CN115552030A - 单分子电子序列检测器及其使用方法 - Google Patents
单分子电子序列检测器及其使用方法 Download PDFInfo
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Abstract
本公开提供了与单分子检测相关的装置、系统和方法。具体而言,本公开提供了用于使用电流波动作为蛋白质结合到核酸靶的读数来序列特异性检测所述核酸靶的装置和方法。如本文所述,所述生物电子装置和方法的某些方面可用于检测和识别任何核酸靶以用于诊断和/或治疗的目的。
Description
政府支持
本发明是在由美国国家卫生研究院颁发的HG010522下借助政府资助进行的。政府拥有本发明的某些权利。
相关申请
本申请要求2020年2月28日提交的美国临时专利申请号63/011,799的优先权和权益,所述申请以引用的方式整体并入本文用于所有目的。
以电子方式提交的材料以引用的方式并入
计算机可读核苷酸/氨基酸序列表与本文同时随同提交并标识如下:一个名为“2021-04-15_38883-601_SQL_ST25.txt”的21,644字节ASCII(文本)文件,创建于2021年4月15日,所述序列表以引用的方式全部并入本文。
技术领域
本公开提供了与单分子检测相关的装置、系统和方法。具体而言,本公开提供了用于使用电流波动作为蛋白质结合到核酸靶的读数来序列特异性检测所述核酸靶的装置和方法。如本文所述,本文所述的生物电子装置和方法的某些方面可用于检测和识别任何核酸靶以用于诊断和/或治疗的目的。
背景技术
簇状规则间隔短回文重复序列(CRISPR)相关Cas核酸酶是一组参与适应性细菌免疫的可编程核糖核蛋白(RNP)。20个核苷酸(在大多数情况下)的特定DNA和RNA靶基序由以下定义:包含靶序列的CRISPR RNA(crRNA)和恒定序列的反式激活crRNA(tracrRNA),两者折叠形成结合Cas9(或其他CRISPR相关蛋白,也称为Cas核酸酶)的茎环结构。Cas9 CRISPR复合物与其靶序列的相互作用是通过扫描样品(例如基因组样品)、解开双链DNA并在前间区序列邻近基序的上游结合,直到它找到与dRNP内的单引导RNA分子(sgRNA)互补的靶序列并与该靶序列结合。由sgRNA编程的RNP是一种在以下应用中用于搜索非常特定的靶序列的有效方法,所述应用诸如基因分型(生殖系和体细胞)、HLA分型、用于靶向基因分型的医学遗传学、循环肿瘤DNA、胎儿DNA测试、传染病检测和监测;任何核酸传感、犯罪学和生物防御。
野生型RNP的功能是切割靶DNA。但是通过使用修饰的RNP(其中核酸酶活性受到抑制),复合物在靶序列处停止,捕获靶DNA。这些核酸酶缺陷型Cas蛋白表示为dCas,例如dCas9。已经开发了一种将许多RNP结合到石墨烯场效应晶体管通道的装置(例如,捕获靶DNA会导致石墨烯通道表面上的电荷增加,这经由流过石墨烯FET通道的电流的变化来检测)。然而,这种检测是不利的,因为检测是模拟的(记录为电流的连续变化),并且需要校准来进行靶DNA的量化。因此,目前可用的装置和系统不足以在单分子水平上检测靶DNA。
发明内容
本公开的实施方案包括一种用于检测靶核酸的生物电子装置。根据这些实施方案,所述装置包括第一电极、第二电极和至少一种CRISPR相关蛋白。在一些实施方案中,所述CRISPR相关蛋白被修饰以与所述第一电极和所述第二电极中的至少一个形成化学键。
在一些实施方案中,所述修饰允许电流通过所述CRISPR相关蛋白,并且所述CRISPR相关蛋白与靶核酸的结合导致电流的偏移。
在一些实施方案中,所述CRISPR相关蛋白是Cas家族成员蛋白,所述Cas家族成员蛋白选自由Cas1、Cas2、Cas3、Cas4、Cas5、Cas6、Cas7、Cas8、Cas10、Cas12、Cas13、Cas14、其核酸酶缺陷型dCas等效物及其任何变体或衍生物组成的组。在一些实施方案中,所述CRISPR相关蛋白是Cas9蛋白或dCas9。
在一些实施方案中,所述修饰包括添加接头。在一些实施方案中,所述修饰包括在CRISPR相关蛋白的至少两个位点上添加至少两个接头,其中所述至少两个接头连接到第一电极和第二电极中的每一个。在一些实施方案中,所述至少两个接头中的一个接头连接到所述CRISPR相关蛋白上的位点,并且所述至少两个接头中的另一个接头连接到所述CRISPR相关蛋白上的不同位点。
在一些实施方案中,所述接头经由共价化学键连接到所述CRISPR相关蛋白的非活性区域。在一些实施方案中,所述修饰包括对所述CRISPR相关蛋白进行生物素化。在一些实施方案中,所述接头包含硫代链霉亲和素。在一些实施方案中,所述CRISPR相关蛋白以及所述第一电极和所述第二电极被生物素化,并且所述接头包含具有至少两个生物素结合位点的链霉亲和素分子。
在一些实施方案中,所述修饰包含HaloTag融合蛋白和氯代烷烃接头。
在一些实施方案中,所述第一电极和/或所述第二电极包含金、钯、铂、银、铜或其任何合金。
在一些实施方案中,所述第一电极包括至少部分地覆盖所述第一电极的顶表面的介电层。
在一些实施方案中,所述介电层的厚度为约1nm至约50nm。
在一些实施方案中,所述第一电极和所述第二电极定位成使得在两个电极之间形成介于约1nm与约50nm之间的间隙。在一些实施方案中,所述间隙为约2至约8nm。
本公开的实施方案还包括一种使用本文描述的任何生物电子装置检测靶核酸的方法。根据这些实施方案,所述方法包括将所述生物电子装置和所述靶核酸与引导RNA组合,在所述第一电极与所述第二电极之间施加100mV或更小的电压偏压,以及检测所述CRISPR相关蛋白和所述引导RNA与所述靶核酸结合时电流的偏移。
在所述方法的一些实施方案中,所述引导RNA与所述靶核酸的一部分互补。
在所述方法的一些实施方案中,与所述CRISPR相关蛋白未与所述靶核酸结合时相比,电流的偏移包括电流的降低。
在所述方法的一些实施方案中,所述靶核酸包含在来自受试者的样品中或来源于所述样品。
在所述方法的一些实施方案中,检测到电流的偏移表明靶核酸存在于样品中。
在所述方法的一些实施方案中,所述样品选自由血液样品、血清样品、血浆样品、唾液样品、尿液样品、粪便样品和粘膜样品组成的组。
在所述方法的一些实施方案中,所述靶核酸是DNA或RNA。
在所述方法的一些实施方案中,所述靶核酸来源于病原生物或与病原生物相关。在所述方法的一些实施方案中,所述靶核酸来源于疾病或病状、与疾病或病状相关或指示疾病或病状。在所述方法的一些实施方案中,所述靶核酸来源于工程生物或与工程生物相关。在所述方法的一些实施方案中,所述靶核酸来源于SARS-CoV-2感染或与SARS-CoV-2感染相关。
本公开的实施方案还包括一种系统,所述系统包括多个本文所述的生物电子装置。在所述系统的一些实施方案中,所述多个生物电子装置被配置为基于对应的引导RNA序列检测超过一种靶核酸。
附图说明
图1:根据本公开的一个实施方案,集成到电子记录电路(例如,生物电子装置)中的示例性CRISPR相关蛋白的代表性示意图。
图2:根据本公开的一个实施方案,当靶DNA序列在存在对应的引导RNA情况下结合CRISPR相关蛋白时产生的电信号的代表性图。
图3A-3B:根据本公开的实施方案,经由两个特定化学接触安装在电极之间(图3A),和经由一个特定化学接触和一个非特定物理接触安装在电极之间(图3B)的单个CRISPR相关蛋白(例如,Cas9)的代表性示意图。
图4:根据本公开的一个实施方案,经由生物素-链霉亲和素键与链霉亲和素接头分子功能性偶联的CRISPR相关蛋白(例如,dCas9)的代表性示意图。
图5A-5D:图5A包括在没有靶DNA的情况下dCas9+sgRNA的单分子电导分布的代表性图形数据。该图在纵轴上提供了电导值的概率,与测量电导的对数(以10为底);两个峰对应于两个特定连接(较高电导)和一个特定连接(较低电导)。图5B包括在存在靶DNA的情况下dCas9+sgRNA的单分子电导分布的代表性图形数据。图5C包括在有(绿点)和没有(蓝点)靶DNA的情况下分布叠加的代表性图形数据。在存在靶DNA的情况下,最高的传导峰大大减小,而较低峰移向更小电导值。图5D包括在没有DNA(蓝点)和有脱靶DNA(绿点)的情况下相同分布叠加的代表性图形数据。分布不变。
图6:根据本公开的一个实施方案,示例性连接方案(多路复用平台)的代表性示意图。
图7A-7B:与sgRNA结合的许多dCas9分子的电导分布的代表性图形数据(图7A),包括在添加靶DNA后测量的分布;箭头指向电导显著变化的区域(图7B)。
具体实施方式
本章节中使用的章节标题和本文的全部公开内容仅用于组织目的,并且不旨在进行限制。
1.定义
除非另有定义,否则本文使用的所有技术和科学术语均具有与本领域普通技术人员通常理解的相同的含义。如有冲突,以本文档(包括定义)为准。下面描述了优选的方法和材料,尽管与本文描述的那些相似或等效的方法和材料也可以用于本公开的实践或测试。本文中提及的所有出版物、专利申请、专利和其他参考文献均以引用的方式整体并入。本文公开的材料、方法和实施例仅仅是说明性的而不是旨在作为限制性的。
如本文所述,公开的实施方案仅出于说明性目的呈现而不是限制性的。其他实施方案是可能的并且被本公开所覆盖,这将从本文所包含的教导中显而易见。因此,本公开的广度和范围不应受上述实施方案中的任一者的限制,而应仅根据本公开所支持的权利要求及其等效物来限定。此外,本公开的实施方案可以包括方法、组合物、系统和设备/装置,其可以进一步包括来自任何其他公开的方法、组合物、系统和装置的任何和所有元件,包括对应于检测蛋白质活性的任何和所有元件。换句话说,来自一个或另一个公开的实施方案的元件可以与来自其他公开的实施方案的元件互换。此外,可以通过将本文公开的一个和/或另一个特征与在以引用的方式并入的材料中公开的方法、组合物、系统和装置以及它们的一个或多个特征组合来实现一些另外的实施方案。此外,公开的实施方案的一个或多个特征/元件可以被去除,并且仍然产生可授予专利的主题(并因此产生本公开的另外更多的实施方案)。此外,一些实施方案对应于与现有技术的教导相比,具体地缺少一个和/或另一个元件、结构和/或步骤(如适用)的方法、组合物、系统和装置,因此表示可授予专利的主题并且可与现有技术教导区分开(即,针对此类实施方案的权利要求可以包含负面限制,以指出缺少现有技术教导的一个或多个特征)。
如本文所定义和使用的所有定义应理解为高于字典定义、以引用的方式并入的文档中的定义和/或所定义术语的普通含义。
如本文在说明书和权利要求中所用的不定冠词“一个”和“一种”,除非明确指明相反,否则应理解为意指“至少一个/一种”。
如本文在说明书和权利要求中所用的短语“和/或”应理解为意指这样结合的元件中的“任一者或两者”,即,在一些情况下结合存在而在其他情况下分离存在的元件。用“和/或”列出的多个元件应以相同的方式解释,即“一个或多个”这样结合的元件。除了以“和/或”子句特别标识的元件之外,可以任选地存在其他元件,无论与那些特别标识的元件相关还是不相关。因此,作为非限制性实例,当与开放式语言诸如“包含”结合使用时,对“A和/或B”的引用在一个实施方案中可以仅指A(任选地包括除B之外的元件);在另一个实施方案中,仅指B(任选地包括除A之外的元件);在又一个实施方案中,指A和B二者(任选地包括其他元件);等等。
如本文在说明书和权利要求中所用的“或”应理解为与如上定义的“和/或”具有相同的含义。例如,当分隔列表中的项目时,“或”或者“和/或”应解释为具有包容性,即包括元件数量或列表中的至少一者,但也包括多于一者,以及任选地另外的未列出项目。仅明确指出相反的术语,诸如“仅一个”或“恰好一个”,或当在权利要求中使用时,“由……组成”将指包括元件数量或列表中的恰好一个元件。一般而言,如本文所用的术语“或”,当前面带有排他性术语时,诸如“任一个”、“一个”、“仅一个”或“恰好一个”,仅应解释为表示排他性的备选项(即“一个或另一个但不是它们二者”)。权利要求中使用的“基本上由……组成”应具有在专利法领域中使用的普通含义。
如本文在说明书和权利要求中所用,在提及一个或多个元件的列表时,短语“至少一个”应理解为意指选自元件列表中的任何一个或多个元件的至少一个元件,但是不一定包括元件列表中特别列出的每个和每一个元件中的至少一个,并且不排除元件列表中的元件的任何组合。此定义还允许除在短语“至少一个”所指的元件列表中特别标识的元件之外的元件可以任选地存在,无论与那些特别标识的元件相关还是不相关。因此,作为非限制性实例,“A和B中的至少一个”(或等效地“A或B中的至少一个”,或等效地“A和/或B中的至少一个”),在一个实施方案中,可以指至少一个A,任选地包括多于一个A,其中B不存在(并且任选地包括除B之外的元件);在另一个实施方案中,指至少一个B,任选地包括多于一个B,其中A不存在(并且任选地包括除A之外的元件);在又一个实施方案中,指至少一个A,任选地包括多于一个A,以及至少一个B,任选地包括多于一个B(并且任选地包括其他元件);等等。
在权利要求以及上述说明书中,所有过渡短语诸如“包含”、“包括”、“携带”、“具有”、“含有”、“涉及”、“持有”、“由……构成”等等应理解为开放式的,即意味着包括但不限于。如美国专利局专利审查程序手册第2111.03节所述,过渡短语“由……组成”和“基本上由……组成”应仅分别为封闭式或半封闭式过渡短语。
如本文所用,“CAS蛋白”或“CAS蛋白家族”包括哺乳动物细胞凋亡易感性(CAS)蛋白。CAS参与细胞凋亡和增殖两者。CAS耗尽细胞中的凋亡受到抑制,而CAS的表达与细胞增殖程度相关。在细胞核中,CAS充当输入蛋白通路中的核转运因子。输入蛋白通路介导有丝分裂和进一步进展所必需的几种蛋白质的核转运。CAS被认为是通过影响这些蛋白质的核转运来影响细胞周期。由于细胞凋亡还需要几种蛋白质(诸如P53和转录因子)的核输入,因此有人提出CAS还通过促进这些必需蛋白质的至少一个子集的核输入来实现细胞凋亡。CAS蛋白家族的成员具有两个结构域。一个含有HEAT重复序列的N端Cse1结构域和一个C端结构域。在一些实施方案中,如本文进一步描述的,CAS蛋白可以包括但不限于Cas1、Cas2、Cas3、Cas4、Cas5、Cas6、Cas7、Cas8、Cas10、Cas12、Cas13、Cas14,和其核酸酶缺陷型dCas等效物,以及其任何变体或衍生物(例如,本文称为“CRISPR相关”蛋白)。在一些实施方案中,CAS蛋白是Cas9或dCas9,其是核酸酶,一种专门用于切断DNA的酶,具有两个活性切断位点(HNH和RuvC),每个位点用于双螺旋的一条链。
如本文所用,“修饰”、“化学修饰”或“经化学修饰”通常是指涉及改变分子的化学成分或结构的多种不同过程中的任一种。例如,可以对CRISPR相关蛋白进行化学修饰,从而与第一电极和第二电极形成化学键。在一个实例中,经化学修饰电极是一种电极,其表面经过化学转化以改变电极的性质,诸如其物理、化学、电化学、光学、电学和/或传输特性。如本文所述,化学修饰还可涉及对CRISPR相关蛋白进行化学改变,使其与结合到电极的接头(例如,生物素/链霉亲和素、HaloTag等)相容。在其他实施方案中,可以经由蛋白质合成产生修饰。例如,当从编码蛋白质和修饰(例如接头)的多核苷酸合成时,CRISPR相关蛋白可以设计成包含一种或多种修饰(例如接头)。
如本文所用,“接触”和“进行接触”可以包括以直接物理结合的方式放置,包括固体与液体形式。“进行接触”可以包括两种不同物质之间的特定化学接触(例如,共价键,或与特定氨基酸残基具有特定配体相互作用的非共价键)。
如本文所用,“互补性”或“互补的”通常是指核酸通过传统的沃森-克里克(Watson-Crick)碱基配对或其他非传统类型与另一核酸序列形成氢键的能力。互补性百分比表示核酸分子中可与第二个核酸序列形成氢键(例如沃森-克里克碱基配对)的残基百分比(例如10个中有5、6、7、8、9、10个为50%、60%、70%、80%、90%和100%互补)。“完全互补”通常表示核酸序列的所有连续残基将与第二个核酸序列中相同数量的连续残基形成氢键。如本文所用的“基本上互补”是指在8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、30、35、40、45、50或更多个核苷酸的区域内为至少60%、65%、70%、75%、80%、85%、90%、95%、97%、98%、99%或100%的互补程度,或指两个核酸在严格条件下杂交。
如本文所用,“CRISPR”(簇状规则间隔短回文重复序列)是指含有碱基序列的短重复段的DNA基因座。每个重复段后面是来自先前暴露于病毒的“间隔DNA”的短区段。大约40%的已测序细菌基因组和90%的已测序古细菌中都发现了CRISPR。CRISPR通常与编码CRISPR相关的蛋白质的Cas基因相关。CRISPR/Cas系统是一种原核免疫系统,它赋予对诸如质粒和噬菌体等外来遗传元件的抵抗力,并提供一种获得性免疫的形式。CRISPR间隔子以类似于真核生物中RNAi的方式鉴别和切断这些外源遗传元件。CRISPR/Cas系统可用于在物种中进行基因编辑(添加、破坏或改变特定基因的序列)和基因调控。通过将诸如Cas9蛋白的Cas蛋白和适当的引导RNA递送到细胞中,可以在任何所需位置切断生物体的基因组。CRISPR相关蛋白是与CRISPR相关的蛋白。
如本文所用,“表达”通常是指多核苷酸从DNA模板转录(诸如转录成mRNA或其他RNA转录物)的过程和/或转录的mRNA随后被翻译成肽、多肽或蛋白质的过程。转录物和编码的多肽可以统称为“基因产物”。如果多核苷酸来源于基因组DNA,则表达可包括真核细胞中mRNA的剪接。
如本文所用,“引导序列”包括与靶多核苷酸序列具有足够互补性以与靶序列杂交并指导CRISPR复合物与靶序列的序列特异性结合的任何多核苷酸序列。在一些实施方案中,当使用合适的比对算法进行最佳比对时,引导序列与其对应靶序列之间的互补程度为约或大于约50%、60%、75%、80%、85%、90%、95%、97.5%、99%或更多。最佳比对可以使用任何合适的序列比对算法来确定,其非限制性实例包括史密斯-沃特曼算法(Smith-Waterman algorithm)、内德勒曼-温施算法(Needleman-Wunsch algorithm)、基于伯罗斯-惠勒变换(Burrows-Wheeler Transform)的算法(例如Burrows Wheeler Aligner)、ClustalW、Clustal X、BLAT、Novoalign(Novocraft Technologies)、ELAND(Illumina,SanDiego,Calif.)、SOAP(可在soap.genomics.org.cn获得)和Maq(可在maq.sourceforge.net获得)。在一些实施方案中,引导序列的长度为约或大于约5、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、35、40、45、50、75或更多个核苷酸。在一些实施方案中,引导序列的长度为小于约75、50、45、40、35、30、25、20、15、12或更少个核苷酸。引导序列指导CRISPR复合物与靶序列的序列特异性结合的能力可以通过任何合适的测定法来评估。例如,可以将足以形成CRISPR复合物的CRISPR系统的组分,包括要测试的引导序列,提供给具有对应靶序列的宿主细胞,诸如通过用编码CRISPR序列的组分的载体转染,然后评估靶序列内的优先切割。类似地,可以在试管中评价靶多核苷酸序列的切割,方法是提供靶序列、CRISPR复合物的组分,包括要测试的引导序列和不同于测试引导序列的对照引导序列,并比较测试与对照引导序列反应之间在靶序列处的结合或切割速率。其他测定法是可能的,并且对本领域技术人员来说可用。
如本文所用,“引导RNA”通常指在称为RNA编辑的过程中引导尿苷残基于动质体原生生物的线粒体mRNA中的插入或缺失的RNA。术语“引导RNA”和“gRNA”也用于涉及CRISPR和Cas9的原核DNA编辑。对于这种原核DNA编辑系统,gRNA赋予CRISPR-Cas9系统以靶序列特异性。这些gRNA是与互补靶DNA序列结合的非编码短RNA序列。引导RNA与Cas9酶结合,并且gRNA序列经由配对将复合物引导到DNA上的特定位置,在该位置处,Cas9通过切断靶DNA链来执行其核酸内切酶活性。如本文进一步描述的,通过抑制或去除核酸内切酶活性,可以对Cas9蛋白进行工程化以在存在互补gRNA的情况下结合靶核酸。
除了表达Cas9核酸酶外,CRISPR-Cas9系统还可以包括特定的RNA分子,以募集核酸酶活性并将其定向到感兴趣的区域。这些引导RNA采用以下两种形式之一:(1)合成的反式激活CRISPR RNA(tracrRNA)加上合成的CRISPR RNA(crRNA),经设计以切割感兴趣的基因靶位点,以及(2)合成或表达的单引导RNA(sgRNA),由crRNA与tracrRNA组成作为单个构建体。crRNA和tracrRNA形成一种复合物,充当Cas9酶的引导RNA。sgRNA可以从DNA模板在体外或体内合成产生或制备。
如本文所用,“分离的”生物组分(例如,诸如核酸分子、蛋白质或细胞)已基本上从该组分天然存在的生物体细胞或生物体本身中的其他生物组分(诸如其他染色体和染色体外DNA和RNA、蛋白质和细胞)中分离或纯化出来。已“分离”的核酸分子和蛋白质可以理解为已通过标准纯化方法纯化。该术语还包括通过在宿主细胞中重组表达制备的核酸分子和蛋白质以及化学合成的核酸分子和蛋白质。
如本文所用,“标记”通常是指能够例如通过ELISA、分光光度法、流式细胞术或显微术来检测的剂。例如,标记可以(间接或直接)连接到核酸分子或蛋白质,从而允许检测核酸分子或蛋白质。标记的实例包括但不限于放射性同位素、酶底物、辅因子、配体、化学发光剂、荧光团、半抗原、酶及其组合。例如,在Sambrook等人(Molecular Cloning:ALaboratory Manual,Cold Spring Harbor,New York,1989)和Ausubel等人(In CurrentProtocols in Molecular Biology,John Wiley&Sons,New York,1998)中讨论了标记方法和选择适于各种目的的标记的指导。
如本文所用,术语“接头”或“连接的”是指直接或间接接合在一起。例如,第一部分可以共价或非共价(例如,静电地)连接到第二部分。这包括但不限于将一个分子与另一个分子共价键合、一个分子与另一个分子非共价键合(例如静电键合)、一个分子与另一个分子通过氢键合非共价键合、一个分子与另一个分子通过范德华力非共价键合,以及此类偶联的任何和所有组合。间接连接是可能的,诸如通过使用“接头”(位于两个部分之间的分子或原子组)。在若干实施方案中,连接的组分以化学或物理方式结合,使得组分不能自由地彼此分散。例如,两种组分可以彼此共价结合,使得两种组分不能单独分散或扩散。
如本文所用,术语“非天然存在”和“工程化”可互换地表示人工参与。当涉及核酸分子或多肽时,这些术语通常表示核酸分子或多肽至少基本上不含与它们在自然界中天然相关的以及在自然界中发现的至少一种其他组分。
如本文所用,“核酸”通常是指脱氧核糖核苷酸或核糖核苷酸聚合物,其可以包括以类似于天然存在的核苷酸的方式与核酸分子杂交的天然核苷酸的类似物。在一个实例中,核酸分子是单链(ss)DNA或RNA分子,诸如探针或引物。在另一个实例中,核酸分子是双链(ds)核酸。在另一个实例中,核酸是修饰的DNA或RNA分子,诸如异种核酸(XNA)。在所有此类实施方案中,这些核酸可以是如本文进一步描述的靶核酸。
如本文所用,“多肽”、“肽”和“蛋白质”通常是指其中单体是通过酰胺键接合在一起的氨基酸残基的聚合物。当氨基酸是α-氨基酸时,可以使用L-光学异构体或D-光学异构体,L-异构体在自然界中是优选的。术语多肽特别旨在涵盖天然存在的蛋白质,以及重组或合成产生的蛋白质。本文所用的基本上纯化的多肽是指基本上不含其他蛋白质、脂质、碳水化合物或与其天然相关的其他材料的多肽。在一个实施方案中,多肽至少50%,例如至少80%不含其他蛋白质、脂质、碳水化合物或与其天然相关的其他材料。在另一个实施方案中,多肽至少90%不含其他蛋白质、脂质、碳水化合物或与其天然相关的其他材料。在另一个实施方案中,多肽至少95%不含其他蛋白质、脂质、碳水化合物或与其天然相关的其他材料。
提供功能相似的氨基酸的保守氨基酸取代表为本领域普通技术人员所熟知。以下六组是被视为相互保守取代的氨基酸实例:1)丙氨酸(A)、丝氨酸(S)、苏氨酸(T);2)天冬氨酸(D)、谷氨酸(E);3)天冬酰胺(N)、谷氨酰胺(Q);4)精氨酸(R)、赖氨酸(K);5)异亮氨酸(I)、亮氨酸(L)、蛋氨酸(M)、缬氨酸(V);和6)苯丙氨酸(F)、酪氨酸(Y)、色氨酸(W)。
非保守氨基酸取代可能由以下项的变化引起:(a)取代区域中氨基酸主链的结构;(b)氨基酸的电荷或疏水性;或(c)氨基酸侧链的体积。通常预期会对蛋白质特性产生最大变化的取代是:(a)亲水残基取代(或被取代成)疏水残基;(b)脯氨酸取代(或被取代成)任何其他残基;(c)具有大侧链的残基,例如苯丙氨酸,取代(或被取代成)不具有侧链的残基,例如甘氨酸;或(d)具有正电侧链的残基,例如赖氨酰基、精氨酰基或组氨酰基,取代(或被取代成)电负性残基,例如谷氨酰基或天冬氨酰基。变体氨基酸序列可以例如与天然氨基酸序列80、90或甚至95或98%一致。用于确定一致性百分比的程序和算法可以在NCBI网站上找到。
如本文所用,“探针”通常是指核苷酸的短序列,诸如长度为至少8、至少10、至少15、至少20或至少21个核苷酸,其可用于通过分子杂交检测是否存在互补序列。在特定实例中,寡核苷酸探针包括允许检测寡核苷酸探针:靶序列杂交复合物的标记。实验室标准和值可以基于已知或确定的总体值来设置,并且可以以图表或表格的形式提供,允许比较测量的、实验确定的值。
如本文所用,术语“纯化的”不需要绝对纯度;相反,它旨在作为一个相对术语。因此,例如,纯化的蛋白质制剂是其中所指的蛋白质比细胞内其自然环境中的蛋白质更纯的制剂。例如,将蛋白质制剂纯化为使得蛋白质占制剂总蛋白质含量的至少50%。类似地,纯化的寡核苷酸制剂是其中寡核苷酸比在包括寡核苷酸的复杂混合物的环境中更纯的制剂。化合物的纯度可以例如通过高效液相色谱法(HPLC)或其他常规方法来确定。
如本文所用,“重组”通常是指重组核酸或蛋白质,它具有非天然存在的序列或具有通过两个其他分开的序列区段的人工组合而产生的序列。此人工组合常常通过化学合成或通过人工操作核酸的分开的区段(例如通过基因工程技术)来完成。术语重组包括仅通过添加、取代或缺失天然核酸分子或蛋白质的一部分而改变的核酸和蛋白质。
如本文所用,术语“受试者”包括人类和非人类动物。“患者”和“受试者”在本文中可互换使用。
如本文所用,术语“基本一致性”或“基本上一致”通常指核酸或其片段,当与另一核酸(或其互补链)在适当的核苷酸插入或缺失下最佳比对时,指核苷酸序列具有至少约95%序列一致性,如通过任何众所周知的序列一致性算法诸如FASTA、BLAST或Gap来测量,如下所讨论。在某些情况下,与参考核酸分子具有基本一致性的核酸分子可以编码具有与参考核酸分子所编码的多肽相同或基本上相似的氨基酸序列的多肽。
当应用于多肽时,术语“基本相似性”或“基本上相似”是指两个肽序列在诸如通过程序GAP或BESTFIT使用默认缺口权重最佳比对时,共享至少95%序列一致性,甚至更优选至少98%或99%序列一致性。优选地,不一致的残基位置因保守氨基酸取代而不同。“保守氨基酸取代”是其中一个氨基酸残基被另一个具有相似化学特性(例如,电荷或疏水性)的侧链(R基团)的氨基酸残基取代。一般来说,保守氨基酸取代基本上不会改变蛋白质的功能特性。在两个或更多个氨基酸序列因保守取代而彼此不同的情况下,可以向上调整序列一致性百分比或相似程度以针对取代的保守性质来校正。进行这种调整的手段对于本领域技术人员来说是众所周知的。参见,例如,Pearson(1994)Methods Mol.Biol.24:307-331,以引用的方式并入本文。具有化学特性相似的侧链的氨基酸组的实例包括(1)脂肪族侧链:甘氨酸、丙氨酸、缬氨酸、亮氨酸和异亮氨酸;(2)脂肪族羟基侧链:丝氨酸和苏氨酸;(3)含酰胺侧链:天冬酰胺和谷氨酰胺;(4)芳族侧链:苯丙氨酸、酪氨酸和色氨酸;(5)碱性侧链:赖氨酸、精氨酸和组氨酸;(6)酸性侧链:天冬氨酸和谷氨酸,以及(7)含硫侧链半胱氨酸和蛋氨酸。优选保守氨基酸取代基团为:缬氨酸-亮氨酸-异亮氨酸、苯丙氨酸-酪氨酸、赖氨酸-精氨酸、丙氨酸-缬氨酸、谷氨酸-天冬氨酸以及天冬酰胺-谷氨酰胺。或者,保守替换是在Gonnet等人(1992)Science 256:1443-1445(以引用的方式并入本文)公开的PAM250对数似然矩阵中具有正值的任何变化。“适度保守”的替换是在PAM250对数似然矩阵中具有非负值的任何变化。
通常使用序列分析软件来测量多肽的序列相似性,也称为序列一致性。蛋白质分析软件使用分配给各种取代、缺失和其他修饰(包括保守氨基酸取代)的相似性度量匹配相似序列。例如,GCG软件含有诸如Gap和Bestfit等程序,这些程序可以在默认参数下使用,以确定密切相关的多肽,诸如来自不同物种生物体的同源多肽之间,或野生型蛋白质与其突变体之间的序列同源性或序列一致性。参见例如GCG 6.1版。多肽序列也可以使用FASTA使用默认或推荐参数进行比较,FASTA是GCG 6.1版中的一个程序。FASTA(例如FASTA2和FASTA3)提供查询序列和搜索序列之间的最佳重叠区的比对和序列一致性百分比(Pearson(2000)上文)。当将本发明的序列与含有来自不同生物体的大量序列的数据库进行比较时,另一个优选的算法是使用默认参数的计算机程序BLAST,尤其是BLASTP或TBLASTN。参见,例如Altschul等人(1990)J.Mol.Biol.215:403-410和Altschul等人(1997)Nucleic AcidsRes.25:3389-402,每个文献都以引用的方式并入本文。
如本文所用,“变体”通常是指通过氨基酸的插入、缺失或保守取代而在氨基酸序列上不同,但保留至少一种生物活性的肽或多肽。“SNP”是指为单核苷酸多态性的变体。“生物活性”的代表性实例包括被特定抗体结合或促进免疫反应的能力。变体还在本文中用于描述其氨基酸序列与参考蛋白质的氨基酸序列基本上一致并保留至少一种生物活性的蛋白质。氨基酸的保守性取代,即用具有相似特性(例如,带电区域的亲水性、程度和分布)的不同氨基酸替换氨基酸,在本领域通常被认为涉及微小变化。这些微小变化可部分地通过考虑氨基酸的亲水指数来识别,如本领域中所理解的。Kyte等人,J.Mol.Biol.157:105-132(1982)。氨基酸的亲水指数是基于其疏水性和电荷的考虑。在本领域中已知具有相似亲水指数的氨基酸可被取代并且仍然保留蛋白质功能。在一方面,具有±2的亲水指数的氨基酸被取代。氨基酸的亲水性还可用于揭示可产生保留生物功能的蛋白质的取代。在肽的情况下氨基酸的亲水性的考虑允许计算所述肽的最大局部平均亲水性,已报道这是一种与抗原性和免疫原性密切相关的有用度量。具有相似亲水性值的氨基酸的取代可产生保留生物活性例如免疫原性的肽,如本领域中所理解的。可利用具有在±2内的亲水性值的氨基酸彼此进行取代。氨基酸的疏水性指数与亲水性值受所述氨基酸的具体侧链影响。与所述观察一致,应理解与生物功能相容的氨基酸取代依赖于氨基酸的相对相似性,特别是所述氨基酸的侧链的相对相似性,如通过疏水性、亲水性、电荷、大小和其他特性所揭示的。
如本文所用,“治疗(treat)”、“治疗(treating)”或“治疗(treatment)”各自可互换使用,以描述逆转、减轻或抑制此类术语适用的疾病和/或损伤或此种疾病的一种或多种症状的进展。取决于受试者的状况,该术语还指预防疾病,并且包括预防疾病的发作,或预防与疾病相关的症状。可以以急性或慢性方式进行治疗。该术语还指在罹患疾病之前减轻疾病或与此种疾病相关的症状的严重性。这种在罹患之前预防或减轻疾病严重性是指将药物组合物施用给受试者,而受试者在施用时并未罹患该疾病。“预防”还指预防疾病或与此种疾病相关的一种或多种症状的复发。“治疗”和“治疗上”是指治疗的行为,正如上文定义的“治疗”。
2.生物电子装置和系统
本公开的实施方案提供了与单分子检测相关的装置、系统和方法。具体而言,本公开提供了用于使用电流波动作为蛋白质结合到核酸靶的读数来序列特异性检测所述核酸靶的装置和方法。如本文所述,所述生物电子装置和方法的某些方面可用于检测和识别任何核酸靶以用于诊断和/或治疗的目的。
根据这些实施方案,本公开的装置包括用于单分子电子序列检测的装置。在一些实施方案中,所述装置包括第一电极、第二电极和与第一电极和第二电极功能性偶联的CRISPR相关蛋白,诸如通过对CRISPR相关蛋白的化学修饰。这允许电流经由CRISPR相关蛋白从第一电极传递到第二电极,从而当CRISPR相关蛋白在存在对应引导RNA的情况下结合靶核酸时,基于指示靶核酸存在的电流波动检测信号(图2)。
本公开的实施方案还包括一种系统,所述系统包括多个CRISPR相关蛋白,每个CRISPR相关蛋白连接到一对电极。根据这些实施方案,将独特的引导RNA引入电极对上的多个位点,诸如将装置暴露于含有多个靶的溶液(例如,来自受试者的样品),导致装置中每个CRISPR相关蛋白与引导RNA和靶核酸形成复合物,这可以测量为特征性电流波动(例如,电流的减少)。
还公开了检测单个靶核酸分子结合的方法的各种实施方案。根据这些实施方案,所述方法包括将包含CRISPR相关蛋白的生物电子装置与引导RNA和对应的靶核酸组合,在第一电极和第二电极之间施加电压偏压(例如,100mV或更小),以及检测形成包含CRISPR相关蛋白、引导RNA和对应靶核酸的复合物时电流的偏移(例如,电流的减少)。在一些实施方案中,所述方法包括记录通过CRISPR相关蛋白的电流,以及检测当CRISPR相关蛋白结合对应于引导RNA的靶互补序列的靶DNA或RNA时电流的变化。
参考图1,本公开的实施方案包括示例性生物电子装置,其包含由单引导RNA(sgRNA)102编程的Cas蛋白101。显示sgRNA的靶序列区域与捕获的双链DNA,103结合,所述双链DNA与靶RNA序列互补,并在该DNA的相反链105上含有前间区序列邻近基序(PAM)序列(许多Cas蛋白的NGG)104。Cas蛋白101在多个位点处进行化学修饰,诸如在蛋白表面上的两个位点106和107,从而与接头分子108和109形成化学键。接头分子108和109转而通过化学键110和111连接到两个金属电极112和113。跨电极施加电压(V)114并记录电流(I)115。如下文进一步描述,Cas蛋白当结合靶DNA序列时将其电导率显著改变诸如约50%至约300%,包括但不限于50%、60%、65%、70%、75%、80%、85%、90%、95%、100%、110%、120%、130%、140%、150%、160%、170%、180%、190%、200%、210%、220%、230%、240%、250%、260%、270%、280%、290%和300%百分比。
在一些实施方案中,Cas蛋白诸如通过一种或多种突变被赋予核酸酶缺陷,产生dCas蛋白。例如,所得到的dCas蛋白可以保持在第一次捕获靶序列时采用的构象,从而使得在找到靶DNA序列后通过Cas蛋白的电流保持在一个新的、通常更高的水平,诸如至少2倍、3倍、5倍或更多倍增加。
图1的装置所期望的信号类型的一个实例提供于图2中。例如,当对于在靶DNA不存在或在不含有靶序列的DNA存在下分子电导为约10nS的情况偏压为50mV时,观察到约0.5nA的电流201。在引入并结合靶DNA后,电导在这种情况下降低至约3nS,对应于约0.15nA的电流202,其中对于与靶保持稳定结合的核酸酶缺陷型dCas蛋白的情况,电流保持稳定在值203。图2是代表性实例并且不意味着限制。本公开的生物电子装置可以检测到结合靶分子时的一系列电导变化,如下文进一步讨论的。
当施加高于100mV的偏压时,通常会在与蛋白质的接触处产生噪声。因此,为了在最佳信噪比下检测与蛋白质构象变化相关的变化,使用约100mV或更低的施加偏压。例如,可以使用约5mV、约10mV、约15mV、约20mV、约25mV、约30mV、约35mV、约40mV、约45mV、约50mV、约55mV、约60mV、约65mV、约70mV、约75mV、约80mV、约85mV、约90mV、约95mV、约100mV的施加偏压,包括任何范围或子范围的值。
下面给出了连接核酸酶缺陷型dCas9蛋白所需的化学步骤的一个实例,但预期CRISPR相关家族中的任何蛋白都可以与本公开的生物电子装置一起使用。除了Cas9之外,实例还包括但不限于Cas1、Cas2、Cas3、Cas4、Cas5、Cas6、Cas7、Cas8、Cas10、Cas12、Cas13、Cas14及其核酸酶缺陷型dCas等效物。示例性Cas蛋白在Marakova等人(Naturereviews.Microbiology,2015.13(11):第722-736页)中公开,其以引用的方式整体并入本文。
在一些实施方案中,针对嗜热栖热菌的III-A型CRISPR-Cas Csm复合物的RNA靶向CRISPR蛋白(Staals等人,Molecular Cell,2014.56(4):第518-530页)与本文公开的生物电子装置一起使用,因此允许在不需要逆转录酶的情况下识别RNA靶。装置的这种能力有利于检测病毒RNA基因组和序列。在一些实施方案中,本公开的生物电子装置可用于直接单分子检测病毒的基因组成分,诸如冠状病毒,例如严重急性呼吸综合征(SARS)、中东呼吸综合征(MERS)和/或SARS-Cov2(参见例如图7A-7B)。
图3A-3B包括图1的装置的实施方案。此处,顶部电极301通过介电质薄层302与底部电极303分隔开。此装置如2020年2月12日提交的美国临时专利申请第62/975,748号和2021年2月11日提交的对应PCT申请第PCT/US21/17583号中所公开的那样制造,这两个申请均以引用的方式整体并入本文用于所有目的。本公开的生物电子装置的各种构型和几何形状可以包括在美国专利第10,422,787号和PCT申请第PCT/US2019/032707号中公开的装置的任何方面,这两个专利均以引用的方式整体并入本文用于所有目的。
简而言之,在一些实施方案中,第一电极和第二电极由金属组合形成。例如,示例性电极可以通过在电极(诸如金电极)上沉积介电质来制造。基板可以是任何介电质材料,诸如玻璃、熔融石英或石英。介电基板可以是介电绝缘层。或者,基板可以是高电阻率硅,上面生长有一层厚(约500nm)的氧化物。例如,氧化物层厚度可以在约400nm至约600nm之间,包括约400nm、约450nm、约500、约550nm或约600nm。金电极可以根据本领域已知的方法,诸如通过标准剥离方法进行图案化。如果使用双层光致抗蚀剂以允许底切掩模,则金电极的边缘可以不具有栅栏凹凸。在一些实施方案中,如果金成角度沉积于具有底切光致抗蚀剂掩模的旋转基板上,则可以使边缘略微倾斜。电极可以为约50nm至约10μm宽并且约5nm至约1μm厚。可以使用标准光刻方法,然后进行原子层沉积(ALD)来在金电极的一端上沉积介电质材料。此介电质可以是SiO2、HfO2、Al2O3或可以使用原子层沉积可靠地沉积为薄膜的任何其他介电质材料。通常,沉积的介电质的量为约1nm至约50nm。在一些实施方案中,非常薄的膜的ALD生长可以通过用非常薄(约1nm或更小)的诸如Cr、Ti或Al的活性金属层处理第一电极(例如,平面电极、底部电极)的表面来获得。在一些实施方案中,介电层沉积在电极之间的间隙中;然而,在其他实施方案中,此间隙之间不需要介电质。
可以沉积第二电极以便位于(例如,平行于)介电质涂覆的第一电极的顶部。第二电极可以是任何贵金属。在一些实施方案中,第二电极由铂或钯制成。第二电极可以为约50nm至约10μm宽并且约5nm至约100nm厚。在确定第二电极的宽度时,约束是第二电极的边缘位于第一电极的平面部分上。
在另一步骤中,使用缓慢湿蚀刻剂将介电质从第一电极蚀刻掉,所述缓慢湿蚀刻剂诸如缓冲的HF(通常是HF和NH4F的溶液)、食人鱼溶液(H2SO4和H2O2)和/或用于HfO2介电层和SiO2的HCl/H2O2溶液以及用于Al2O3介电层的四甲基氢氧化铵(TMAH)或类似的碱,如KOH。氧化物沉积的最后一个原子层的两性性质可以产生对碱性蚀刻剂的抗性,并且添加的酸洗剂改善了层去除的完全性。结果是在结下方的介电质的轻微底切。
用介电质覆盖金电极边缘可以防止或减少金电极边缘原子的运动。通过对第二电极使用更稳定的金属(例如,Pd、Pt),第二电极的边缘相对于下面的平面金表面界定了尖锐的结。另一重要的方面是避免RIE或其他粒子轰击方法来暴露结,如在一些早期的分层结装置设计中所使用的。
在一些实施方案中,在第一金电极的边缘处并入另外的保护可以是期望的。在另一步骤中,可以在第一金电极的边缘上图案化第二层介电质。
在一些实施方案中,整个装置可以使用例如约500nm至约15μm厚的SU8聚合物层进行钝化,打开以在每侧几微米的小窗口中暴露结。替代方案是约50nm至约500nm厚的HfO2、Al2O3、SiNx或SiO2层,优选地通过原子层沉积来进行沉积。在一些实施方案中,层厚度为约50nm至约400nm。在一些实施方案中,层厚度为约50nm至约300nm。在一些实施方案中,层厚度为约50nm至约200nm。在一些实施方案中,层厚度为约50nm至约100nm。在一些实施方案中,层厚度为约100nm至约500nm。在一些实施方案中,层厚度为约200nm至约500nm。在一些实施方案中,层厚度为约300nm至约500nm。在一些实施方案中,层厚度为约500nm至约500nm。在一些实施方案中,层厚度为约100nm至约400nm。在一些实施方案中,层厚度为约100nm至约300nm。在一些实施方案中,层厚度为约200nm至约400nm。
一旦窗口打开,分子结可以通过暴露于氧等离子体、UV臭氧或其他等离子体物质来进一步清洁,并用分子功能化,如Zhang等人(以上引用)所述,其以引用的方式并入本文。第二电极和第一电极可以各自被功能化。在一些实施方案中,Cas蛋白314经由接头316(参见图3A-3B;图1中的108的等效物)连接到顶部电极301并且经由接头315(参见图3A-3B;图1中的109的等效物)连接到底部电极。在接头是蛋白质和电极之间的直接短共价键的情况下,电极320之间的间隙可以小至1nm。如果接头分子是链霉亲和素(如下所述),间隙可为约2至约8nm。如果使用纤维蛋白作为接头,间隙可为约5nm至约50nm。
在许多情况下,当仅与电极之一形成一个特定化学接触时也获得信号,第二接触317通过与第二电极的物理非特定接触来进行。这在图3B中说明,其中特定接触315被示为对底部电极进行,而第二非特定接触对顶部电极进行。
本领域的普通技术人员根据本公开将认识到,由于金属合金的功函数通常由其组成金属的功函数的加权平均值给出,因此可以用金合金代替第一电极。例如,白金(例如含有钯和/或银的合金)和其他金合金(诸如含有铜或镍)可以用于代替纯金。通常,任何贵金属合金都可用于制造第一电极和/或第二电极,包括但不限于诸如钯-铂、钯-银、铂-银等合金。
在一些实施方案中,修饰的Cas蛋白,诸如dCas9,与所公开的装置和方法一起使用。在一些实施方案中,dCas9是来自酿脓链球菌(S.pyogenes)的双点突变Cas9,其保留可编程功能但缺乏核酸酶活性。突变是D10A和H840A,分别位于RuvC和HNH核酸酶结构域中。通过在dCas9上的两个点处插入avitag可生物素化序列来进行电气连接。在此实施方案中,avitag序列被插入到N和C末端处,末端序列是:N-末端序列: 和C-末端序列:在这些序列中,avitag肽以斜体显示,可生物素化的赖氨酸以粗体显示。在一些实施方案中,His标签被插入N和C末端区域两者处以用于蛋白质纯化。这些avitag使用BirA酶进行生物素化。然后这些生物素形成图1中106和107所示的化学连接,并与图1中用作接头108和109的链霉亲和素分子复合。电极用硫醇化生物素分子功能化,形成图1中标记为110和111的第二化学键。
组装的分子装置如图4所示。在N-和C-末端402、403生物素化的dCas9蛋白401经由生物素-链霉亲和素键与链霉亲和素分子404、405结合。用硫醇化生物素406、407功能化的电极408、409通过生物素-链霉亲和素键与链霉亲和素分子404、405结合。硫醇化生物素分子的结构由图4中的410详细显示。
在一些实施方案中,Halo-Tag肽序列可以并入dCas9的N-和C-末端。Halo-Tag肽序列提供如下:MHHHHHHGGGGSGGGGSGGGGSMAEIGTGFPFDPHYVEVLGERMHYVDVGPRDGTPVLFLHGNPTSSYVWRNIIPHVAPTHRCIAPDLIGMGKSDKPDLGYFFDDHVRFMDAFIEALGLEEVVLVIHDWGSALGFHWAKRNPERVKGIAFMEFIRPIPTWDEWPEFARETFQAFRTTDVGRKLIIDQNVFIEGTLPMGVVRPLTEVEMDHYREPFLNPVDREPLWRFPNELPIAGEPANIVALVEEYMDWLHQSPVPKLLFWGTPGVLIPPAEAARLAKSLPNCKAVDIGPGLNLLQEDNPDLIGSEIARWLSTLEISGDKKYSIGLAIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAEATRLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQLVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVMGRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYVDQELDINRLSDYDVDAIVPQSFLKDDSIDNKVLTRSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQLGGDSRADPKKKRKVMAEIGTGFPFDPHYVEVLGERMHYVDVGPRDGTPVLFLHGNPTSSYVWRNIIPHVAPTHRCIAPDLIGMGKSDKPDLGYFFDDHVRFMDAFIEALGLEEVVLVIHDWGSALGFHWAKRNPERVKGIAFMEFIRPIPTWDEWPEFARETFQAFRTTDVGRKLIIDQNVFIEGTLPMGVVRPLTEVEMDHYREPFLNPVDREPLWRFPNELPIAGEPANIVALVEEYMDWLHQSPVPKLLFWGTPGVLIPPAEAARLAKSLPNCKAVDIGPGLNLLQEDNPDLIGSEIARWLSTLEISG(SEQ ID NO:3)。Halo-Tag是一种33kDa诱变的卤代烷烃脱卤酶,可与取代的氯代烷烃接头衍生物(Halo-Ligand)形成共价连接。与链霉亲和素-生物素连接类似,氯代烷烃接头延伸1.4nm进入Halo-Tag的疏水核心。市售的Halo-ligand衍生物包括不变的氯代烷烃部分,后跟4个乙二醇重复,以及反应性巯基、琥珀酰亚胺酯、胺或碘乙酰胺基团,以及许多其他选项。
在一些实施方案中,电极表面用硫醇-PEG4-氯代烷烃配体(Halo-Tag Thiol O4Ligand)进行功能化,相距4.5nm,并通过N和C-末端Halo-Tag融合物捕获dCas9/Cas13a。在一些实施方案中,通过改变终止密码子的用途以并入诸如叠氮基-丙氨酸或叠氮基赖氨酸的非天然氨基酸,在Cas蛋白上的任何选定的位点对处插入化学反应性氨基酸。这些用作生物素化或硫醇化化学接头的连接位点。
综上所述,本发明的实施方案包括一种用于检测靶核酸的生物电子装置。在一些实施方案中,所述装置包括第一电极、第二电极和至少一种CRISPR相关蛋白。在一些实施方案中,CRISPR相关蛋白被化学修饰以与第一电极和第二电极中的至少一个形成化学键。在一些实施方案中,所述化学修饰允许电流通过CRISPR相关蛋白,并且CRISPR相关蛋白与靶核酸的结合导致电流的偏移。在一些实施方案中,所述CRISPR相关蛋白是Cas家族成员蛋白,所述Cas家族成员蛋白选自由Cas1、Cas2、Cas3、Cas4、Cas5、Cas6、Cas7、Cas8、Cas10、Cas12、Cas13、Cas14、其核酸酶缺陷型dCas等效物及其任何变体或衍生物组成的组。在一些实施方案中,所述CRISPR相关蛋白是Cas9蛋白或dCas9。
如本文进一步描述的,本公开的生物电子系统和装置识别和/或检测靶核酸的能力至少部分取决于引导RNA对给定靶核酸的特异性(例如,在来自受试者的样品中)。CRISPR-Cas系统的特异性是本领域众所周知的;然而,本公开的生物电子系统和装置利用CRISPR-Cas系统的特异性来开发能够快速、敏感和特异性分析核酸序列的方法,这通过提供对临床相关的遗传信息的直接洞察,对精确的疾病诊断和有效的临床治疗产生积极影响。本公开的生物电子系统和装置将CRISPR/Cas系统重新用于诊断功能,从而为临床和护理点设置提供具有增强的灵活性、敏感性和特异性的稳健诊断平台。
例如,如本文进一步描述的,可以使用本公开的生物电子装置靶向任何RNA或DNA分子(或其衍生物)以进行检测。在一些实施方案中,可以识别特定的RNA或DNA靶序列(例如,在来自受试者或来自环境或工业样品的样品中)并且可以产生对应的引导RNA。用于识别给定RNA或DNA靶的引导RNA序列的方法包括但不限于以下中公开的那些:Li,B.等人,“CRISPR-SE:a brute force search engine for CRISPR design,”NAR Genomics andBioinformatics,第3卷,第1期,2021年3月(lqab013),以及任何相关的引导RNA数据库(例如,http://renlab.sdsc.edu/CRISPR-SE/);Metsky,H.C.等人,“Diagnostic design withmachine learning model-based optimization,”bioRxiv 2020.11.28.401877(doi:https://doi.org/10.1101/2020.11.28.401877);和Ackerman,C.M.等人,“Massivelymultiplexed nucleic acid detection with Cas13,”Nature第582卷,第277-282页(2020年),所有这些都以引用的方式整体并入本文。
为了促进本公开的生物电子装置和系统的产生,可以对CRISPR相关蛋白进行化学修饰,包括添加接头以促进与一个或多个电极的连接。在一些实施方案中,化学修饰包括在CRISPR相关蛋白上的至少两个位点上添加至少两个接头,其中至少两个接头连接到第一电极和第二电极中的每一个。在一些实施方案中,所述至少两个接头中的一个接头连接到所述CRISPR相关蛋白上的位点,并且所述至少两个接头中的另一个接头连接到所述CRISPR相关蛋白上的不同位点。
在一些实施方案中,所述接头经由共价化学键连接到所述CRISPR相关蛋白的非活性区域。在一些实施方案中,化学修饰包括生物素化所述CRISPR相关蛋白。在一些实施方案中,所述接头包含硫代链霉亲和素。在一些实施方案中,所述CRISPR相关蛋白以及所述第一电极和所述第二电极被生物素化,并且所述接头包含具有至少两个生物素结合位点的链霉亲和素分子。在一些实施方案中,化学修饰包含Halo-Tag融合蛋白和氯代烷烃接头。
本公开的实施方案还包括一种使用本文描述的任何生物电子装置和系统检测靶核酸的方法。根据这些实施方案,所述方法包括将生物电子装置与CRISPR相关蛋白与靶核酸和对应的引导RNA组合。将CRISPR相关蛋白引入靶核酸和对应的引导RNA并与其组合的方式将取决于与系统参数(例如,单路或多路)、被检测的靶和/或在生物电子装置中使用的CRISPR相关蛋白的类型相关的各种因素而变化。例如,在一些实施方案中,可以最初将引导RNA与Cas蛋白一起温育,然后可以将Cas蛋白功能性地偶联到电极。在其他实施方案中,可以最初温育引导RNA和对应的靶核酸,然后可以将它们引入已经与电极功能性偶联的Cas蛋白。在其他实施方案中,可以将引导RNA与功能性偶联到电极的Cas蛋白一起温育,然后可以引入靶核酸。
根据这些实施方案,所述方法还包括在第一电极和第二电极之间施加100mV或更小的电压偏压,如本文进一步描述的。所述方法还包括检测形成包含CRISPR相关蛋白、引导RNA和靶核酸的复合物时电流的偏移(例如,增加或减少的电流)。电流的偏移表明存在靶核酸(例如,在从受试者获得的样品中)。在所述方法的一些实施方案中,与所述CRISPR相关蛋白未与所述靶核酸结合时相比,电流的偏移包括电流的降低。在所述方法的一些实施方案中,与所述CRISPR相关蛋白未与所述靶核酸结合时相比,电流的偏移包括电流的增加。
本公开的生物电子装置和系统可以用于以多种方式检测靶核酸。例如,本公开的实施方案可用于检测较大靶核酸靶的一部分,用于检测靶核酸内的单核苷酸多态性(SNP)(例如,对生物体诸如病毒进行基因分型),用于检测剪接接点和/或选择性剪接的核酸靶(例如,指示疾病状况),以及任何其他遗传改变。如本领域普通技术人员根据本公开将容易理解,靶核酸可来源于病原生物和寄生虫和/或与病原生物和寄生虫相关,包括但不限于病毒(流感病毒、冠状病毒(例如,SARS-CoV-2检测)、黄曲霉、甲型病毒、副流感病毒、肝炎病毒等)、细菌(结核分枝杆菌、链球菌、沙门氏菌、鼠疫耶尔森菌、炭疽杆菌等)和真菌(念珠菌、芽生菌、曲霉病等)。靶核酸还可以与受试者的疾病状态或状况、感染类型(例如细菌或病毒)或一种或多种生理参数相关。例如,靶核酸可以与癌症生物标志物(例如,来自循环肿瘤DNA的癌症特异性突变)、免疫指标(例如,细胞因子和降钙素原表达)和/或治疗状况(例如,评估给定治疗是否已经对受试者有影响)相关。
在所述方法的一些实施方案中,靶核酸包含在受试者的样品中或来源于来自受试者的样品,诸如身体样品。在一些实施方案中,样品是血液样品、血清样品、血浆样品、唾液样品、尿液样品、粪便样品、脑脊液(CSF)样品、粘膜样品(例如,呼吸样品)、汗液样品、泪液样品和羊水样品。
如本文所用,“样品”、“测试样品”和“生物样品”通常是指含有或怀疑含有靶核酸的流体样品。样品可以来源于任何合适的来源。在一些情况下,样品可以包含液体、流动的颗粒固体或固体颗粒的流体悬浮液。在一些情况下,可以在本文所述的分析之前处理样品。例如,样品可以在分析之前从其来源中分离或纯化。在特定实例中,来源是哺乳动物(例如,人)身体物质(例如,体液、血液诸如全血(包括例如毛细血管血、静脉血等)、血清、血浆、尿液、粪便、唾液、汗液、痰液、精液、粘液、泪液、淋巴液、羊水、间质液、下呼吸道标本,诸如但不限于痰液、气管内吸出物或支气管肺泡灌洗液、脑脊液、粪便、组织、器官、一个或多个干血斑等)。组织可以包括但不限于口咽标本、鼻咽标本、骨骼肌组织、肝组织、肺组织、肾组织、心肌组织、脑组织、骨髓、宫颈组织、皮肤等。样品可以是液体样品或固体样品的液体提取物。在某些情况下,样品的来源可以是器官或组织,诸如活检样品,其可以通过组织崩解/细胞裂解而溶解。此外,样品可以是使用一个或多个拭子获得的鼻咽或口咽样品,一旦获得,将其放置在含有病毒转运介质(VTM)或通用转运介质(UTM)的无菌管中以进行测试。从来自患者的样品中单离或分离靶核酸的各种方法在本领域中是已知的,并且可以与本公开的方法结合使用(例如,Sureni V Mullegama,Michael O Alberti,Cora Au,Yan Li,TraciToy,Vanina Tomasian,Rena R Xian,“Nucleic Acid Extraction from HumanBiological Samples,”Methods Mol Biol.2019;1897:359-383.doi:10.1007/978-1-4939-8935-5_30)。此外,“样品”可以包括环境样品或来源于环境的样品,包括但不限于工业加工流、生物实验室、废水样品、表面样品(例如擦拭门把手、扶手)、食品加工样品、药物样品(例如,小分子和生物制品)等。在一些实施方案中,靶核酸来源于工程生物或工程微生物或与工程生物或工程微生物相关。在一些实施方案中,所述方法包括对特定环境进行取样以检测工程生物或工程微生物。
本公开的方法可以涉及使用广泛范围体积的流体样品,以使用本文所述的生物电子装置和系统进行分析。在一些示例性实施方案中,样品体积可为约0.5nL、约1nL、约3nL、约0.01μL、约0.1μL、约1μL、约5μL、约10μL、约100μL、约1mL、约5mL、约10mL等。在一些情况下,流体样品的体积介于约0.01μL与约10mL之间、介于约0.01μL与约1mL之间、介于约0.01μL与约100μL之间、或介于约0.1μL与约10μL之间。在某些情况下,流体样品可以在用于测定法之前进行稀释。例如,在含有靶核酸的来源是人体液(例如,血液、血清)的实施方案中,可以用合适的溶剂(例如,缓冲液,诸如PBS缓冲液)稀释体液。流体样品可以在使用之前稀释约1倍、约2倍、约3倍、约4倍、约5倍、约6倍、约10倍、约100倍或更多倍。在其他情况下,流体样品在用于测定法之前不被稀释。
在一些情况下,样品可能会进行分析前处理。分析前处理可以提供额外的功能,诸如非特异性蛋白质去除和/或混合功能。分析前处理的一般方法可以包括使用电动捕获、AC电动、表面声波、等速电泳、介电泳、电泳或本领域已知的其他预浓缩技术。在一些情况下,流体样品可以在用于测定法之前进行浓缩。例如,在含有靶核酸的来源是人体液(例如,血液、血清)的实施方案中,可以通过沉淀、蒸发、过滤、离心或其组合来浓缩流体。流体样品可以在使用之前被浓缩约1倍、约2倍、约3倍、约4倍、约5倍、约6倍、约10倍、约100倍或更多倍。在一些实施方案中,样品可以进行富集,诸如基于综合征的靶向富集和基于PCR的靶富集。
本公开的实施方案还包括一种系统,所述系统包括多个本文所述的生物电子装置(图6)。在所述系统的一些实施方案中,所述多个生物电子装置被配置为基于对应的引导RNA序列检测超过一种靶核酸。将本公开的多个生物电子装置配置成多路复用平台的能力赋予当前可用的诊断平台若干优点,包括但不限于直接和快速的单核酸检测。大多数(如果不是全部)当前可用的方法依赖于间接检测(例如,旁系切割)或集合检测(例如,石墨烯FET),这通常涉及首先发生旁系切割以产生信号,因此增加了检测时间。此外,本公开的多路复用系统是“无标记的”;因此,它们不受当前可用荧光标记数量的限制。换言之,可以在单个测定平台中检测大量靶(例如,所有约265种已知病毒),因为检测不会受到可同时使用的非重叠荧光团的可用性的限制。此外,本公开的多路复用系统具有数字量化能力,而其他当前可用的方法只能关联荧光强度或总FET信号,两者都不是那么精确。
在一些方面,包括多个本公开的生物电子装置的多路复用系统在检测其靶时不需要持续监测蛋白质(例如,CRISPR相关蛋白质);可以对它们进行定期监测以评估CRISPR相关蛋白与靶核酸的结合。这方面特别有用,因为靶检测取决于遗传物质扩散到蛋白质所需的时间以及CRISPR相关蛋白质在遗传物质中搜索靶所需的时间。例如,通过具有使用相同引导序列的许多CRISPR相关蛋白,本公开的多路复用系统可以快速减少检测时间。根据这些方面,本公开的实施方案包括具有多个结的多路检测系统,所述结具有相同复合物,使得来自多个结的信号的增加可用于样品中靶遗传物质的量化。在一些实施方案中,可以优化 芯片检测平台上复合物的位置以通过考虑扩散的影响(例如,限制最小扩散长度以增加检测时间)来最大化检测信号强度、检测时间和准确度,并规避非特异性扩增的准确度潜在挑战。在一些实施方案中,单个结用超过一种CRISPR相关蛋白功能化,所有这些蛋白都具有相同的引导序列。
提供以下实施例以说明某些实施方案的特定特征。然而,下面描述的特定特征不应被解释为对本公开范围的限制,而是作为实例,本领域普通技术人员将从这些实例中鉴别出等效物。本领域的普通技术人员基于本公开将认识到,通过化学手段在任何Cas蛋白上的两个电连接的任何布置都将实现本文公开的装置,诸如图1中所呈现。
3.实施例
对本领域技术人员而言,显而易见的是,本文所述的本公开方法的其他合适的修饰和修改是容易应用和可理解的,并且可以使用合适的等效物来做出,而不背离本公开或本文所公开的方面和实施方案的范围。现在已经对本公开进行了详细描述,通过参考以下实施例将更清楚地理解本公开,这些实施例仅用于说明本公开的一些方面和实施方案,并且不应被视为对本公开的范围进行限制。本文提及的所有期刊参考文献、美国专利和出版物的公开内容均以引用的方式整体并入本文。
本公开具有通过以下非限制性实例说明的多个方面。
实施例1
引导RNA序列。如本文进一步描述的,本公开的生物电子装置和系统的各种实施方案可用于识别或检测任何核酸靶,这至少部分归因于本领域已知的CRISPR-Cas系统的特异性。例如,引导RNA序列被设计用于检测与包括但不限于SARS-CoV-2和HPV16的病毒相关的靶核酸,如下表1所示。
表1:用于利用本公开的生物电子装置检测其对应靶核酸的示例性引导RNA序列。
如表1所示,靶互补序列用小写字母表示。茎环区域和GAAA四环以大写字母显示。PAM序列是与鉴别位点互补的链3'末端上所需的三个核苷酸,都具有dCas9的通用序列NGG。通过找到在双链DNA上互补鉴别序列的3'侧上具有适当的PAM序列的所用Cas蛋白的正确长度的独特序列(此处给出的dCa9实例为20个核苷酸)来选择序列。
实施例2
结合靶DNA的电导变化。使用本公开的生物电子装置和系统进行实验以确定当CRISPR相关蛋白和引导RNA结合靶DNA时发生的电导变化的类型。例如,图5A-5D包括通过用GFP1靶向序列(参见表1;SEQ ID NO:13)对dCas9进行编程而获得的代表性数据。如Zhang等人(Zhang,B.,H.Deng,S.Mukherjee,W.Song,X.Wang,and S.Lindsay,Engineering anEnzyme for Direct Electrical Monitoring of Activity.ACS Nano,2020,14:1630-1638)(在此以引用的方式整体并入)的方法所述,通过记录电流-电压曲线来测量电导。图5A显示在没有靶GFP序列DNA的情况下,sgRNA编程的dCas9的电导分布。-0.5(0.3nS)501处的低电导峰对应于单连接分子。双连接分子主要在大约+1(10nS)502处出现峰。当相同的分子集合暴露于靶DNA(图5B)时,电导分布发生了变化。由单连接分子引起的峰仍然存在503,但移向较低的电导值。由双连接分子引起的峰504大大减小。这些分布在重复测量时是稳定的,可能对应于dCas9的稳定构象。这些变化由溶液中存在(绿点)和不存在(蓝点)靶DNA情况下的叠加分布显示。单连接峰501在结合靶DNA时移向较低值503,而双连接峰502在结合靶DNA时几乎消失504。
为了证明特异性,使用蓝色荧光蛋白(BFP)作为脱靶DNA序列重复这些实验。当将脱靶DNA序列引入加载sgRNA的dCas9分子时,电导值506的分布没有改变(图5D)。靶的结合由电导的变化指示,通常为较低的值。虽然本实施例对应于使用包含dCas9的生物电子装置,但本领域普通技术人员将基于本公开认识到该方法可用于校准任何Cas蛋白结合任何DNA或RNA靶时的电导变化。
实施例3
系统和装置阵列。本公开的实施方案还包括能够检测单个样品内的多个DNA和/或RNA靶的生物电子系统(例如,装置阵列或多路复用装置)。这种系统的示例性配置在图6中示出。这里,制造了包括由介电层(参见例如图3)隔开的两个电极的结的阵列,它们相互连接,使得任何一对电极仅寻址一个结。每个结都可以用Cas蛋白进行功能化,具体实例显示为601和603。蛋白质601经由电极610和620寻址。蛋白质603经由电极611和622寻址。如果每个结或结集合(在需要重复测量的情况下)间隔开足够的距离(例如,10微米),则可以例如通过点印将不同的sgRNA应用于每个结或结集合。因此,Cas蛋白603可以用一个sgRNA 604编程,而蛋白质601可以用另一个靶向不同序列的sgRNA 602编程。本领域普通技术人员基于本公开将认识到,图6所示的连接方案可以改变并且形成装置阵列不限于特定方案。例如,每个装置都可使用单独的一对导线进行寻址。
实施例4
还进行了实验以检测来自SARS-CoV-2的靶序列。对于这些实验,使用引导RNA来检测SARS-CoV-2的核衣壳蛋白的一部分(参见表1;SEQ ID NO:9)。来自图7A-7B的代表性数据显示与sgRNA结合的许多dCas9分子的电导分布(图7A),包括在添加靶DNA后测量的分布。箭头指向电导显著变化的区域(图7B)。因此,这些数据证明了本公开的生物电子装置用于检测病毒靶核酸的功效和特异性。
本领域的技术人员将容易理解,本公开很好地适用于实现所提及的目标并且获得所提及的目的和优点,以及其中固有的那些。本文所述的本公开目前代表优选的实施方案,是示例性的,并且不旨在限制本公开的范围。本领域的技术人员将想到其中的变化和其他用途,这些变化被涵盖在由权利要求的范围限定的本公开的精神内。
不承认任何参考文献,包括本说明书中引用的任何非专利或专利文档,构成现有技术。具体而言,应当理解,除非另外指明,否则对本文中的任何文档的引用不构成承认这些文档中的任一者在美国或任何其他国家形成本领域公知常识的一部分。对参考文献的任何讨论都说明了其作者的主张,申请人保留质疑本文引用的文档中的任一者的准确性和相关性的权利。除非另外明确说明,否则本文引用的所有参考文献均以引用的方式完全并入。如果在引用的参考文献中发现的任何定义和/或描述之间存在任何差异,则应以本公开为准。
序列表
<110> 代表亚利桑那大学的亚利桑那校董事会
<120> 单分子电子序列检测器及其使用方法
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Pro Ala Ala Phe Lys Tyr Phe Asp Thr Thr Ile Asp Arg Lys Arg
1640 1645 1650
Tyr Thr Ser Thr Lys Glu Val Leu Asp Ala Thr Leu Ile His Gln
1655 1660 1665
Ser Ile Thr Gly Leu Tyr Glu Thr Arg Ile Asp Leu Ser Gln Leu
1670 1675 1680
Gly Gly Asp Ser Arg Ala Asp Pro Lys Lys Lys Arg Lys Val Met
1685 1690 1695
Ala Glu Ile Gly Thr Gly Phe Pro Phe Asp Pro His Tyr Val Glu
1700 1705 1710
Val Leu Gly Glu Arg Met His Tyr Val Asp Val Gly Pro Arg Asp
1715 1720 1725
Gly Thr Pro Val Leu Phe Leu His Gly Asn Pro Thr Ser Ser Tyr
1730 1735 1740
Val Trp Arg Asn Ile Ile Pro His Val Ala Pro Thr His Arg Cys
1745 1750 1755
Ile Ala Pro Asp Leu Ile Gly Met Gly Lys Ser Asp Lys Pro Asp
1760 1765 1770
Leu Gly Tyr Phe Phe Asp Asp His Val Arg Phe Met Asp Ala Phe
1775 1780 1785
Ile Glu Ala Leu Gly Leu Glu Glu Val Val Leu Val Ile His Asp
1790 1795 1800
Trp Gly Ser Ala Leu Gly Phe His Trp Ala Lys Arg Asn Pro Glu
1805 1810 1815
Arg Val Lys Gly Ile Ala Phe Met Glu Phe Ile Arg Pro Ile Pro
1820 1825 1830
Thr Trp Asp Glu Trp Pro Glu Phe Ala Arg Glu Thr Phe Gln Ala
1835 1840 1845
Phe Arg Thr Thr Asp Val Gly Arg Lys Leu Ile Ile Asp Gln Asn
1850 1855 1860
Val Phe Ile Glu Gly Thr Leu Pro Met Gly Val Val Arg Pro Leu
1865 1870 1875
Thr Glu Val Glu Met Asp His Tyr Arg Glu Pro Phe Leu Asn Pro
1880 1885 1890
Val Asp Arg Glu Pro Leu Trp Arg Phe Pro Asn Glu Leu Pro Ile
1895 1900 1905
Ala Gly Glu Pro Ala Asn Ile Val Ala Leu Val Glu Glu Tyr Met
1910 1915 1920
Asp Trp Leu His Gln Ser Pro Val Pro Lys Leu Leu Phe Trp Gly
1925 1930 1935
Thr Pro Gly Val Leu Ile Pro Pro Ala Glu Ala Ala Arg Leu Ala
1940 1945 1950
Lys Ser Leu Pro Asn Cys Lys Ala Val Asp Ile Gly Pro Gly Leu
1955 1960 1965
Asn Leu Leu Gln Glu Asp Asn Pro Asp Leu Ile Gly Ser Glu Ile
1970 1975 1980
Ala Arg Trp Leu Ser Thr Leu Glu Ile Ser Gly
1985 1990
<210> 4
<211> 62
<212> RNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 4
ucuaaagccg aaaaacccug guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cg 62
<210> 5
<211> 62
<212> RNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 5
gcuacacuac gugcccgccg guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cg 62
<210> 6
<211> 62
<212> RNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 6
uugcgcguac gcguuccaug guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cg 62
<210> 7
<211> 62
<212> RNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 7
caauacgaag auguccacga guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cg 62
<210> 8
<211> 62
<212> RNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 8
aguuguggca ucuccugaug guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cg 62
<210> 9
<211> 62
<212> RNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 9
gggcgcgauc aaaacaacgu guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cg 62
<210> 10
<211> 62
<212> RNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 10
ccaccuauag gggaacacug guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cg 62
<210> 11
<211> 62
<212> RNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 11
uaaggaguac cuacgacaug guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cg 62
<210> 12
<211> 62
<212> RNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 12
gcaacaguua cugcgacgug guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cg 62
<210> 13
<211> 62
<212> RNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 13
gagcuucagc uaccgcuacg guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cg 62
<210> 14
<211> 62
<212> RNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 14
guacugauaa ggcugacuug guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cg 62
Claims (29)
1.一种用于检测靶核酸的生物电子装置,其包括:
第一电极;
第二电极;和
至少一种CRISPR相关蛋白,所述CRISPR相关蛋白被修饰以与所述第一电极和所述第二电极中的至少一个形成化学键。
2.如权利要求1所述的装置,其中所述修饰允许电流通过所述CRISPR相关蛋白,并且其中所述CRISPR相关蛋白与靶核酸的结合导致所述电流的偏移。
3.如权利要求1或权利要求2所述的装置,其中所述CRISPR相关蛋白是Cas家族成员蛋白,所述Cas家族成员蛋白选自由Cas1、Cas2、Cas3、Cas4、Cas5、Cas6、Cas7、Cas8、Cas10、Cas12、Cas13、Cas14、其核酸酶缺陷型dCas等效物及其任何变体或衍生物组成的组。
4.如权利要求1至3中任一项所述的装置,其中所述CRISPR相关蛋白是Cas9蛋白或dCas9。
5.如权利要求1至4中任一项所述的装置,其中所述修饰包括添加接头。
6.如权利要求1至5中任一项所述的装置,其中所述修饰包括在所述CRISPR相关蛋白上的至少两个位点上添加至少两个接头,并且其中所述至少两个接头中的一个连接到所述第一电极和所述第二电极中的每一个。
7.如权利要求5或权利要求6所述的装置,其中所述接头经由共价化学键连接到所述CRISPR相关蛋白的非活性区域。
8.如权利要求1至7中任一项所述的装置,其中所述修饰包括对所述CRISPR相关蛋白进行生物素化。
9.如权利要求5至8中任一项所述的装置,其中所述接头包含硫代链霉亲和素。
10.如权利要求5至9中任一项所述的装置,其中所述CRISPR相关蛋白以及所述第一电极和所述第二电极被生物素化,并且其中所述接头包含具有至少两个生物素结合位点的链霉亲和素分子。
11.如权利要求5至7中任一项所述的装置,其中所述修饰包含HaloTag融合蛋白和氯代烷烃接头。
12.如权利要求1至11中任一项所述的装置,其中所述第一电极和/或所述第二电极包含金、钯、铂、银、铜或其任何合金。
13.如权利要求1至12中任一项所述的装置,其中所述第一电极包括至少部分地覆盖所述第一电极的顶表面的介电层。
14.如权利要求13所述的装置,其中所述介电层的厚度为约1nm至约50nm。
15.如权利要求1至14中任一项所述的装置,其中所述第一电极和所述第二电极被定位成使得在所述两个电极之间形成介于约1nm与约50nm之间的间隙。
16.如权利要求15所述的装置,其中所述间隙为约2至约8nm。
17.一种使用如权利要求1至16中任一项所述的生物电子装置检测靶核酸的方法,所述方法包括:
将所述生物电子装置和所述靶核酸与引导RNA组合;
在所述第一电极与所述第二电极之间施加100mV或更低的电压偏压;以及
检测所述CRISPR相关蛋白和所述引导RNA与所述靶核酸结合时电流的偏移。
18.如权利要求17所述的方法,其中所述引导RNA与所述靶核酸的一部分互补。
19.如权利要求17或权利要求18所述的方法,其中与所述CRISPR相关蛋白未与所述靶核酸结合时的电流相比,所述电流的偏移包括电流的减少。
20.如权利要求17至19中任一项所述的方法,其中所述靶核酸包含在来自受试者的样品中或来源于所述样品。
21.如权利要求20所述的方法,其中检测到所述电流的偏移表明所述靶核酸存在于所述样品中。
22.如权利要求20或21所述的方法,其中所述样品选自由血液样品、血清样品、血浆样品、唾液样品、尿液样品、粪便样品和粘膜样品组成的组。
23.如权利要求17至22中任一项所述的方法,其中所述靶核酸是DNA或RNA。
24.如权利要求17至23中任一项所述的方法,其中所述靶核酸来源于病原生物或与病原生物相关。
25.如权利要求17至24中任一项所述的方法,其中所述靶核酸来源于疾病或病状或与疾病或病状相关。
26.如权利要求17至25中任一项所述的方法,其中所述靶核酸来源于工程生物或与工程生物相关。
27.如权利要求24至26中任一项所述的方法,其中所述靶核酸来源于SARS-CoV-2感染或与SARS-CoV-2感染相关。
28.一种系统,其包括多个如权利要求1至17中任一项所述的生物电子装置。
29.如权利要求28所述的系统,其中所述多个生物电子装置被配置为基于对应的引导RNA序列检测超过一种靶核酸。
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US202063011799P | 2020-04-17 | 2020-04-17 | |
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PCT/US2021/027650 WO2021211950A1 (en) | 2020-04-17 | 2021-04-16 | Single-molecule electronic sequence detector and methods of use |
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BR112020023494A2 (pt) * | 2018-05-17 | 2021-03-30 | Stuart Lindsay | Dispositivo, sistema e método para medição elétrica direta de atividade enzimática, bem como método para sequenciamento |
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