CN1882699A - 带有多个能共价结合生物分子的官能基团的表面固定化多电解质 - Google Patents

带有多个能共价结合生物分子的官能基团的表面固定化多电解质 Download PDF

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CN1882699A
CN1882699A CNA200480033807XA CN200480033807A CN1882699A CN 1882699 A CN1882699 A CN 1882699A CN A200480033807X A CNA200480033807X A CN A200480033807XA CN 200480033807 A CN200480033807 A CN 200480033807A CN 1882699 A CN1882699 A CN 1882699A
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汪新文
苏堪塔·本纳吉
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Abstract

具有多个暴露官能团的多电解质固定化到一个表面上，目的是结合于一个生物分子，其中每个基团能够与一个分子共价结合。生物分子可以是例如核酸，如胺官能化的寡核苷酸。多电解质可以包括，如使用共价固定化方案结合于官能化表面的BSA(牛血清白蛋白)，此方案如，与甲苯磺酰基－活化的微粒表面的反应。这样反应后，能进一步使用蛋白质上暴露的活性官能团，诸如胺、羧基、巯基、羟基，以通过适当的化学作用与感兴趣的寡核苷酸共价地偶联。

Description

带有多个能共价结合生物分子的官能基团的表面固定化多电解质
相关申请
本发明要求提交于2003年9月22日的美国临时申请No.60/504,716的优先权。
发明领域
本发明属于多电解质化学领域。
发明背景
作为解决寡核苷酸的“点阵列”的诊断使用带来的许多问题的一个选择方案(这些问题略述于2002年8月23日提交的美国申请No.10/204,799、WO01/98765“使用特异-应用的随机颗粒阵列的多分析物分子分析”)，通过把寡核苷酸探针结合于编码的微珠颗粒上，形成优选的阵列，其中编码颗粒由聚合物树脂制成。见于提交于2002年10月15日的美国专利申请No.10/271,602“通过同时探查和酶介导检测的多态性位点多重分析”和之前的申请No.10/204,799。然后编码的颗粒-探针结合体装配在2D分析格式中，并放到与样品接触，预期样品含有亚序列与探针互补的靶多核苷酸，其中样品中的靶多核苷酸预先用荧光标记。由荧光分析信号的存在确定探针与靶之间的结合。产生阳性分析信号的特定探针可以通过解码阵列确定。
有许多已知的和商业上的方法用于连接寡核苷酸探针和微珠。已经设计了大量方案用于把寡核苷酸探针共价固定化于微粒，这在公开文献或商业上都可得到。传统的共价固定化技术使用官能化的珠子(即，用活性基团如氨基、羧基、甲苯磺酰基、乙醛基、环氧基、酰肼及其它基团官能化珠子)，连接到寡核苷酸探针末端的互补官能团上(Marie K.Walsh，XinwenWang and Bart C.Weimer，Optimizing the immobilization of single-strandedDNA onto glass beads，J.Biochem.Biophys.Methods 2001；47：221-231)。通常，这种结合设计导致不适宜的空间构向和立体障碍问题。可以由引入间隔分子提高这种共价固定化探针的杂交性能(Edwin Southern，Kalim Mirand Mikhail Shchepinov；Molecular Interactions on Microarrays.NatureGenetics Supplement，21，1999，pp.5-9)，然而，通常是难以实现和不实用的。
因此，一种可操作和强的探针结合化学作用对优化基于微珠阵列的分析是重要的。这种化学作用必须允许探针以高效率与颗粒结合，以便保持珠子表面上的探针浓度一致，同时反应也必须不改变探针-靶结合的效率。而且，反应必须具有最小的批之间变异率。在通常使用的一个方法中，官能化的微粒用中性抗生物素蛋白(Neutravidin)(Pierce，Rockford，IL)、链霉抗生物素蛋白(streptavidin)或抗生物素蛋白包被，这些蛋白是生物素结合蛋白，从而介导生物素化探针的固定。
抗生物素蛋白-生物素相互作用是高度特异的，是最强的已知反应之一(在含水溶液中缔合常数(KA)为1015M-1级)，并且提供珠子表面固定化蛋白与生物素化探针分子之间几乎不可逆的键。见于上述美国专利申请No.10/271,602。以下描述的结合探针到多电解质的方法优于这些已知方法，因为证明它们能够引导更多寡核苷酸与珠子联结。
发明概要
具有多个暴露官能团的多电解质固定化到一个表面上，目的是结合一个生物分子，所述多电解质的每个官能团能够与一个分子共价结合。生物分子可以是例如核酸，如胺官能化的寡核苷酸。多电解质可以包括，如使用共价固定化方法结合于官能化表面的BSA(牛血清白蛋白)，此方法如，与甲苯磺酰基-活化的微粒表面的反应。这样反应后，蛋白质上暴露的活性官能团，诸如胺、羧基、巯基、羟基，运用适当的化学作用，能进一步用于共价结合感兴趣的寡核苷酸
在一个实施例中，在末端位置(3’或5’末端位置)以胺类修饰的寡核苷酸(如，氨基修饰的寡核苷酸)由一个EDAC(1-乙基-3-(3-二甲基氨丙基)碳二亚胺)反应与BSA共价结合(见于，如，D.Seligal et al.，AnalyticalBiochemistry 218：87091(1994))。共价反应导致在寡核苷酸末端的胺基与BSA的羧基之间形成一个酰胺键。反应见于图1。
官能化的表面可以是一个珠子或微粒的表面，此珠子或微粒由大量材料中的任意材料组成，材料包括聚合物、聚合树脂、玻璃、橡胶或其它能官能化以固定多电解质的材料。进行试验以比较BSA-包被的珠子与另一种范例多电解质：人类血清白蛋白(“HSA”)，以及中性抗生物素蛋白。杂交试验的结果表示，BSA-包被的珠子能够把更高浓度的寡核苷酸联结到珠子上。
附图说明
图1表示利用EDAC反应BSA与官能化的珠子的结合，和寡核苷酸探针与BSA的结合。
图2表示来自寡-官能化BSA偶联的珠子的杂交信号，作为用于偶联胺化探针的量的一个函数。一个完全匹配的探针联结于两套BSA-偶联的珠子。BSA与第一套珠子在65℃偶联，与第二套在37℃偶联。在第一套珠子上观察到较高的杂交效率(较高的信号)，BSA在65℃对其偶联。第三套珠子在65℃与BSA偶联，并与一个不匹配的阴性对照探针官能化，表现出可以忽略的杂交，从而表示信号的增强不是非-特异性结合增加的结果。
图3表示偶联于珠子的BSA的滴定结果。如图2所示，偶联BSA的珠子在较高温度下的杂交效率比在较低温度下的大，这显示于靶位上结合于BSA-偶联的珠子的一个寡核苷酸探针接触的杂交信号的差异，其中BSA与一套珠子在37℃偶联，而BSA与另一套珠子在65℃偶联。(见实例4)
图4表示BSA与甲苯磺酰基官能化的珠子在不同温度下偶联效率的差异，参照杂交分析法确定，其中寡核苷酸探针结合于固定于珠子上的BSA，然后与互补的荧光标记靶反应。(见实例6)
图5表示在65℃或更高温度培养大约1小时，对BSA与甲苯磺酰基活化珠子的偶联反应，BSA与珠子表面的结合效率不受影响，这显示于靶位上结合于BSA-偶联的珠子的一个寡核苷酸探针接触的杂交信号的差异。(见实例7)
图6A显示BSA包被的甲苯磺酰基官能化珠子与中性抗生物素蛋白-包被的甲苯磺酰基官能化珠子相比，在结合了探针和与一个靶杂交之后，给出更均一和更强的杂交信号。(见实例8)
图6B显示图6A中信号的变异系数。
图7显示当包被在甲苯磺酰基官能化珠子上的多电解质是HAS而不是BSA时，杂交有显著差异，其中寡核苷酸探针分别结合于固定于珠子上的BSA或HSA，然后与互补的荧光标记靶反应。
发明详述
实例1：制备BSA-包被的甲苯磺酰基官能化珠子
在10mL PBS中溶解50mg BSA而制备浓度为5mg/mL的BSA溶液。向一个15mL离心管中加入2.0mL PBS-T。转移1mL浓度为1％固体(10mg)荧光着色的珠子到此离心管中，并由涡旋转动而充分混合。通过3,500rpm离心4+/-0.5分钟沉淀珠子，并倒出上清液。向管中加入3.0mL PBST并由涡旋转动而充分混合，把珠子再次-悬浮。通过3,500rpm离心4+/-0.5分钟再次沉淀珠子，并倒出上清液。向珠子加入3.0mL BSA溶液(5mg/mL)并由涡旋运动而充分混合。把离心管放在37℃培养箱中的振荡器上，使珠子在250rpm振荡下反应过夜。
然后，通过3,500rpm离心4分钟沉淀珠子，并倒出上清液。然后通过向离心管加入3.0mL PBS-T洗涤珠子，并在涡旋混合器上混合。之后再次把珠子以3,500rpm离心4+/-0.5分钟，并倒出上清液。然后重复洗涤和离心步骤。
加入3.0mL贮存缓冲液(含有0.1％NaN3的0.1M PBS)，并在涡旋混合器上混合。再次把珠子以3,500rpm离心4+/-0.5分钟，倒出上清液。然后在1ml贮存缓冲液中涡旋运动再次悬浮珠子。珠子浓度为1％固体(10mg/mL)，在4-6℃贮存。它们易于通过EDAC反应联结含有-胺的生物材料(如，BSA)，如以下实例3中所述。
实例2：制备BSA-包被的羧基官能化珠子
BSA与羧基化颗粒的偶联如下实现。转移100μl浓度为1％固体的羧基化颗粒到一个2ml Eppendorf管中。然后由离心沉淀珠子，移去上清液。之后，用1ml MES(细节)缓冲液(pH4.5)洗涤珠子一次。用MES缓冲液分别制备BSA储存液(5mg BSA/mL)和EDC储存液(20mg/mL)。向珠子沉淀加入100μl BSA储存液，涡旋转动充分混合悬浮液。之后，向珠子悬浮液加入400μl EDC储存液，涡旋转动混匀并在室温下通过底-头-底的混合方式反应1小时。培养1小时后，向悬浮液加入100μl PBS-T，离心珠子。用1ml PBS-T由离心-再分散循环洗涤小球2次，最后珠子悬浮在100μl贮存缓冲液(含有0.1％叠氮化钠，NaN3的0.1M PBS)并贮存于4-6℃。
实例3：把胺化的寡核苷酸探针偶联到BSA珠子的EDAC反应
胺化的寡核苷酸探针与珠子的偶联，制备如同实例1和2，如下实现。取一系列1.5ml Eppendorf管并且做标记，用于区分微粒的类型和将要偶联的寡核苷酸探针类型。之后，向每个管中加入500μl PBST，然后加入100μl浓度为1％固体的BSA偶联的珠子。用涡旋混合器混合10秒钟而充分混合。然后9,500rpm离心2+/-0.5分钟，沉淀珠子，倒出上清液。向沉淀加入等分的500μl 0.05M MES缓冲液(pH4.5)，并由涡旋运动充分混合。然后把珠子在9,500rpm离心2+/-0.5分钟，并倒出上清液。向珠子加入等分的500μl 0.05M用MES缓冲液制备的EDAC(使用前制备)，并由涡旋运动充分混合。然后，加入10μL浓度100μM氨基修饰的DNA探针(如，探针MS-508N25，购自Integrated DNA Technologies，Inc.，CoralvilleIA)到各个含有珠子悬浮液的离心管，充分混合。使此反应在室温下(20-25℃)以底-头-底的混合方式进行1小时。
培养后，向各管加入100μL PBS-T，并由涡旋运动混合。然后以9,500rpm离心2+/-0.5分钟沉淀珠子，倒出上清液。用500μl PBS-T通过离心-再分散循环的方式洗涤珠子2次。
把珠子再次悬浮于100μL PBST，得到终浓度为1％的固体，在4-6℃贮存以便进一步的使用。
寡核苷酸官能颗粒的杂交性能(试验步骤见实例4)作为用于添加寡聚物的量(100μM/200μg颗粒的0.25、0.5、1、2、4、8μl)的一个函数表示于图2。于是上述量100μM/lmg的10μl代表饱和浓度。BSA与珠子的偶联在较高温度表现较高杂交性能，这些后面有详述。
实例4：使用寡核苷酸官能化珠子的杂交分析
1.在8个不同芯片上装载珠子混合物。储备的荧光标记DNA靶溶液(MS508-90mer-CY5)制备于杂交缓冲液(1×TMAC)中。从储备靶溶液制备8个不同系列稀释溶液。然后向8个单独芯片加入20μl每种系列稀释的靶溶液。
2.把含有这些芯片的一个载玻片放到杂交加热器/振荡器中，并在100rpm和55℃培养20分钟。
3.移去载玻片并冷却到室温，用移液管移去杂交液。
4.向各芯片加入20μl的1×TMAC，用移液管吸取释放溶液的方式洗涤芯片8到10次。
5.移去洗涤液，向各芯片加入5ml封片液(1×TMAC)，使用一个盖玻片在荧光显微镜下读出分析信号(CY5)。
6.绘制杂交信号(CY5)与DNA探针浓度的滴定曲线。
滴定曲线的例子表示于图3。
实例5
进行试验以比较向珠子-探针悬浮液两次加入EDAC的效果(已知EDAC在酸性pH下很快水解)，以评价这是否导致探针与BSA层结合的增加。首先在以下每种条件(10μl 100μM探针/100μl 1％珠子)下，探针MS-508-N25偶联于BSA-包被的珠子。反应1小时后，从1×管移去一半珠子，加入新的EDAC，然后在此管中反应再进行1小时。然后对非-匹配的探针SSP36重复整个过程。每套珠子和非-特异性珠子集中在一起，装配在一个芯片上，然后在杂交条件下，所有套珠子都与靶MS508-40mer-Cy5接触。然后纪录结果，并总结在表II。加入2次EDAC提供了更高的杂交信号。
                         表II
探针浓度   模型分析Cy5信号 CV   非-特异性Cy5信号 CV
  1×EDAC   536.1   0.17   79.9   0.26
  2×额外EDAC   732.9   0.17   53.3   0.19
实例6：BSA在不同温度下偶联于甲苯磺酰基活化珠子及它们的杂交特性
向5个15mL离心管中各加入2.0mL PBST和1mL浓度为1％固体(10mg)荧光着色的珠子，并由涡旋运动充分混合珠子。通过以3,500rpm离心4+/-0.5分钟而沉淀珠子，倒出上清液。然后把珠子再次悬浮于3.0mLPBST中，涡旋运动充分混合珠子，再次以3,500rpm离心4+/-0.5分钟沉淀珠子。倒出上清液。
向各试管加入2mL PBS(pH7.2)和1mL BSA溶液(PBS中50mg/mL)并由涡旋运动充分混合。培养箱中对各试管的环境温度设置如下：管A-22℃、管B-37℃、管C-50℃、管D-65℃、管E-75℃，并使珠子在指定温度下以底-头-底的混合方式与BSA反应14小时。然后把各管冷却到室温，通过以3,500rpm离心4分钟而沉淀珠子，倒出上清液。向管中加入3.0mL PBST洗涤珠子，由涡旋混合器混合，在3,500rpm离心4+/-0.5分钟沉淀珠子。倒出上清液。
加入1mL贮存缓冲液(含有0.1％NaN3的PBS)，并将试管置于涡旋混合器上混合。珠子浓度为1％固体(10mg/mL)。BSA偶联的珠子在4-6℃下贮存。
由上述EDAC偶联方法，把25-mer MS-508N25生物素化的寡核苷酸探针与各套珠子偶合。然后在杂交条件下，每套珠子与用于探针的固定浓度的标记靶(用Cy-5标记的90-mer寡核苷酸)接触。珠子上标记的量与珠子上探针浓度相关。
如图4所示，偶联于BSA的珠子在较高温下表现更多与显示在珠子表面的寡核苷酸探针的靶结合。这表示，这种珠子表面上探针浓度更高，这可能是因为在65℃，BSA变性并展开，呈现更多可用于结合探针的位点。
实例7：不同培养时间对BSA与甲苯磺酰基官能化珠子偶联的比较
进行一个试验以研究BSA与甲苯磺酰基官能化珠子偶联反应的时间过程。在进行如上述实例1和实例5的同样步骤之后，12个单独管，每个含有一种BSA-甲苯磺酰基颗粒反应混合物，培养于65℃烘箱中，同时1个对照管培养于37℃。在每一个预定培养阶段之后取出一个管，以实例3中列出的方法洗涤并用一个寡核苷酸探针(包括一个对照探针)偶联。然后，进行杂交反应并记录实验强度(见实例4)。结果表示于图5，说明BSA偶联反应基本上在少于1小时内完成。
实例8：与常用生物素-抗生物素蛋白寡核苷酸偶联和中性抗生物素蛋白包被化学作用的比较
进行一个试验以比较寡-结合的、BSA-官能化珠子与生物素化的寡-联结的中性抗生物素蛋白珠子的捕获和杂交效率。使用实例1中列出的步骤，在37℃把蛋白质偶联于珠子表面。然后，生物素化的(也胺化的)寡聚物偶合于颗粒(如实例3中)，和一个同源的靶实行杂交分析。
取两种不同编码但却是相同的BSA包被颗粒，一种匹配探针结合于一个组，一种非-匹配探针结合于另一个组。类似地，取两种其它中性抗生物素蛋白-官能化珠子并结合于匹配和非匹配的生物素化探针。
实验结果表示于图6A和图6B。明显的是，BSA包被比使用中性抗生物素蛋白捕获化学作用提供了更均一(较低CV)和更高的信噪比(认为非匹配探针的杂交强度是噪音)。
实例9：与HSA包被比较
HSA(人类血清白蛋白)在那些用于BSA与甲苯磺酰基-官能化颗粒偶联的相同条件下进行偶联。然后HSA官能化颗粒与寡核苷酸探针偶联，并杂交(滴定)于荧光标记的模式DNA靶(如实例4中)。结果表示于图7。结果说明，对结合寡核苷酸探针，HSA包被不如BSA包被有效，尽管事实上，像BSA一样，HSA具有可用于结合寡核苷酸探针的许多官能羧基基团。
实例10：BSA偶联的批之间变异
3批各为10mg的珠子分别在65℃偶联BSA 14小时，其中BSA-珠子比是5(W/W，mg/mg)。偶联的反应体积是3mL。作为对照，1批珠子在37℃偶联于BSA。基于偶联于珠子的DNA探针与同源靶的杂交强度而确定偶联效率。杂交在55℃1×TMAC中进行20分钟，靶是浓度为400nM的MS508-90mer-CY5。实验读出的整体时间是200ms。结果表示于表I。
            表I
  批   CY5强度(100ms)
  1   6864
  2   6515
  3   6431
  对照   3964
65℃批次的强度一致地比在37℃偶联的批次的强度高，并且批之间变异率很小。
上述术语、表述和实例仅仅是范例而非限制，本发明只由以下的权利要求限定，并包括权利要求的主旨的所有等价物。

Claims (16)

1.一种固定化于一个表面的多电解质，具有多个暴露的官能团用于与生物分子共价结合。
2.根据权利要求1所述的多电解质，其中所述官能团是羧基或胺基。
3.一种包括多电解质的，其中所述多电解质固定化于一个表面并共价结合于一种核酸。
4.根据权利要求3所述的产物，其中所述多电解质是一种蛋白质，并且所述表面是用甲苯磺酰基活化的。
5.根据权利要求3所述的产物，其中所述蛋白质是BSA，并且所述核酸是一种寡核苷酸。
6.根据权利要求4所述的产物，其中所述寡核苷酸是通过EDAC反应形成的酰胺键结合于所述蛋白质的。
7.根据权利要求5所述的产物，其中所述寡核苷酸是在其5’末端生物素化的。
8.根据权利要求3所述的产物，其中所述表面是一种微粒的表面，这种微粒是由一种聚合物、一种聚合树脂、玻璃或橡胶组成的。
9.一种方法，包括把一种核酸共价结合到固定化于一个表面上的一种多电解质。
10.根据权利要求9所述的方法，其中所述核酸是在5’末端用一个胺基团官能化或生物素化的一种寡核苷酸。
11.根据权利要求9所述的方法，其中所述多电解质是一种蛋白质，包括BSA，并且在固定蛋白质之前，表面用甲苯磺酰基活化。
12.根据权利要求11所述的方法，其中所述多电解质是由所述多电解质的COOH官能团通过一个EDAC反应结合于所述表面的。
13.根据权利要求10所述的方法，其中所述寡核苷酸是由一个EDAC反应结合于所述蛋白质的，从而在所述寡核苷酸和所述蛋白质之间形成一个酰胺键。
14.根据权利要求11所述的方法，其中所述蛋白质是在65℃或更高温度进行的一个反应中固定化到所述表面。
15.根据权利要求13所述的方法，其中所述表面是一种微粒的表面，这种微粒是由一种聚合物、一种聚合树脂、玻璃或橡胶组成的。
16.由权利要求9至14中任一权利要求所述的方法形成的一种产物。
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