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CN1617937A - 标记过的核苷酸 - Google Patents

标记过的核苷酸 Download PDF

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CN1617937A
CN1617937A CNA028278321A CN02827832A CN1617937A CN 1617937 A CN1617937 A CN 1617937A CN A028278321 A CNA028278321 A CN A028278321A CN 02827832 A CN02827832 A CN 02827832A CN 1617937 A CN1617937 A CN 1617937A
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S·巴拉苏布拉马尼安
C·巴恩斯
刘小海
H·斯维尔德罗
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Abstract

披露了通过可裂解的接头基团与可检测的标记连接的核苷和核苷酸。

Description

标记过的核苷酸
发明领域
本发明涉及标记过的核苷酸。具体地讲，本发明披露了具有可除去的标记的核苷酸，及其在多核苷酸测序方法中的用途。
背景
分子研究方面的进展部分是由于用于表征所述分子或它们的生物学反应的技术的改良。具体地讲，核酸DNA和RNA的研究，业已从用于序列分析的发展中的技术和杂交事件的研究中受益。
业已改善了核酸研究的所述技术的一种例子，是固定化核酸的组装的阵列的发展。所述阵列通常包括固定在固体支持材料上的多核苷酸的高密度距阵。例如，参见Fodor等，Trends Biotech.12：19-26，1994，该文献披露了组装核酸的方法，其中使用用掩膜保护的化学敏化的玻璃表面，不过，暴露了特定的部位，以便能够结合适当修饰过的核苷酸亚磷酰胺。组装的阵列还可以通过将已知的多核苷酸“点”在固体支持物的预定位置上而生产(例如Stimpson等，Proc.Natl.Acad.Sci.USA 92：6379-6383，1995)。
阵列技术的另一种发展，是将所述多核苷酸连接在固体支持材料上，以便形成单分子阵列。这种类型的阵列披露于国际专利申请号WO00/06770中。所述阵列的优点是，可以在单分子水平上监测反应，并且可以从单个反应中采集到大量单分子的信息。
为了使DNA阵列能够使用，必须确定所述分子的序列。美国专利号5,302,509披露了对固定在固体支持物上的多核苷酸进行测序的方法。所述方法取决于在存在DNA聚合酶的条件下，具有不同荧光标记的3′-封闭的碱基A，G，C和T向所述固定化多核苷酸中的掺入。所述聚合酶能够掺入与所述靶核苷酸互补的碱基，但是，能防止进一步添加3′-封闭基团。然后，可以确定所述掺入碱基的标记，并且通过化学裂解除去所述封闭基团，以便可以发生进一步的聚合。
Welch等(Chem.Eur.J.5(3)：951-960，1999)披露了用3′-O-封闭基团修饰的核苷三磷酸的合成，所述封闭基团是光不稳定性的，并且能发出荧光。打算将所述修饰过的核苷酸用于DNA测序实验。不过，证明了所述核苷酸难于掺入在现有的多核苷酸上，因为它不能结合到所述聚合酶的活性位点。
Zhu等(Cytometry 28：206-211，1997)还披露了通过所述碱基基团连接在所述核苷酸上的荧光标记的用途。希望将所述标记过的核苷酸，用于在原位杂交(FISH)实验中发出荧光，其中，需要一系列掺入的标记过的核苷酸，以便产生荧光“条形码”。
发明概述
在本发明中，通过与碱基连接的可裂解的接头基团，将核苷或核苷酸分子连接在可检测的标记上，使得所述分子可用于使用标记过的核苷或核苷酸的技术中，例如，测序反应，多核苷酸合成，核酸扩增，核酸杂交分析，单核苷酸多态性研究，以及其他使用诸如聚合酶，逆转录酶，末端转移酶，或其他DNA修饰酶的酶的其他技术。本发明特别适用于使用标记过的dNTPs的技术，如切口翻译，随机引物标记，末端标记(例如，使用末端脱氧核苷酸转移酶)，逆转录或核酸扩增。本发明的分子与现有技术不同，其中，所述标记连接在核糖或脱氧核糖上，或者，其中，所述标记是通过不可裂解的接头连接的。
根据本发明的第一方面，核苷酸或核苷分子或它们的类似物具有通过可裂解的接头连接在可检测的标记上的碱基。
本发明涉及具有通过可裂解的接头连接在可检测标记上的碱基的核苷酸或核苷分子。所述碱基可以是嘌呤或嘧啶。所述碱基可以是脱氮嘌呤。所述分子可以具有核糖或脱氧核糖糖部分。所述核糖或脱氧核糖可以包括通过2’或3’氧原子连接的保护基团。可以将所述保护基团除去，以便暴露出3’-OH基团。所述分子可以是脱氧核糖核苷三磷酸。所述可检测的标记可以是荧光团。所述接头可以是酸不稳定性接头，光不稳定性接头，或可以包括二硫键。
本发明还涉及标记核酸分子的方法，其中，所述方法包括将核苷酸或核苷分子掺入到所述核酸分子上，其中，所述核苷酸或核苷分子具有通过可裂解的接头连接在可检测的标记上的碱基。所述掺入步骤可以通过末端转移酶，聚合酶或逆转录酶完成。所述碱基可以是嘌呤或嘧啶。所述碱基可以是脱氮嘌呤。所述核苷酸或核酸分子可以具有核糖或脱氧核糖糖部分。所述核糖或脱氧核糖可以包括通过2’或3’氧原子连接的保护基团。可以将所述保护基团除去，以便暴露出3’-OH基团。所述分子可以是脱氧核糖核苷三磷酸。所述可检测的标记可以是荧光团。所述接头可以是酸不稳定性接头，光不稳定性接头，或可以包括二硫键。所述可检测的标记和/或可裂解的接头可以具有足以阻止第二个核苷酸或核苷掺入到所述核酸分子上的大小。
在另一方面，本发明涉及用于测定靶单链多核苷酸序列的方法，其中，所述方法包括监测互补性核苷酸的依次掺入，其中，每一个所述核苷酸具有通过可裂解的接头与可检测的标记连接的碱基。并且，其中，每一个掺入的核苷酸的身份是通过检测与所述碱基连接的标记确定的，并且，随后除去所述标记。
本发明还涉及用于测定靶单链多核苷酸的序列的方法，其中，该方法包括：(a)提供核苷酸，其中，所述核苷酸具有通过可裂解的接头与可检测的标记连接的碱基，并且，其中，所述与每一种类型的核苷酸连接的可检测的标记，在检测时可以与用于标记其他类型的核苷酸的可检测标记区分开来；(b)将核苷酸掺入到所述靶单链多核苷酸的互补体上；(c)检测(b)的核苷酸的标记，以便确定掺入的核苷酸的类型；(d)除去(b)的核苷酸的标记；和(e)任选重复步骤(b)-(d)一次或多次，以便测定靶单链多核苷酸的序列。
在本文所披露的方法中，可以让每一个核苷酸依次与所述靶接触，在添加下一个核苷酸之前除去未掺入的核苷酸，其中，所述标记的检测和除去是在添加每一个核苷酸之后，或在添加所有四种核苷酸之后进行的。
在所述方法中，可以让所有核苷酸同时与所述靶接触，即让包括所有不同核苷酸的组合物与所述靶接触，并且在检测之前除去未掺入的核苷酸，并且随后除去所述标记。
所述方法可以包括第一个步骤和第二个步骤，其中，在第一个步骤中，让包括四种核苷酸中的两种的第一种组合物与所述靶接触，并且在检测之前除去未掺入的核苷酸，并且随后除去所述标记，并且，其中，在第二个步骤中，让包括第一种组合物中所不包括的两种核苷酸的第二种组合物与所述靶接触，并且在检测之前除去未掺入的核苷酸，并且随后除去所述标记，并且，其中，任选重复所述第一个步骤和第二个步骤一次或多次。
本文所披露的方法还可以包括第一个步骤和第二个步骤，其中，在第一个步骤中，让包括四种核苷酸中的一种的组合物与所述靶接触，并且在检测之前除去未掺入的核苷酸，并且随后除去所述标记，并且，其中，在第二个步骤中，让包括第一种组合物中所不包括的三种核苷酸的第二种组合物与所述靶接触，并且在检测之前除去未掺入的核苷酸，并且随后除去所述标记，并且，其中，任选重复所述第一个步骤和第二个步骤一次或多次。
本文所披露的方法还可以包括第一个步骤和第二个步骤，其中，在第一个步骤中，将包括四种核苷酸中的三种的组合物与所述靶接触，并且在检测之前除去未掺入的核苷酸，并且随后除去所述标记，并且，其中，在第二个步骤中，让包括第一种组合物中所不包括的核苷酸的组合物与所述靶接触，并且在检测之前除去未掺入的核苷酸，并且随后除去所述标记，并且，其中，任选重复所述第一个步骤和第二个步骤一次或多次。
在另一方面，本发明涉及一种试剂盒，其中，所述试剂盒包括：(a)各个核苷酸，其中，每一个核苷酸具有通过可裂解的接头与可检测的标记连接的碱基，并且，其中，与每一种核苷酸连接的所述可检测的标记，在检测时可以与用于标记其他三种核苷酸的可检测标记区分开来；和(b)它们的包装材料。所述试剂盒还可以包括酶和适合所述酶作用的缓冲液。
所述核苷酸/核苷适用于很多不同的基于DNA的方法中，包括DNA合成和DNA测序方法。
根据本发明的另一方面，用于确定靶多核苷酸序列的方法包括监测互补性核苷酸的依次掺入，其中，所述核苷酸包括通过可裂解的接头与所述核苷酸的碱基部分连接的可检测的标记，通过监测所述标记而检测掺入，并且将所述标记除去，以便能够进行进一步的核苷酸掺入。
附图说明
图1表示用于本发明的典型核苷酸结构。对于每一种结构来说，X可以是H，磷酸，二磷酸或三磷酸。R1和R2可以相同或不同，并且可以选自H，OH，或可以转化成OH的任何基团。
图2表示用于本发明的接头的结构，除了可以使用的所述接头的一般定义之外，包括(1)二硫接头和酸不稳定性接头，(2)二烷氧基苄基接头，(3)Sieber接头，(4)吲哚接头和(5)叔丁基Sieber接头。
图3表示用于本发明的某些功能性分子，包括某些可裂解的接头。在所述结构中，R1和R2可以相同或不同，并且可以是H，OH，或可以转化成OH的任何基团，包括羰基。R3表示独立地选自烷基，烷氧基，氨基，或卤素的一个或多个取代基。另外，可以用任何用在3′-封闭基团上的不稳定性官能团，构建可裂解的接头。
图4表示变性凝胶，展示用Klenow聚合酶进行的实施例1的三磷酸的掺入。
图5表示变性凝胶，展示用Klenow聚合酶进行的实施例3的三磷酸的掺入。
图6表示变性凝胶，展示用Klenow聚合酶进行的实施例4的三磷酸的掺入。
详细说明
本发明涉及通过可裂解的接头连接标记的方式修饰过的核苷酸和核苷，以便使得所述分子可用于所述标记过的分子与酶相互作用的技术中，如测序反应，多核苷酸合成，核酸扩增，核酸杂交分析，单核苷酸多态性研究，使用诸如聚合酶，逆转录酶，末端转移酶的酶的技术，使用标记过的dNTPs的技术(例如，切口翻译，随机引物标记，末端标记(例如，使用末端脱氧核苷酸转移酶)逆转录，或核酸扩增)。
正如本领域所公知的，“核苷酸”由含氮碱基，糖，以及一个或多个磷酸基团组成。在RNA中，所述糖是核糖，而在DNA中，所述糖是脱氧核糖，即缺少存在于核糖中的羟基的糖。所述含氮碱基是嘌呤或嘧啶的衍生物。所述嘌呤是腺嘌呤(A)和鸟嘌呤(G)，而所述嘧啶是胞嘧啶(C)和胸腺嘧啶(T)(或对于RNA来说，是尿嘧啶(U))。将脱氧核糖的C-1原子键合于嘧啶的N-1或嘌呤的N-9。核苷酸也是核苷的磷酸酯，酯化发生在与所述糖的C-5连接的羟基上。核苷酸通常是单磷酸，二磷酸或三磷酸酯。
“核苷”在结构上类似于核苷酸，但是，缺少了磷酸部分。核苷类似物的一种例子是其中的标记与所述碱基连接的核苷，并且，没有与糖分子结合的磷酸基团。
尽管所述碱基通常被称作嘌呤或嘧啶，技术人员可以理解的是，可以获得不会改变所述核苷酸或核苷进行Watson-Crick碱基配对的能力的衍生物和类似物。“衍生物”或“类似物”表示其核心结构与母体化合物相同或非常接近的化合物或分子，不过，它具有化学或物理修饰，如不同的或额外的侧基，这使得所述衍生的核苷酸或核苷能够与其他分子连接。例如，所述碱基可以是脱氮嘌呤。所述衍生物应当能够进行Watson-Crick配对。“衍生物”和“类似物”还表示具有修饰过的碱基部分和/或修饰过的糖部分的合成核苷酸或核苷衍生物。例如，所述衍生物和类似物披露于以下文献中：Scheit，NucleotideAnalogs(John Wiley & Son，1980)和Uhlman等，Chemical Reviews90：543-584，1990。核苷酸类似物还可以包括修饰过的磷酸二酯键，包括硫代磷酸酯，二硫代磷酸酯，烷基磷酸酯，phosphoranilidate和氨基磷酸酯键。所述类似物应当能够进行Watson-Crick碱基配对。本文所使用的“衍生物”和“类似物”可以交换使用，并且包括在本文所定义的术语“核苷酸”和“核苷”的范围内。
本发明可以利用常规可检测标记。检测可以通过任何合适的方法进行，包括荧光光谱法或通过其他光学方法。优选的标记是荧光团，它在吸收能量之后，能发射出特定波长的辐射。很多合适的荧光标记是已知的。例如，Welch等(Chem.Eur.J.5(3)：951-960，1999)披露了丹酰-官能化荧光部分，可将它用于本发明中。Zhu等(Cytometry28：206-211，1997)披露了荧光标记Cy3和Cy5的用途，还可将其用于本发明中。适合使用的标记还披露于以下文献中：Prober等(Science 238：336-341，1987)；Connell等(BioTechniques 5(4)：342-384，1987)，Ansorge等(Nucl.Acids Res.15(11)：4593-4602，1987)和Smith等(Nature 321：674，1986)。其他可通过商业渠道获得的荧光标记包括，但不局限于荧光素，罗丹明(包括TMR，德克萨斯红和Rox)，alexa，bodipy，吖啶，香豆素，芘，苯并蒽和花青苷。
还可以将多种标记用于本发明中。例如，双荧光团FRET盒(Tet.Letts.46：8867-8871，2000)为本领域所熟知，并且可用于本发明中。还可以使用多荧光树枝型聚合物系统(J.Amer.Chem.Soc.123：8101-8108，2001)。
尽管荧光标记是优选的，对于本领域普通技术人员来说，其他形式的可检测标记显然是可利用的。例如，微颗粒，包括量子斑点(Empodocles等，Nature 399：126-130，1999)，金纳米颗粒(Reichert等，Anal.Chem.72：6025-6029，2000)，微珠(Lacoste等，Proc.Natl.Acad.Sci USA 97(17)：9461-9466，2000)，以及可以通过质谱法检测的标记都可以使用。
还可以将多成分标记用于本发明中。多成分标记是取决于与用于检测的另一种化合物相互作用的标记。生物学中所使用的最常见的多成分标记是生物素-链亲和素系统。将生物素用作与所述核苷酸碱基连接的标记。然后单独添加链亲和素，以便能够进行检测。可以获得其他多成分系统。例如，二硝基苯酚具有可以通过商业渠道获得的能用于检测的荧光抗体。
所述标记(或标记和接头构建体)可以具有足以发挥阻断其他核苷酸掺入到本发明的核苷酸上的大小或结构。这使得能够进行受控制的聚合。所述阻断可能是由于空间位阻造成的，或者可能是由于大小，电荷和结构的组合造成的。
将针对核苷酸对本发明作进一步说明。不过，除非另有说明，对核苷酸的说明同样适用于核苷。还将针对DNA对本发明作进一步说明，不过，这种说明还适用于RNA，PNA，以及其他核酸，除非另有说明。
本发明的修饰过的核苷酸利用可裂解的接头将所述标记连接在核苷酸上。可裂解的接头的使用，能确保所述标记可以在检测之后除去(如果必要的话)，避免了任何干扰信号，并且随后可以掺入任何标记过的核苷酸。
可裂解的接头为本领域所公知，并且可以采用常规化学方法，以便将接头连接在核苷酸碱基和标记上。所述接头可以通过任何合适的方法裂解，包括接触酸，碱，亲核试剂，亲电试剂，自由基，金属，还原或氧化试剂，光照，温度，酶等。合适的接头可以用标准化学封闭基团改良，正如在以下文献中所披露的：Greene & Wuts，ProtectiveGroups in Organic Synthesis，John Wiley & Sons。Guillier等披露了用于固相合成的其他合适的可裂解的接头(Chem.Rev.100：2092-2157，2000)。
术语“可裂解的接头”的使用并非意味着需要将整个接头从核苷酸碱基上除去。裂解位点可能位于所述接头上的位置，以便确保在裂解之后所述接头的部分保持与所述核苷酸碱基连接。
所述接头可以连接在核苷酸碱基的任何位置上，其前提是，仍然能进行Watson-Crick碱基配对。对于嘌呤碱基来说，如果所述接头是通过所述嘌呤或优选的脱氮嘌呤类似物的7号位置，通过8-修饰过的嘌呤，通过N-6修饰过的腺嘌呤或N-2修饰过的鸟嘌呤连接的话将是优选的。对于嘧啶来说，连接优选是通过胞嘧啶，胸腺嘧啶和尿嘧啶上的5号位置和胞苷上的N-4位置连接的。合适的核苷酸结构如图1所示。对于图1中的每一种结构来说，X可以是H，磷酸，二磷酸或三磷酸。R1和R2可以相同或不同，并且可以选自H，OH，或能够转化成OH的任何基团，包括，但不局限于羰基。
合适的接头总体上在图2中示出，并且，包括，但不局限于二硫接头(1)，酸不稳定性接头(2，3，4和5；包括二烷氧基苄基接头(例如2)，Sieber接头(例如)，吲哚接头(例如4)，叔丁基Sieber接头(例如))，亲电可裂解的接头，亲核可裂解的接头，光可裂解的接头，在还原条件，氧化条件下裂解，通过使用保险栓(safety-catch)接头进行的裂解，以及通过消除机制进行裂解。
A.亲电子裂解的接头。
亲电子裂解的接头通常是由质子裂解的，并且包括对酸的裂解敏感性。合适的接头包括修饰过的苄基系统，如三苯甲基，对烷氧基苄基酯，和对烷氧基苄基酰胺。其他合适的接头包括叔丁氧羰基(Boc)基团，和缩醛系统(例如，在图3中示出的O-C(R4)(R5)-O-R6)。
为了制备合适的接头分子，还可以考虑将诸如镍，银或汞的亲硫金属用于硫代缩醛或其他含硫的保护基团的裂解。
B.亲核裂解的接头
亲核裂解也是得到充分认可制备接头分子的的方法。可以使用在水中不稳定的诸如酯的基团(即，可以在碱性pH下简单地裂解)，以及对非水亲核试剂不稳定的基团。可以用氟离子裂解诸如三异丙基硅烷(TIPS)或叔丁基二甲基硅烷(TBDMS)的基团中的硅-氧键。
C.光可裂解的接头。
光可裂解的接头业已被广泛用于糖类化学。优选的是，激活裂解所需要的光不会影响所述修饰过的核苷酸的其他成分。例如，如果用荧光团作标记的话，如果它所吸收的光的波长与裂解所述接头分子所需要的光的波长不同，则是优选的。合适的接头包括基于O-硝基苄基化合物和硝基藜芦基化合物的接头。还可以使用基于二苯乙醇酮化学的接头(Lee等，J.Org.Chem.64：3454-3460，1999)。
D.在还原条件下的裂解
存在很多已知容易受还原性裂解的接头。业已将使用基于钯的催化剂的催化氢化作用裂解苄基和苄基氧基羰基基团。二硫键还原也是本领域所公知的。
E.在氧化条件下的裂解
基于氧化的方法为本领域所熟知。其中包括对烷氧基苄基的氧化以及硫和硒接头的氧化。利用含水的碘裂解二硫接头和其他基于硫或硒的接头也属于本发明的范围。
F.保险栓接头
保险栓接头是分两个步骤裂解的接头。在一种优选系统中，第一个步骤是制备反应性亲核中心，然后进行的第二个步骤包括会导致裂解的分子内环化。例如，可以用肼或光化学处理乙酰丙酸酯键，以便释放活性胺，然后可以将所述活性胺环化，以便裂解所述分子中其他部位的酯(Burgess等，J.Org.Chem.62：5165-5168，1997)。
G.通过消除机制裂解
还可以使用消除反应。例如，可以使用诸如Fmoc和氰乙基的基团的碱催化的消除，和烯丙基系统的钯催化的还原型消除。
除了所述裂解位点之外，所述接头可以包括间隔单位。所述间隔基团将所述核苷酸碱基与所述裂解位点或标记分开。所述接头的长度是不重要的，其前提是，所述标记保持离开所述核苷酸的足够距离，以便不干扰所述核苷酸和酶的任何相互作用。
所述修饰过的核苷酸还可以包括其他基团或所述糖基团的修饰。例如，可以制备在核糖环结构上缺少两个氧的双脱氧核糖衍生物(位于2′和3′位置上)，并且用作生长的寡核苷酸链上的其他核苷酸掺入的封闭基团。所述保护基团要被用于阻止核苷酸掺入在新生的多核苷酸链上，并且可以在特定条件下除去，以便能够进行聚合。与现有技术相反，没有结合在核糖3’位置上的可检测的标记。由此确保降低对所述聚合酶的空间位阻，但仍然能够用所述保护基团控制掺入。
技术人员将会理解如何将合适的保护基团连接在核糖环上，以便阻断与3′-OH的相互作用。所述保护基团可以直接连接在3’位置上，或者可以连接在2’位置上(所述保护基团具有足够的大小或电荷，以便阻断3’位置上的相互作用)。另外，所述保护基团可以连接在3′和2′位置，并且可以裂解，以便暴露出3′OH基团。
合适的保护基团对本发明技术人员来说是显而易见的，并且可以用披露于以下文献中的任何合适的保护基团制备：Green和Wuts，同上。所述保护基团应当是可以除去的(或可以修饰的)，以便产生3′OH基团。用于获得3′OH的方法，可以是任何合适的化学或酶促反应。
所述不稳定性的接头，可以包括能够在与所述封闭相同的条件下裂解的官能团。这将使得所述脱保护方法更为有效，因为裂解所述标记和封闭基团只需要一次处理。因此，所述接头可以包括如图3所示的官能团，它可以与位于所述残余核苷上的羟基官能团或所述除去的标记一起裂解。所述接头还可以包括完全不同的化学官能团，所述官能团对于用于裂解所述封闭基团的条件来说是不稳定的。
术语“烷基”包括直链和支链烷基，除非本文中另有说明，术语“烷基”表示具有1-8个碳原子的基团，并且通常具有1-6个碳原子，例如1-4个碳原子。烷基的例子，包括甲基，乙基，丙基，异丙基，正丁基，异丁基，叔丁基，正戊基，2-戊基，3-戊基，2-甲基丁基，3-甲基丁基和正己基以及它们的异构体。
环烷基的例子是具有3-10个环原子的基团，具体例子包括源于环丙烷，环丁烷，环戊烷，环己烷和环庚烷，双环庚烷和萘烷的基团。
链烯基的例子包括，但不局限于乙烯基(烯基)，1-丙烯基，2-丙烯基(烯丙基)，异丙烯基，丁烯基，丁-1，4-二烯基，戊烯基，和己烯基。
环链烯基的例子包括，但不局限于环丙烯基，环丁烯基，环戊烯基，环戊二烯基，和环己烯基。
术语“烷氧基”表示C1-6烷氧基，除非另有说明：-OR，其中，R是C1-6烷基。C1-6烷氧基的例子包括，但不局限于-OMe(甲氧基)，-OEt(乙氧基)，-O(nPr)(正丙氧基)，-O(iPr)(异丙氧基)，-O(nBu)(正丁氧基)，-O(sBu)(仲-丁氧基)，-O(iBu)(异丁氧基)，和-O(tBu)(叔-丁氧基)。
术语氨基表示NR1R2类型的基团，其中，R1和R2独立地选自氢，C1-6烷基(又称之为C1-6烷基氨基或二-C1-6烷基氨基)。
本文所使用的术语“卤素”包括氟，氯，溴，和碘。
本发明的核苷酸分子适用于很多不同的方法，其中，需要检测核苷酸。
DNA测序方法，如可以用所述核苷酸进行披露于美国专利号5,302,509中的方法。
用于测定靶多核苷酸序列的方法可以这样进行：让靶多核苷酸分别与不同的核苷酸接触，以便形成所述靶核苷酸的互补体，并且检测所述核苷酸的掺入。所述方法利用了聚合，使得聚合酶通过掺入互补于所述靶的正确的核苷酸，以延伸所述互补链。所述聚合反应还需要特殊引物来启动聚合作用。
对每一轮反应来说，所述标记过的核苷酸的掺入，是通过聚合酶进行的，并且，然后测定所述掺入事件。存在很多不同的聚合酶，并且，对本领域普通技术人员来说，显而易见的是哪一种酶是最适合使用的。优选的酶包括DNA聚合酶I，Klenow片段，DNA聚合酶III，T4或T7 DNA聚合酶，Taq聚合酶或vent聚合酶。还可以使用通过工程方法改造成具有特定性质的聚合酶。
所述测序方法优选对排列在固体支持物上的靶多核苷酸进行。可以通过接头分子将多个靶多核苷酸固定在所述固体支持物上，或者可以连接在诸如微球体的颗粒上，所述颗粒还可以连接在固体支持材料上。
可以通过多种方法将所述多核苷酸连接在所述固体支持物上，包括使用生物素-链亲和素相互作用。用于将多核苷酸固定在固体支持物上的方法为本领域所公知，并且，包括石板印刷技术以及将每一种多核苷酸“点”在固体支持物的特定位置上。合适的固体支持物为本领域所公知，并且包括玻璃载玻片和珠，陶瓷和硅表面和塑料材料。所述支持物通常是平面，尽管也可以使用微珠(微球体)，并且还可以通过已知方法将后者连接在其他固体支持物上。所述微球体可以具有任何合适的大小，其直径通常为10-100纳米。在优选实施方案中，将所述多核苷酸直接连接在平面上，优选连接在平的玻璃表面上。连接优选通过共价键的形式进行。所使用的阵列优选是单分子阵列，它包括位于独特的光学可分辨区域的多核苷酸，例如，正如在国际申请号WO00/06770中所披露的。
所述测序列方法可以针对单个多核苷酸分子和多个多核苷酸分子阵列进行，即具有不同的各个多核苷酸分子的阵列，和具有包括一种多核苷酸分子的多个拷贝的不同区域的阵列。单分子阵列使得每一种多核苷酸可以独立分辨。优选使用单分子阵列。对单一分子阵列的非破坏性测序，使得能够形成可以空间寻址的阵列。
所述方法利用聚合反应制备所述靶的互补序列。进行聚合的必须条件，对技术人员来说是显而易见的。
为了进行所述聚合酶反应，通常首先必须使引物序列与所述靶多核苷酸退火，所述引物序列是由所述聚合酶识别的，并且起着所述互补链随后延伸的起始位点的作用。所述引物序列可以相对所述靶多核苷酸作为独立的成分添加。另外，所述引物和靶多核苷酸可以分别是一个单链分子的一部分，由所述引物部分与所述靶的一部分形成分子内双链体，即发卡环结构。可以在所述分子的任何位点，将该结构固定在所述固体支持物上。进行所述聚合酶反应所必需的其他条件，对本领域技术人员来说是显而易见的，这些条件包括温度，pH，缓冲液组成。
然后，让本发明的修饰过的核苷酸与所述靶多核苷酸接触，以便能够进行聚合。所述核苷酸可以依次添加，即分别添加每一种类型的核苷酸(A，T，G或C)，或同时添加。如果所述核苷酸是同时添加的话，优选用不同的标记对每一种类型的核苷酸进行标记。
让所述聚合步骤进行足以掺入一个核苷酸的时间。
然后除去未掺入的核苷酸，例如，通过对所述阵列实施洗涤步骤，并且随后可以进行对掺入标记的检测。
检测可以通过常规方法进行，例如，如果所述标记是荧光部分的话，掺入的碱基的检测，可以通过使用共焦扫描显微镜进行，用激光扫描所述阵列的表面，以便使直接结合在所述掺入的碱基上的荧光团成像。另外，可以用灵敏的2-D探测器，如电荷偶连的探测器(CCD)观察所产生的每一种信号。不过，可以获得诸如扫描近场光学显微方法(SNOM)的其他技术，并且可用于使密集的阵列成像。例如，使用SNOM可以分辨间隔距离小于100纳米，例如，10纳米-10微米的各个多核苷酸。有关扫描近场光学显微方法的说明，可以参见Moyer等，Laser Focus World 29：10，1993。用于使多核苷酸阵列成像的合适的装置是公知的，并且其技术参数为技术人员所公知。
在检测之后，可以用裂解所述接头的合适条件除去所述标记。
修饰过的核苷酸的使用并不局限于DNA测序技术，还可用本发明的核苷酸实施包括多核苷酸合成，DNA杂交分析，和单核苷酸多态性研究的其他形式。涉及到核苷酸和酶之间的相互作用的任何技术，都可以利用本发明的分子。例如，可以将所述分子用作逆转录酶或末端转移酶的底物。
合适的结构披露于以下实施例中，并且在附图中示出。
实施例
实施例1.二硫接头的合成
Figure A0282783200181
将叔丁基-N-(2-巯基乙基)氨甲基酸酯(3mmol，0.5mL)滴加到将1.32g(6.0mmol)aldrithiol溶解在15mL MeOH中制成的溶液中。在1.5小时之后，该反应业已结束，并且蒸发所述溶剂。通过在二氧化硅上面用乙酸乙酯∶石油醚(1∶4)层析而纯化所述粗制产物。产物1a是以浅黄色油状物形式获得的(0.76g，2.67mmol，89％)。1HNMR(500Mhz，D6-DMSO)：d＝1.38(s，9H，tBu)，2.88(t，J＝6.6Hz，2H，SCH2)，3.20(q，J＝6.6Hz，2H，CH2NH)，7.02(bs，1H，NH)，7.24(ddd，J＝7.3Hz，J＝4.9Hz，J＝1.0Hz，1H，H-5)，7.77(dt，J＝8.1Hz，J＝1.0Hz，1H，H-3)，7.82(ddd，J＝8.1Hz，J＝7.4Hz，J＝1.8Hz，1H，H-4)，8.46(ddd，J＝4.9Hz，J＝1.8Hz，J＝1.0Hz，1H，H-6)。
Figure A0282783200182
为了对1a的胺脱保护，将17mg(60μmol)溶解在0.5mL DCM和0.5mL三氟乙酸的混合物中。在室温下将该混合物搅拌2.5小时，然后在减压条件下除去溶剂。重复三次将残余物重新溶解在2mL DCM中，并且蒸发至干燥。在高真空条件下将所述脱保护的产物干燥3小时，然后溶解在1mL干燥DMF中。假设所述脱保护作用业已完成。
向将15mg 5-羧甲基四甲基罗丹明(35μmol)溶解在2mL DMF中制成的溶液中添加8.0mg N-羟基琥珀酰亚胺(70μmol)和7.8mg DCC(38μmol)。在黑暗中搅拌该混合物6小时。然后添加22μl DIPEA(126μmol)和溶解在1mL DMF中的脱保护的1a的溶液。在黑暗中搅拌该反应混合物过夜，然后在减压条件下除去溶剂。将残余物溶解在DCM中，并且用饱和氯化钠溶液洗涤。在硫酸镁上干燥之后，用CHCl3∶MeOH(3∶1)作溶剂在二氧化硅上纯化所述粗制混合物。1b是以暗红色固体形式分离的，产率为90％(19.2mg，31.4μmol)。1H NMR(500MHz，D6-DMSO)：δ＝3.09(t，J＝6.7Hz，2H，SCH2)，3.63(q，J＝6.2Hz，2H，CH2NH)，6.48-6.53(m，6H，H-蒽)，7.23-7.26[m，1H，(吡啶)]，7.32(d，J＝7.9Hz，1Hz，H-3)，7.81-7.82[m，2H，H-3+H-4(吡啶)]，8.21(d，J＝7.9Hz，1H，H-4)，8.43(s，1H，H-6)，8.47[dt，J＝4.7Hz，J＝1.3Hz，1H，H-6(吡啶)]，9.03(t，J＝5.2Hz，1H，NH)。
将巯基丙酸(20.6μmol，1.8ml)添加到由19.6mg 1b(32.7μmol)溶解在2mL MeOH中制成的溶液中。在黑暗中搅拌2.5小时。在减压条件下除去所述溶剂。用CHCl3∶MeOH∶AcOH 15∶1∶0.5作溶剂混合物，通过在二氧化硅上层析，纯化所述粗制产物。可以分离15.5mg(26μmol，80％)暗红色晶体1c。1H NMR(500MHz，D20)：δ＝2.53(t，J＝7.0Hz，2H，CH2COOH)，2.88(t，J＝7.0Hz，2H，CH2CH2COOH)，2.96-2.99(m，2H，CH2CH2NH)，3.73(t，J＝6.3Hz，2H，CH2NH)，6.53(d，J＝2.4Hz，2H，H-蒽)，6.81(dd，J＝9.5Hz，J＝4.5Hz，2H，H-蒽)，7.12(d，J＝9.5Hz，2H，H-蒽)，7.48(d，J＝7.9Hz，1H，H-3)，7.95(dd，J＝8.1Hz，J＝1.9Hz，1H，H-2)，8.13(d，J＝1.9Hz，1H，H-1)。+v电子喷射(C30H31N3O6S2)：预计为593.17；实测为594.3[M+H]，616.2[M+Na]。
将9.9mg N-羟基琥珀酰亚胺(86.8μmol)和9.7mg DCC(47.1μmol)添加到通过将25.8mg 1c(43.4μmol)溶解在3mL DMF(无水)制成的溶液中。在室温下，在黑暗中将该混合物搅拌5小时，然后放入冰箱中过夜。通过棉绒塞将该混合物过滤到新的烧瓶中，并且向该混合物中添加865μL propargylamino dUTP(14.7μmol，17μmol，溶解在1mL H2O)和3mL硼酸钠缓冲液(0.1M溶液，pH9)的溶液中。搅拌该混合物过夜。在除去溶剂之后，将残余物溶解在尽可能少的水中，并且通过HPLC纯化。使用Zorba×C18柱，用0.1M三乙基碳酸氢铵(TEAB)和乙腈作缓冲液。31p NMR(400MHz，D2O)：δ＝-4.73(d)，-9.93(d)，19.03(t)。-ve电子喷射(C42H47N6O19P3S2假定4H+抗衡离子)。预计为1096.16；实测为1092.9。在水中的UV：λ(max)＝555nm，A(555)＝0.885(c＝0.036μmol)。
用Klenow DNA聚合酶成功地掺入了三磷酸(1)。所述反应是在以下条件下进行的：50mM Tris·HCl(pH7.5)，10mM NaCl，2mM DTT，0.1mM EDTA，5mM MgCl2，2μM化合物3，100nM DNA模板(事先用P32和T4多核苷酸激酶标记过的)和10个单位的市售外-Klenow(Amersham Corp.，Arlington Heights，Illinois，USA)。所述DNA模板是自我互补的发卡结构(5′-TACCgTCgACgTCgACgCTggCg-AgCgTgCTgCggTTTTT(C6-氨基)TTACCgCAgCACgCTCgCCAgCg；SEQ ID NO：1)。所述反应是在37℃下，在100μL体积中进行的，时间点选择为0，1，3，5和10分钟。使所述反应产物沿变性的(8M尿素)20％聚丙烯酰胺凝胶电泳，并且在typhoon磷成像仪上成像。在1分钟内观察到了完全的单碱基延伸，表明具有有效的聚合酶掺入(二硫接头凝胶，图4)。示出了第二组泳道，其中，在掺入之后，让所述材料接触DTT。可以看到一个不同的带移动，表明从所述DNA构建体上除去了所述染料。因此，业已使用这种二硫化物化合物证实了一轮聚合酶掺入和裂解。
实施例2.无TMR-Sieber接头的酸的合成。
将5-[-9-[9-(芴基-甲基氧基羰基)氨基]呫吨-3-基]戊酸(42.8mg，80μmol)在室温下，与二琥珀酰碳酸酯(22.5mg，88μmol)和N，N-二甲基氨基吡啶(10.8mg，88μmol)一起在DMF中搅拌。5分钟之后，添加单-5-羧基TMR乙二胺(198.9mg，40μmol)，然后添加DIPEA(13.9μl，80μmol)。在室温下搅拌所述反应混合物。2小时之后，用二氯甲烷(100mL)稀释所述反应混合物，并且用1M含水的磷酸二氢钾(50mL)提取所得到的溶液。分离DCM层，并且在减压下蒸发。通过短的柱层析纯化所述残余物。收集用在氯仿中配制的40％甲醇洗脱的所述级份，并且在减压条件下蒸发。然后，将所述残余物溶解在无水DMF(1mL)和N-(2-巯基乙基)氨基甲基聚苯乙烯(200mg，400μmol)和DBU(12μL，80μmol)中。在室温下放置10分钟之后，过滤所述残余物，并且用无水DMF(1mL)漂洗。合并所有的滤液，然后添加到将琥珀酸酐(80mg，800μmol)，DIPEA(139μL，800μmol)和DMAP(9.8mg，80μmol)溶解在DMF(1mL)中制备的溶液中。然后，在室温下搅拌所述反应混合物。在过夜(16小时)之后，在减压下蒸发所有的溶剂，并且通过短的柱层析纯化所述残余物。以紫色粉末形式获得了用溶解在氯仿中的30％的甲醇洗脱的标题化合物(22mg，总产率63％)。1HNMR[D6-DMSO]：8.82(1H，t，J5.4，ex.)，8.75(1H，d，J8.9，ex.)，8.42(1H，d，J1.5)，8.20(1H，dd，J8.0和1.5)，7.95(1H，t，J5.9，ex.)，7.34(1H，d，J7.3)，7.30-7.27(2H，m)，7.21(1H，d，J8.5)，7.16-7.07(2H，m)，6.68(1H，dd，J8.8和2.5)，6.65(1H，d，J2.4)，6.49-6.43(6H，m)，6.18(1H，d，J5.6)，3.95(1H，t，J5.9)，3.39-3.36(2H，m)，3.30-3.27(2H，m)，2.92(12H，s)，2.37-2.33(2H，m)，2.14(2H，t，J7.2)和1.70-1.62(4H，m)。MS[(ES(+)]，m/z 868.5(MH+)。
实施例3.TMR-Sieber接头-dUTP(3)的合成
Figure A0282783200221
在室温下，将无TMR-sieber接头的酸(4.34mg，5μmol)与二琥珀酰碳酸酯(1.74mg，7.5μmol)和N，N-二甲基氨基吡啶(0.92mg，7.5μmol)在DMF(1mL)中搅拌。10分钟之后，将所有反应温和物添加到5-(3-氨基丙炔基)-2′-脱氧尿苷-5′-三磷酸的四-(三-丁铵)盐(10mL)中。在室温下搅拌该反应混合物4小时，并且在冰箱中保存过夜。然后用冷却水(10mL)稀释所述反应混合物，并且将所有得到的溶液加样到DEAE A-25的短柱上。首先用0.1M TEAB缓冲液洗脱所述柱，然后用0.7M TEAB缓冲液洗脱。收集0.7M TEAB洗脱剂，并且在减压下蒸发。用MeOH(2×10mL)共同蒸发残余物，然后通过制备HPLC纯化。以三乙铵盐的形式获得了标题化合物，产率为31％(根据在水中，在555nm波长下对TMR的定量测定(pH7))。在D2O中的1HNMR表明了两种非对映异构体，这是由于sieber接头部分，并且存在大约三个三乙铵抗衡离子。1HNMR[D2O]：8.18(1H，m)，8.06(1H，m)，7.76(0.55H，s)，7.74(0.45H，s)，7.36-7.09(5H，m)，6.89-6.72(3H，m)，6.59-6.37(5H，m)，6.12(0.55H，t，J6.6)，6.05(0.45H，t，J6.6)，5.99(0.45H，d，J2.5)，5.91(1.1H，m)，5.88(0.45H，s)，4.49(0.55H，m)，4.43(0.45H，m)，4.00-3.35(9H，m)，3.30-2.95(32H，m)，2.65-2.52(4H，m)，2.25-2.05(4H，m)，1.62-1.42(4H，m)和1.23(27H，t，J7.3)。31P[D2O]：-9.91(γP，d，J19.2)，[-11.08(αP，d，J20.1)，和-11.30(αP，d，J20.1)，由于两种非对称异构体1和-22.57(βP，m)。MS[(ES(-))m/z1369.1(M-)。
用Klenow DNA聚合酶成功地掺入了三磷酸(3)。所述反应是在以下条件下进行的：50mM Tris-HCl(pH7.5)，10mM NaCl，2mM DTT，0.1mM EDTA，5mM MgCl2，2μM化合物3，100nM DNA模板(事先用P32和T4多核苷酸激酶标记过)和10个单位的市售外-Klenow(Amersham Corp.Arlington Heights，Illinois，USA)。所述DNA模板是自我互补的发卡结构(5′-TACCgTCgACgTCgACgCTggCg-AgCgTgCTgCggTTTTT(C6-氨基)TTACCgCAgCACgCTCgCCAgCg；SEQ ID NO：1)。所述反应是在37℃下，在100μL体积中进行的，时间点选择为0，1，3，5和10分钟。使所述反应产物沿变性的(8M尿素)20％聚丙烯酰胺凝胶电泳，并且在typhoon磷成像仪上成像。在1分钟内出现了完全的单碱基延伸,表明有效的聚合酶掺入(Sieber接头凝胶，图5)。
实施例4.TMR-吲哚接头-dUTP(4)的合成
Figure A0282783200241
用KlenowDNA聚合酶成功地掺入了三磷酸(4)。所述反应是在以下条件下进行的：50mM Tris·HCl(pH7.5)，10mM NaCl，2mM DTT，0.1mM EDTA，5mM MgCl2，2μM化合物3，100nM DNA模板(事先用P32和T4多核苷酸激酶标记过)和10个单位的市售外-Klenow(Amersham Corp.Arlington Heights，Illinois，USA)。所述DNA模板是自我互补的发卡结构(5′-TACCgTCgACgTCgACgCTggCg-AgCgTgCTgCggTTTTT(C6-氨基)TTACCgCAgCACgCTCgCCAgCg；SEQ ID NO：1)。所述反应是在37℃下，在100μL体积中进行的，时间点选择为0，1，3，5和10分钟。使所述反应产物沿变性的(8M尿素)20％聚丙烯酰胺凝胶电泳，并且在typhoon磷成像仪上成像。在1分钟内观察到了完全的单碱基延伸，表明有效的聚合酶掺入(吲哚接头凝胶，图6)。
本文所引用的所有专利，专利申请，和公开的参考文献被以它们的全文形式收作本文参考。尽管业已结合本发明的优选实施方案对本发明进行了具体图示和说明，本领域技术人员可以理解的是，可以对其中的形式和细节进行各种改变，而又不超出由所附权利要求书所包含的本发明的范围。

Claims (25)

1.一种核苷酸或核苷分子，具有通过可裂解的接头与可检测的标记连接的碱基。
2.如权利要求1的分子，其中，所述碱基是嘌呤或嘧啶。
3.如权利要求1或2的分子，其中，所述碱基是脱氮嘌呤。
4.如权利要求1-3中任意一项的分子，具有核糖或脱氧核糖糖部分。
5.如权利要求4的分子，其中，所述核糖或脱氧核糖包括通过2′或3′氧原子连接的保护基团。
6.如权利要求1-5中任意一项的分子，它是脱氧核糖核苷三磷酸。
7.如权利要求1-6中任意一项的分子，其中，所述可检测的标记是荧光团。
8.如权利要求1-7中任意一项的分子，其中，所述接头是酸不稳定性的，光不稳定性的，或包括二硫键。
9.一种标记核酸分子的方法，该方法包括将核苷酸或核苷分子掺入到所述核酸分子中，其中，所述核苷酸或核苷分子具有通过可裂解的接头与可检测的标记连接的碱基。
10.如权利要求9的方法，其中，所述掺入是通过末端转移酶，聚合酶或逆转录酶进行的。
11.如权利要求9或10的方法，其中，所述碱基是脱氮嘌呤。
12.如权利要求9-11中任意一项的方法，其中，所述核苷酸或核苷分子具有核糖或脱氧核糖糖部分，并且，其中，所述核糖或脱氧核糖包括通过2′或3′氧原子连接的保护基团，并且可以对它进行修饰或将其除去，以便暴露出3′OH基团。
13.如权利要求9-12中任意一项的方法，其中，所述核苷酸是脱氧核糖核苷酸三磷酸。
14.如权利要求9-13中任意一项的方法，其中，所述标记是荧光团。
15.如权利要求9-14中任意一项的方法，其中，所述接头是酸不稳定性的，光不稳定性的，或包括二硫键。
16.如权利要求9-15中任意一项的方法，其中，所述可检测的标记和/或可裂解的接头具有足以阻止第二个核苷酸或核苷掺入到所述核酸分子中的大小。
17.一种用于测定靶单链多核苷酸的序列的方法，包括监测互补核苷酸的依次掺入，其中，每个所述核苷酸具有通过可裂解的接头与可检测的标记连接的碱基，并且，其中，每一个掺入的核苷酸的身份是通过检测与所述碱基连接的标记确定的，并且随后除去所述标记。
18.一种用于确定靶单链多核苷酸的序列的方法，包括：
(a)提供核苷酸，其中，所述核苷酸具有通过可裂解的接头与可检测的标记连接的碱基，并且，其中，所述与每一种类型的核苷酸连接的可检测的标记，在检测时可以与用于标记其他类型的核苷酸的可检测标记区分开来；
(b)将核苷酸掺入到所述靶单链多核苷酸的互补体上；
(c)检测(b)的核苷酸的标记，以便确定掺入的核苷酸的类型；
(d)除去(b)的核苷酸的标记；和
(e)任选重复步骤(b)-(d)一次或多次；
以便测定靶单链多核苷酸的序列。
19.如权利要求17的方法，其中，让每一个核苷酸依次与所述靶接触，在添加下一个核苷酸之前除去未掺入的核苷酸，并且其中所述标记的检测和除去是在添加每一个核苷酸之后，或在添加所有四种核苷酸之后进行的。
20.如权利要求17的方法，其中，让所有核苷酸同时与所述靶接触，并且在检测之前除去未掺入的核苷酸，并且随后除去所述标记。
21.如权利要求17的方法，包括第一个步骤和第二个步骤，其中，在第一个步骤中，让包括四种核苷酸中的两种的第一种组合物与所述靶接触，并且在检测之前除去未掺入的核苷酸，并且随后除去所述标记，并且，其中，在第二个步骤中，让包括第一种组合物中所不包括的两种核苷酸的第二种组合物与所述靶接触，并且在检测之前除去未掺入的核苷酸，并且随后除去所述标记，并且，其中，任选重复所述第一个步骤和第二个步骤一次或多次。
22.如权利要求17的方法，包括第一个步骤和第二个步骤，其中，在第一个步骤中，让包括四种核苷酸中的一种的组合物与所述靶接触，并且在检测之前除去未掺入的核苷酸，并且随后除去所述标记，并且，其中，在第二个步骤中，让包括第一种组合物中所不包括的三种核苷酸的第二种组合物与所述靶接触，并且在检测之前除去未掺入的核苷酸，并且随后除去所述标记，并且，其中，任选重复所述第一个步骤和第二个步骤任选一次或多次。
23.如权利要求17的方法，包括第一个步骤和第二个步骤，其中，在第一个步骤中，将包括四种核苷酸中的三种的组合物与所述靶接触，并且在检测之前除去未掺入的核苷酸，并且随后除去所述标记，并且，其中，在第二个步骤中，让包括第一种组合物中所不包括的核苷酸的组合物与所述靶接触，并且在检测之前除去未掺入的核苷酸，并且随后除去所述标记，并且，其中，任选重复所述第一个步骤和第二个步骤一次或多次。
24.一种试剂盒，所述试剂盒包括：
(a)各个核苷酸，其中，每一个核苷酸具有通过可裂解的接头与可检测的标记连接的碱基，并且，其中，与每一种核苷酸连接的所述可检测的标记，在检测时可以与用于标记其他三种核苷酸的可检测标记区分开来；和
(b)它们的包装材料。
25.如权利要求21的试剂盒，所述试剂盒还包括酶和适合所述酶起作用的缓冲液。
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