISTICS:
(A) T~ : 9 amino acids (B) TYPE: amino acid (D) TOPOLOGY: circular WO 97/04008 PCTtUS96tO384 ( ii ) ~T.TccuT~Tc TYPE: pept~de (ix) FEATURE:
(A) NAME/REY: mi~c_feature (D) OTHER lNruR~ATION: "XMP.360"
(ix) FEATURE:
(A) NAME/RLY: Modified--~ite (B) LOCATION: 1 & 9 (C) OTHER INFORMATION: /label= D-Ly~
/note= "Positions 1 & 9 are D--lysine."
(ix) FEATURE:
(A) NAME/REY: ModLfied--~ite (B) LOCATION: 2 (C) OTHER IN~vE~ilATION: /label= D--Cys /note= "Po~ition 2 i~ D--cy~teine."
(ix) FEATURE:
(A) NAME/KEY: Modified--~ite (B) LOCATION: C ., in~
(D) OTHER lNr~ATION: tlabel= Amidation /note~ "The C . i n--~ in P i~1~t (xi) :~yu~ DT~grT~TPTION: SEQ ID NO:l91:
Ly~ Cy~ Leu Ile Gln Leu Phe Cys Lys (2) lNrOkhATION FOR SEQ ID NO:192:
(i) :i~yu~.._~ CHARACTERISTICS:
(A) LENGTH: 9 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: circular ( ii ) ~lT T~CUT-T~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: misc_feature (D) OTHER lNrv.~ATION: "XMP.361"
(ix) FEATURE:
(A) NAME/REY: Modified--~ite (B) LOCATION: 1 & 9 (C) OTHER lNr~ 5ATION: /label~ D--Lyn /note= "PoE~itionff 1 & 9 are D--lyE~ine."
(ix) FEATURE:
(A) NAME/KEY: Modified--~ite (B) LOCATION: C--T-~ i nl~n (D) OTHER lNruE~SATION: /label= Amidation /note= "The C i. i n~ Amidated"
(Xi) ~yUL.._~'; D~gr~TPTION: SEQ ID NO:192:

Ly~ Cy~ Leu Ile Gln Leu Phe Cy~ Ly~

(2) lNrv~ATION FOR SEQ ID NO:193:
(i) silsyu~r~:r; CHARACTERISTICS:
(A) LENGTH: 11 amino acidf~

-(B) TYPE: amino acLd ~ (D) TOPOLOGY: circular ( ii ) ~nT~T~!CU~-~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: misc_feature (D) OTHER lN~ ATION: "XMP.362"
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: 1 & 11 (C) OTHER lN~Oh~ATION: /label= D-LyA
/note= "Positions 1 & 11 are D-lysine."
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: C ._ in.ln (D) OTHER INFORMATION: /label= Amidation /note= "The C 1~ in~A iA A~idated"
(Xi) ~UL.._~ DESCRIPTION: SEQ ID NO:193:
Lys Lys Cys Leu le Gln Leu Phe Cys Lys Lys (2) lr~rO~TION FOR SEQ ID NO:194:
(i) SEQUENCE rT~ARArT~T~TSTICS:
(A) L~NGTH: 10 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~T-T!C~TT~T TYPE: peptide (ix) FEATURE:
(A) NAME/REY: misc feature (D) OTHER lNr~.W.TION: "XMP.363"
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: 1, 9 & 10 (C) OTHER lN~.~ATION: /label~ D-Lys /notes "Positions 1, 9 & 10 are D-lysine."
(ix) FEATURE:
(A) NAME/~EY: Modified-site (B) LOCATION: 2 (C) OTHER INFORMATION: /label= D-Trp /notes "Position 2 is D-tryptophan."
(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: C-l. in--~
- (D) OTHER INFORMATION: /label= Amidation /note= "The C i~ inl-n is Amidated"
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:194:
Lys Trp Leu Ile Gln Leu Phe Hiu Lys Lys (2) INFORMATION FOR SEQ ID NO:195:

CA 02227292 l998-0l-l9 (i) SEQUENCE CHARACTER}STICS:
(A) LENGTH: lO amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~T.T~CI~T.T~' TYPE: peptide (ix) FEATURE:
(A) NAME/REY: mi~c_feature (D) OTHER lN~uRrL~TION: "XMP.364"
(ix) FEATURE:
(A) NAME/KEY: Modified-site (B) LOCATION: 1 (D) OTHER lN~u~ATION: /label= Acetylated /note= "Ponition l i~ acetylAted"
(ix) FEATURE:
(A) NAME/~EY: Modified-~ite (B) LOCATION: l, 9 & lO
(C) OTHER INFORMATION: /label= D-Lys /note= "Positions l, 9 h lO are D-lysine."
(ix) FEATURE:
(A) NAME/KEY: Modified-site (B) LOCATION: 2 (C) OTHER lN~ u_l{ATION: /label= D-Trp /note= ~Position 2 is D-tryptophan."
(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: C .. ;n.l~
(D) OTHER lNru_l~ATION: /label= Amidation /note= "The C ., inll~ is P i~-te~"
xi) ~L~u~ T~ DT~Cr~TpTIoN: SEQ ID NO:195:
Lys Trp Leu Ile Gln Leu Phe His Ly~ Lys l 5 lO
(2) lNr~ATION FOR SEQ ID NO:196:
(i) ~uL.CE CHARACTERISTICS:
(A) T- ~ 0 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) M~T T'CUT-T' TYPE: peptide (ix) FEATURE:
(A) NAME/REY: misc_feature (D) OTHER lNr-uKMATION: ~XMP.365 (ix) FEATURE:
(A) NAME/KEY: Modified-site (B) LOCATION: l-lO
(D) OTHER INFORMATION: /label= D-Amino Acids /note= ~Positions l-lO are D i no acids"
(ix) FEATURE:
(A) NAME/KEY: Modified-site (B) LOCATION: C . inlln (D) OTHER INFORMATION: /label= Amidation /note= ~The C~ n~R i~ Amidated"
(xi) SEQUENCE DT~!-CrRTPTION: SEQ ID NO:196:
Lyn Trp Leu Ile Gln Leu Phe His Ly~ Ly~

(2) l~ru~TION FOR SEQ ID NO:197:
(i) Sr~uL-~cE CHARACTERISTlCS:
(A) LENGTH: 10 amino acid~
(B) TYPE: ~mino acid (D) TOPOLOGY: linear (ii) ~nLTCcuLE TYPE: peptide (ix) FEATURE:
(A) NAME/~EY: misc_feature (D) OTHER lN~oKMATIoN: "XMP.366"
(ix) FEATURE:
(A) NAME/~EY: Modified-site (B) LOCATION: 1 (D) OTHER lN~u.~lATION: /label= Acetylated /note= ~Position 1 is acetylated"
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: 1-10 (D) OTHER lNr-u.llATION: /label~ D r ino Acids /note= ~Po~itions 1-10 are D ~ i no acids~
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: C ~ i nll R
(D) OTHER lNru.~ATION: /label= Amidation /note= ~The C-l~ i n--Q i8 Amidated"
(xi) ~u~._~ DT~'-c~RTPTIoN: SEQ ID NO:197:
Lys Trp Leu Ile Gln Leu Phe His Lys Lys (2) lNruRMaTION FOR SEQ ID NO:198:
( i ) ~UL_. ~ CHARACTERISTICS:
(A) T- ~ 0 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT.T'c~Tr.TC TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "XMP.367 (ix) FEATURE:
(A) NANE/REY: Modified-site (B) LOCATION: 1-10 (D) OTHER INFORMATION: /label= D ~ ino Acids /note= "Positions 1-10 are D-amino acids"
(ix) FEATURE:

W O 97/04008 PCT~US96/03845 (A) NAME/REY: Modified-site (B) LOCATION: C ~. in.lQ
(D) OTHER INFORMATION: /label= Amidation /notes "The C i. in-7n i~ Amidated~
(xi) SEQUENCE D~SC~TPTION: SEQ ID NO:198:
Ly~ Ly~7 Hi~ Phe Leu Gln Ile Leu Trp Ly~

(2) INr~ATION FOR SEQ ID NO:l99:
(i) ~urr._r; CHARACTERISTICS:
(A) LENGTH: 10 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~nT~CuT~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: misc_feature (D) OTHER lNr-okMATIoN: "XMP.368"
(ix) FEATURE:
(A) NAME/KEY: Modified-~ite (B) LOCATION: 1 (D) OTHER l~ru.llATION: /label- Acetylated /note= "Position 1 i~ acetylated"
(ix) FEATURE:
(A) NAME/ ~ Y: Modified-site (B) LOCATION: 1-10 (D) OTHER INFORMATION: /label= D r ;no Acids /note- "PoDition~ 1-10 are D . i no acid~"
(ix) FEATURE:
(A) NAME/~EY: Modified-~ite (B) LOCATION: C .~- i n~-~
(D) OTHER lNrOh~ATION: /label= Amidation /note= "The C ~ i n--~ iQ Amidated"
(xi) sr;yu~Nur; DESCRIPTION: SEQ ID NO:l99:
Ly~ Lys Hi~ Phe Leu Gln Ile Leu Trp Ly~

(2) INFORMATION FOR SEQ ID NO:200:
(i) SEQUENCE CHARACTERISTICS:
(A) T- ~ 0 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MnT.~C~T~ TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: minc_feature (D) OTHER INFOR~ATION: "XMP.369"
(ix) FEATURE:
(A) NAME/ ~ Y: Modified-nite (B) LOCATION: 5 (D) OTHER lNroRMATIoN: /label= Orn W O 97l04008 PCT~US96/03845 /note= "Po~ition 5 i~ Ornithine"
(ix) FEAT'JRE:
(A) NAME/ ~ Y: Modified-~ite (B) LOCATION: C-T~ inl-R
(D) OTHER lN~u_~ATION: /label~ Amidation /notQ= ~The C-T~ i n--~ is Amidated"
(x$) SEQ'JEN OE D'~Q~RTPTION: SEQ ID NO:200:
Ly~ Tr~~ Leu Ile Xaa Leu Phe Hi~ Lys Lys (2) ~ SATION FOR SEQ ID NO:201:
(i) ~r~uhl.~E CHAPACTERISTICS:
(A) LENGTH: 10 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) I r~T~JT r~ TYPE: peptide (ix) FEAT'JRE:
(A) NAME/~EY: mi~c_feature (D) OTHER l~OR~ATION: "XMP.370"
(ix) ~EATURE:
(A) NAME/~Y: Modified-~ite (B) LOCATION: 5 (D) OTHER lN~O~IATION: /label= Orn /not~= nPosition 5 is Ornithine"
(ix) ~EATURE:
(A) NAME/~EY: Modified-~ite (B) LOCATION: 1 (D) OT'~ER IN~ORMATION: /label= Acetylated /note= "Position 1 i~ acetylated"
(ix) FEAT'JRE:
(A) NAME/~EY: Modified-~ite (B) LOCATION: C I. i n-l~
(D) OTHER INFORMATION: /label= Amidation /note= "The C-Te i~ Amidated"
(xi) ~hyu-~-~ D'~Q~RTPTION: SEQ ID NO:201:
Ly~ Trp Leu Ile Xaa Leu Phe His Lys Lys (2) lNr~7~nATION FOR SEQ ID NO:202:
( i ) ~hyu _._r. CHARACTERISTICS:
(A) LENGTH: 10 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MnT ~CuT~ TYPE: peptide (ix) FEATURE:
(A) NA~E/~EY: mi~c_feature (D) OT B R INFORMATION: "XMP.371"
(ix) FEATURE:

CA 02227292 l998-0l-l9 (A) NAME/XEY: Modlfied-~ite r (B) LOCATION: 5 (D) OTHER INFORMATION: /label= Dbu /note= "Po~ition 5 i~ Di~ inobutyric acid"
(ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: C .. inl~
(D) Oln~R lN~O~ATION: /label= P i~Jtinn /note= "The C .. inlln i~ Amidated"
(xi) SEQUENCE D~S~TPTION: SEQ ID NO:202:
Ly~ Trp Leu Ile Xaa Leu Phe Hi~ Ly~ Lyn (2) INFORMATION FOR SEQ ID NO:203:
(i) SEQUENCE CHARACTERISTICS:
(A) T- ~ 0 amino acidn (8) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) M~T~CUT~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: mi~c_feature (D) OTHER Ih~ ~.TION: "XMP.372"
(ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: 5 (D) OTHER lhroR~ATIoN: /label~ Dbu /note= "Po~ition 5 i~ Di~ in~buLy~ic acid"
(ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: 1 (D) OTHER lNr~l~TION: /label~ Acetylated /note= "Position 1 i~ acetylated"
(ix) FEATURE:
(A) NAME/REY: Modified-~ite (8) LOCATION: C .. i n--~
(D) OTHER lNrOR~ATION: /label= Amidation /note= "The C ., ~nl-n iB Amidated"
(Xi) ~hyU~ ~ DESCRIPTION: SEQ ID NO:203:
Ly~ Trp Leu Ile Xaa Leu Phe His Ly~ Ly~

(2) l~rvk~ATION FOR SEQ ID NO:204:
(i) ~r;yu~r._r; CHARACTERISTICS:
(A) T- ~ 0 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) MnT.T~!~JT.~ TYPE: peptide (ix) FEATURE:
(A) NAME/REY: minc_feature W O 97/04008 PCT~US96/03845 (D) OTn~R INFORMAT~ON: "XMP.373 (ix) FEATURE:
(A) NAME/REY: Modified-site (B) LOCATION: 1 (D) OTHER INFORMATION: /label= Acetylated /note= ~Position 1 is acetylated"
(ix) FEATURE:
(A) NAME/REY: Modified-~ite (B) LOCATION: C i. inun (D) OTHER lNr~Ar~.TION: /label= Amidation /note= ~The C~ nlls i~ Amidated"
(xi) SEQUENCE n~PTPTION: SEQ ID NO:204:
Ly~ Trp Leu Ile Gln Leu Phe His Lys Lys (2) lN~okMATIoN FOR SEQ ID NO:20S:
(i) SEQUEN ~ CHARACTERISTICS:
A~ LENGTH: 1813 base pairs Bl TYPE: nucleic acid rC~ S~RA~ CS: ~ingle ~DJ TOPOLOGY: linear ( ii ) ~nT-~C~ TYPE: cDNA
(ix) FEATURE:
(A) NAME/REY: CDS
(B) LOCATION: 31..1491 (ix) FEATURE:
(A) NAME/~EY: mat_peptide (B) LOCATION: 124..1491 (ix) FEATURE:
(A) NAME/KEY: misc_feature (D) OTHER lh~ OR~ATION: n rBPI~
(xi) SEQUEN OE n~,5~TPTrON: SEQ ID NO:205:
CAGGCCTTGA ~ GGCA G~ AGG ATG AGA GAG AAC ATG GCC AGG GGC 54 Met Arg Glu A~n Met Ala Arg Gly Pro Cy~ Asn Ala Pro Arg Trp Val Ser Leu Met Val Leu Val Ala Ile Gly Thr Ala Val Thr Ala Ala Val Asn Pro Gly Val Val Val Arg Ile Ser Gln Lys Gly Leu Asp Tyr Ala Ser Gln Gln Gly Thr Ala Ala Leu Gln Ly~ Glu Leu Ly~ Arg Ile Lys Ile Pro Asp Tyr Ser A~p Ser Phe CA 02227292 l998-Ol-l9 Ly~ Ile Lys His Leu Gly Lys Gly His Tyr Ser Phe Tyr Ser Met Asp Ile Arg Glu Phe Gln Leu Pro Ser Ser Gln Ile Ser Met Val Pro Ann Val Gly Leu Lys Phe Ser Ile Ser Asn Ala Asn Ile Ly~ Ile Ser Gly Lyn Trp Lys Ala Gln Lys Arg Phe Leu Lys Met Ser Gly Asn Phe A~p Leu Ser Ile Glu Gly Met Ser Ile Ser Ala Asp Leu Lys Leu Gly Ser A~n Pro Thr Ser Gly Ly~ Pro Thr Ile Thr Cys Ser Ser Cys Ser Ser CAC ATC AAC AGT GTC CAC GTG CAC ATC TCA AAG AGC A~A GTC GGG TGG 582 His Ile Asn Ser Val Hi~ Val His Ile Ser Lyn Ser Lys Val Gly Trp Leu Ile Gln LQU Phe Hin Ly~ Lys Ile Glu Ser Ala Leu Arg Asn Ly~

ATG AAC AGC CAG GTC TGC GAG A~A GTG ACC AAT TCT GTA TCC TCC AAG 678 Met Asn Ser Gln Val Cys Glu Lys Val Thr Asn Ser Val Ser Ser Lys Leu Gln Pro Tyr Phn Gln Thr Leu Pro Vnl Met Thr Lyn Ile Asp Ser Val Ala Gly Ile Asn Tyr Gly Leu Val Ala Pro Pro Ala Thr Thr Ala Glu Thr Leu A~p Val Gln Met Lys Gly Glu Phe Tyr Ser Glu Asn His His Asn Pro Pro Pro Phe Ala Pro Pro Val Met Glu Phe Pro Ala Ala Hin A~p Arg Met Val Tyr Leu Gly Leu Ser Asp Tyr Phe Phe Asn Thr Ala Gly Leu Val Tyr Gln Glu Ala Gly Val Leu Lyn Met Thr Leu Arg A~p Asp Met Ile Pro Lys Glu Ser Lys Phe Arg Leu Thr Thr Lys Phe -TTT GGA ACC TTC CTA CCT GAa GTG GCC AAG AAG TTT CCC AAC ATG AAG 1062 Phe Gly Thr Phe Leu Pro Glu Val Ala Ly~ Lys Phe Pro A~n Met Ly~

Ile Gln Ile Hi8 Val Ser Ala Ser Thr Pro Pro Hi~ Leu Ser Val Gln Pro Thr Gly Leu Thr Phe Tyr Pro Ala Val A~p Val Gln Ala Phe Ala Val Leu Pro Ann Ser Ser Leu Ala Ser Leu Phe Leu Ile Gly Met Hi~

Thr Thr Gly Ser Met Glu Val Ser Ala Glu Ser A~n Arg Leu Val Gly Glu Leu Ly~ Leu Asp Arg Leu Leu Leu Glu Leu Ly~ Hin Ser Ann Ile Gly Pro Phe Pro Val Glu LQU Leu Gln A~p Ile Met Asn Tyr Ile V~l Pro Ile Leu Val Leu Pro Arg Val A~n Glu Lys Leu Gln Lyn Gly Phe Pro Leu Pro Thr Pro Ala Arg Val Gln Leu Tyr A~n Val Val Leu Gln Pro Hi~ Gln A~n Phe Leu Leu Phe Gly Ala A~p Val Val Tyr Ly~

Tr-AA~rCCArC AGGGG~GCCG GGGGCTGTCA GCCGr~rCTG llC~l~ATGG GCTGTGGGGC 1551 ACCGGCTGCC ...CCC~r,G GAA.C~. .C CAGATCTTAA CrAAr-Ar~CC CTTGCAAACT 1611 ~ ~GACTC AGATTCAGAA ATGATCTAAA c~r-~r~-~A CATTATT QT TGrAAAAr~TG 1671 CAl~L~ ATTTTAGGGA TTATGAGCTT CTTTCAAGGG CTAAGGCTGC A~-~ATATTT 1731 CCTCrAr-r-AA ~.~l~A ATTGTAACCA AGAAATTTCC ATTTGTGCTT CAT~-AAAAAA 1791 AA~.... G~ -~ATG TG 1813 (2) INFORMATION FOR SEQ ID No:206:
( i ) S~Uhr._~ CHARACTERISTICS:
(A) LENGTH: 487 amino acid~
(B) TYPE: amino acid (D) TOPOLOGY: linear ( ii ) ~ T-T'CUT~ TYPE: protein (Xi) ~U~r.~ DESCRIPTION: SEQ ID NO:206:

M~t Arg Glu Ann ~5et Ala Arg Cly Pro Cy8 Ann Ala Pro Arg Trp Val Ser Leu Met Val Leu Val Ala Ile Gly Thr Ala Val Thr Ala Ala Val ~rln Pro Gly Val Val Val Arg Ile Ser Gln Lyn Gly Leu A~p Tyr Ala ~er Gln Gln Gly Thr Ala Ala Leu Gln Ly~ Glu Leu Ly~s Arg I le Lyn Ile Pro A~p Tyr Ser A3p Ser Phe Ly~ Ile Ly~ Hin Leu Gly Ly~ Gly Hin Tyr Ser Phe Tyr Ser Met A~p I le Arg Glu Phe Gln Leu Pro Ser ~er Gln Ile Ser Met Val Pro AE~n Val Gly Leu Lyl3 Phe Ser Ile Ser ~~n Ala A~n Ile Ly~ Ile Ser Gly Ly~ Trp LYB Ala Gln Lyn Arg Phe ~eu Ly~ Met Ser Gly A~n Phe A~p Leu Ser Ile Glu Gly Met Ser Ile Ser Ala A~p Leu Lys Leu Gly Ser Asn Pro Thr Ser Gly Ly~ Pro Thr Ile Thr Cys Ser Ser Cy~ Ser Ser Hi~ Ile A~n Ser Val His Val Hi~

~le Ser Lys Ser Ly~ Val Gly Trp Leu Ile Gln Leu Phe HiE~ Ly~ Lyn ~le Glu Ser Ala Leu Arg A~n Lyn Met A~n Ser Gln Val Cyl3 Glu Ly~

Val Thr A~n Ser Val Ser Ser Ly~ Leu Gln Pro Tyr Phe Gln Thr Leu Pro Val Met Thr Ly~ Ile A~p Ser Val Ala Gly Ile Asn Tyr Gly Leu Val Ala Pro Pro Ala Thr Thr Ala Glu Thr Leu A~p Val Gln Met Ly~

~ly Glu Phe Tyr Ser Glu A~n Hi~ Hin AE~n Pro Pro Pro Phe Ala Pro ~ro Val Met Glu Phe Pro Ala Ala Hi~ A~p Arg Met Val Tyr Leu Gly Leu Ser A~p Tyr Phe Phe AEln Thr Ala Gly Leu Val Tyr Gln Glu Ala Gly Val Leu Ly~ Met Thr Leu Arg AE~p A~p Met I le Pro Ly~ Glu Ser Ly~ Phe Arg Leu Thr Thr Lyç~ Phe Phe Gly Thr Phe Leu Pro Glu Val _ Ala Ly~ Ly~ Phe Pro Asn Met ~.y~ Ile Gln Ile Hin Val Ser Ala Ser ~ 310 315 320 Thr Pro Pro Hin Leu Ser Val Gln Pro Thr Gly Leu Thr Phe Tyr Pro Ala Val A~p Val Gln Ala Phe Ala Val Leu Pro Asn Ser Ser Leu Ala Ser Leu Phe Leu Ile Gly Met His Thr Thr Gly Ser Met Glu Val Ser Ala Glu Ser A~n Arg Leu Val Gly Glu Leu Lyn Leu Anp Arg Leu Leu Leu Glu Leu Ly~ Hi~ Ser A~n Ile Gly Pro Phe Pro Val Glu Leu Leu Gln A~p Ile Met Asn Tyr Ile Val Pro Ile Leu Val Leu Pro Arg Val Asn Glu Lys Leu Gln Ly~ Gly Phe Pro Leu Pro Thr Pro Ala Arg Val Gln Leu Tyr A~n Val Val Leu Gln Pro Hi~ Gln Ann Phe Leu Leu Phe Cly Ala A~p Val Val Tyr Ly~

Claims (8)

1. An antifungal peptide derived from amino acids 142-169 of bactericidal/permeability-increasing protein (BPI) having from seven to twelve amino acids and having the amino acid sequence that is any one of SEQ ID NOS: 205-223, 239-247 or 249-250.

2. A pharmaceutical composition comprising an antifungal peptide according to Claim 1 and a pharmaceutically acceptable diluent, adjuvant or carrier.

3. An in vitro method for killing or inhibiting replication of fungi comprising contacting the fungi with an antifungal peptide according to Claim 1.

4. An in vitro method according to Claim 3 comprising the additional step of contacting the fungi with an antifungal agent that is not the antifungal peptide according to Claim 1.

5. A method of treating fungal infections comprising administering to a subject suffering from a fungal infection a therapeutically effective amount of a peptide according to Claim 1.

6. A method according to Claim 5 comprising the additional step of administering an antifungal agent that is not the antifungal peptide according to Claim 1.

7. The use of an antifungal peptide according to Claim 1 for the manufacture of a medicament for the treatment of a fungal infection alone.

8. The use of an antifungal peptide according to any of Claims 1 to 7 in combination with another antifungal agent.