CN114369158A - 一种抗新冠病毒的信息菌素及其应用 - Google Patents
一种抗新冠病毒的信息菌素及其应用 Download PDFInfo
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- CN114369158A CN114369158A CN202111515678.XA CN202111515678A CN114369158A CN 114369158 A CN114369158 A CN 114369158A CN 202111515678 A CN202111515678 A CN 202111515678A CN 114369158 A CN114369158 A CN 114369158A
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Abstract
本发明涉及一种抗新型冠状病毒SARS‑CoV‑2的信息菌素。首次选择较为保守、突变概率较低的新型冠状病毒E蛋白和M蛋白作为靶点设计了抗体模拟物——两种28肽。经过分别用三株新型冠状病毒株(流行株GD108、南非株SA、印度株IND)进行的药效学实验证实，将所述28肽与大肠菌素连接得到的融合蛋白能够有效对抗新型冠状病毒SARS‑CoV‑2造成的肺损伤，可以作为新型冠状病毒治疗和预防药物。
Description
技术领域：
本发明属于生物医药领域，涉及一种抗新型冠状病毒SARS-CoV-2的药物，包括抗新冠病毒的信息菌素、抗体模拟物及其制备方法与应用。
背景技术：
新型冠状病毒(Severe Acute Respiratory Syndrome Coronavirus 2, SARS-CoV-2)，简称“新冠病毒”感染带来的疫情给全球公共卫生造成巨大威胁，因此针对新冠病毒的诊断、预防(疫苗)、药物的需求迫在眉睫。
目前已报道的针对新冠病毒的候选药物多为化学药，化学药的使用会对病毒产生一个筛选作用，而病毒繁殖变异快，突变概率高，极易产生耐药性。
在生物制药领域，目前研究开发治疗新冠病毒疫苗和药物的思路，大都聚焦在将新冠病毒的S蛋白作为靶点。但是，众所周知，新冠病毒的S蛋白突变概率较高。一旦发生变异，就不容易正确识别和杀伤变异病毒。
另外，疫苗需要等待抗体产生后(数十天以后)才能生效，而且对突变的病毒株没有效果。现有技术的药物对被感染宿主细胞没有杀伤作用，因此难于对抗炎症性细胞因子风暴，也不能缓解炎症造成的毒性损伤。
因此，亟须有对新冠病毒和被感染宿主细胞有强大的杀伤力，感染病毒后可以立即使用和生效，并且具备抗新冠病毒的广谱性药物(即，不仅能对抗病毒流行株也能对抗突变株)的药物问世。
大肠菌素是细菌素的经典标本。大肠菌素有二十余种，分别攻击其他株大肠杆菌的基因、蛋白合成体系、或破坏大肠杆菌的细胞膜。可形成离子通道(在细胞膜上形成离子通道，从而杀伤大肠杆菌)的E1族大肠菌素(channel-forming E1 family colicins)由大肠菌素E1、大肠菌素Ia、大肠菌素Ib、大肠菌素A、大肠菌素B、大肠菌素N等组成。
可形成离子通道的E1族大肠菌素(channel-forming E1 family colicins)E1、Ia、Ib、 A、B、N等，是维持肠道菌群多样性与进化的调节动力之一。其杀菌原理在于，以大肠菌素Ia为例，其通常具有3个结构域：位移结构域(translocation domain)、受体结构域(receptor domain)、通道形成结构域(channel-forming domain)，其中通道结构域可在细菌的细胞膜(脂质双分子膜)上形成电压门控型离子通道(voltage-activated ionchannel)。大肠菌素Ia位于羧基端的通道结构域由175个氨基酸、10个α螺旋组成，在亲疏水作用力驱动下，会不消耗能量地插入到大肠杆菌的内膜(细胞膜)内形成离子通道。该通道一感受到-50mv的跨膜电位，就会打开，由于该通道的孔径很大，约为
几乎各种离子都可以从这个巨大的水性孔道中泄漏出去，导致细菌的能量和离子储备耗尽，胞膜破裂，细胞内容物泄漏造成大肠杆菌死亡。这样的杀菌过程是一个物理过程，它无需改变或影响细菌生长、代谢、繁殖所需的酶或代谢就可实现杀菌的目的，因此自数亿年以来直至此刻，仍在有效的杀灭同种异株的细菌。
大肠菌素Ia是E1族大肠菌素的模式标本，其基因、蛋白质结构、和工作机制是E1族大肠菌素之中了解得最为完善和详尽的。
发明内容
本发明的目的是提供一种抗新型冠状病毒SARS-CoV-2的药物，能够特异性识别新冠病毒的某些表面抗原(蛋白和/或碳氢化合物)，并且可以对抗变异病毒株。
具体的，本发明通过如下工作达到了上述发明目的：
1、本发明开创性地设计出特异性针对新冠病毒的抗体模拟物(AntibodyMimetic,Ab Mimetic)。
所述抗体模拟物选自两种28肽，其氨基酸序列分别是SEQ ID NO.1、SEQ ID NO.2(以下简称为28肽1、28肽2)。
所述抗体模拟物是以公开的抗新冠病毒E蛋白、M蛋白抗体序列为蓝本构建的，可以识别新冠病毒的E蛋白和M蛋白。
2、将可形成离子通道的E1族大肠菌素与SEQ ID NO.1和/或SEQ ID NO.2所示序列的多肽相连接，得到的融合蛋白为抗新冠病毒药物—抗新型冠状病毒SARS-CoV-2的信息菌素。
所述可形成离子通道的E1族大肠菌素的成员包括：大肠菌素E1、Ia、Ib、A、B、N。
优选的大肠菌素为大肠菌素Ia，其氨基酸序列如SEQ ID NO.3所示。
所述连接，其方式是将所述28肽1和/或28肽2连接到大肠菌素的羧基端和/或氨基端。
优选连接在大肠菌素的羧基端，以共价键方式连接。
当需要连接两个28肽时，优选的连接方式中，排列顺序如下所示：
大肠菌素—28肽1—28肽2；
或者，大肠菌素—28肽2—28肽1。
即，抗新型冠状病毒SARS-CoV-2的信息菌素的多肽的排列方式优选为以下顺序的融合蛋白：
SEQ ID NO.3—SEQ ID NO.1；
SEQ ID NO.3—SEQ ID NO.2；
SEQ ID NO.3—SEQ ID NO.1—SEQ ID NO.2；
或者，SEQ ID NO.3—SEQ ID NO.2—SEQ ID NO.1。
在本发明下文中，将上述抗体模拟物与大肠菌素的连接物亦称为“信息菌素”。
本发明的信息菌素具有独特的破坏脂质双分子膜完整性的杀病毒机制。本发明应用发明人设计出来的VHCDR1-VHFR2-VLCDR3一级结构顺序所构建之28肽抗体模拟物结构，以公开的抗新冠病毒E蛋白、M蛋白抗体序列为蓝本，构建了可以识别E蛋白和M蛋白的两种28肽抗体模拟物，分别将它们连接到大肠菌素Ia的羧基端和氨基端，构建出了8 种信息菌素，它们分别是抗体模拟物连接在大肠菌素羧基端的信息菌素-COVID19-E (Pheromonicin-COVID19-E,PMC-E)、信息菌素-COVID19-M(Pheromonicin-COVID19-M, PMC-M)、信息菌素-COVID19-E/M(Pheromonicin-COVID19-E/M,PMC-E/M)、信息菌素 -COVID19-E/M(Pheromonicin-COVID19-M/E,PMC-M/E)和抗体模拟物连接在大肠菌素羧基端的PMC-氨基端E(E-大肠菌素Ia),PMC-氨基端M(M-大肠菌素Ia),PMC-氨基端 E/M(E/M-大肠菌素Ia),PMC-氨基端M/E(M/E-大肠菌素Ia)。
所述抗体模拟物由识别新型冠状病毒SARS-CoV-2的E蛋白抗体的Fab段中选择VHCDR1 (重链抗原结合区1)、VHFR2(重链骨架区2)、VLCDR3(轻链抗原结合区3)这三个片段按VHCDR1-VHFR2-VLCDR3一级结构顺序线性连接而成；
优选地，识别新型冠状病毒SARS-CoV-2的E蛋白的抗体的NCBI登录号为7CWN_E和7L06_E；
优选地，所述抗体模拟物由识别新型冠状病毒SARS-CoV-2的M蛋白抗体的Fab段中选择 VHCDR1,VHFR2,VLCDR3这三个片段按VHCDR1-VHFR2-VLCDR3一级结构顺序线性连接而成；
优选地，识别新型冠状病毒SARS-CoV-2的M蛋白的抗体的NCBI登录号为7CWU_M 和7CWS_M；
本发明还提供了一种抗新型冠状病毒SARS-CoV-2的药物的制备方法，其特征在于，将具有如SEQ ID NO.1和/或SEQ ID NO.2所示氨基酸序列的蛋白与大肠菌素连接，得到的融合蛋白即为抗新冠病毒药物。
所述大肠菌素的成员包括：大肠菌素E1、Ia、Ib、A、B、N。
优选的大肠菌素为大肠菌素Ia.
所述抗新冠病毒药物可根据临床使用的要求，添加各种药物可接爱的辅料制备成所需的不同剂型。
本发明的有益效果和创新点：
1、选用可形成离子通道之大肠菌素
发明人经大量研究发现，大肠菌素可以在不同组分、不同厚度的多种脂质双分子膜上形成离子通道。这就提示，如果能够改变大肠菌素固有的靶向性(该固有靶向性只能识别同种异株的大肠杆菌)，就有可能识别其它细菌、真菌、包膜病毒、甚至真核细胞，从而在这些生命体的包膜，或胞膜(脂质双分子膜)上形成离子通道去杀伤它们。
2、选择E蛋白和M蛋白作为靶点
与现在大量的研究开发都聚焦在新冠病毒S蛋白作为靶点的思路不同，本发明选择较为保守、突变概率较低的E蛋白和M蛋白作为靶点。这样选择的优点是，(即使是变异病毒(突变多半是在S蛋白上发生的)，(因为E蛋白和M蛋白较少变异，应该改写成)由于变异病毒的变异多半是发生在S蛋白的变异，而E蛋白和M蛋白较少变异，因此本发明的信息菌素仍旧能够识别变异病毒的蛋白和M蛋白，从而杀伤变异病毒，这是目前使用的疫苗和药物都不具备的优点。
本发明通过大量动物实验充分证实，本发明包含可识别新冠病毒的E蛋白和/或M蛋白的抗体模拟物的上述4种信息菌素(PMC-E、PMC-M、PMC-E/M、PMC-M/E)均可有效缓解并降低新冠病毒流行株(GD108)、南非株(SA)和印度株(IND,Delta株)染毒后的动物肺部的病理状态及病理评分。
综上，本发明的信息菌素具备如下优点：对新冠病毒和被感染宿主细胞有强大的杀伤力，本发明信息菌素抗病毒的活性部分为大肠菌素Ia，本发明的发明人前期已证实大肠菌素Ia(Colicin Ia)可以下调炎症性细胞因子风暴，从而缓解炎症造成的毒性损伤。试验证实大肠菌素Ia能让IL-6,IL-12,MIP-1a,MIP-1b,IL-12,KC等因子在炎症时产生的高峰被极显著的降低(Qiu et al,Defending the homeland:Microbiome molecules provideprotection to their vertabrate hosts.Future Microbiology,15:1697-1712(2020Dec)doi: 10.2217/fmb-2020-0008E pub 2020Dec.22)。
3、作为治疗药物，能够对抗病毒流行株和突变株，显著减轻重症急性呼吸综合症(英文缩写SARS)造成的致死性肺部损伤
本发明的信息菌素作为药物，可以立即使用和生效，而疫苗需要等待抗体产生后(数十天以后)才能生效。不仅如此，本发明的信息菌素具有对抗病毒流行株和突变株的能力，即其具备抗新冠病毒的广谱性；更重要的是，本发明的实验例证实信息菌素可以显著减轻新冠病毒所致的肺部损伤，帮助病人挺过死亡关，这对于临床治疗新冠肺炎而言意义重大。
本发明用三株新型冠状病毒株(流行株GD108、南非株SA、印度株IND)进行了四种本发明信息菌素的药效学实验。
结果表明，本发明的四种信息菌素对上述三个病毒株造成的肺部损伤均有极显著的保护作用(详见实施例1)。
本发明还进行了所述信息菌素对抗新型冠状病毒SARS-CoV-2的病毒滴度检测试验，结果表明，信息菌素可以有效的杀伤病毒，从而减少活病毒滴度(详见实施例2)。
附图说明
图1为本发明的抗体模拟物所针对的新型冠状病毒表面的抗原靶蛋白，相比目前已报道或市面已有的新冠疫苗或药物选择的抗原靶蛋白均针对S蛋白(S protein)，本发明选择E蛋白(E protein)和M蛋白(M protein)作为抗体模拟物识别的靶蛋白。
图2为本发明的实施例提供的本发明的信息菌素的结构示意图；其中：图2a为本发明的一个实施例提供的信息菌素，图2b为本发明的另一个实施例提供的信息菌素，在本发明中VHCDR1-VHFR2-VLCDR3 28肽抗体模拟物之一级结构选自SEQ ID NO.1、和/或，SEQ IDNO.2所示的氨基酸序列。图2c为本发明的另一个实施例提供的信息菌素，其C端可同时连接2个抗体模拟物：Ab Mimetic I和Ab Mimetic II，在具体的实施例中，Ab Mimetic I的一级结构可以是SEQ ID NO.1(抗体模拟物-E)或SEQ ID NO.2(抗体模拟物-M)，相应地， AbMimetic II的一级结构可以是SEQ ID NO.2(抗体模拟物-M)或SEQ ID NO.1(抗体模拟物-E)。
图3为本发明的实验例1用新型冠状病毒株GD108#对30只仓鼠攻毒第5天左肺病理组织切片(苏木精-伊红染色)；其中GD108-Model为模型对照组的小鼠染色结果，PMC-E 为实验组：PMC-E的小鼠染色结果，PMC-M为实验组：PMC-M的小鼠染色结果，PMC-E/M 为实验组：PMC-E/M的小鼠染色结果，PMC-M/E为实验组：PMC-M/E的小鼠染色结果。
图4为本发明的实验例1不同实验组仓鼠感染新型冠状病毒株GD108#后肺组织病理评分比较图，其中，Model为模型对照组的小鼠病理评分统计结果；E为实验组：PMC-E的小鼠病理评分统计结果；M为实验组：PMC-M的小鼠病理评分统计结果；E/M为实验组： PMC-E/M的小鼠病理评分统计结果；M/E为实验组：PMC-M/E的小鼠病理评分统计结果。
图5为本发明的实验例2用新型冠状病毒株SA对30只仓鼠攻毒第5天左肺病理切片HE 染色图；其中SA-Model为模型对照组的小鼠染色结果，PMC-E为实验组：PMC-E的小鼠染色结果，PMC-M为实验组：PMC-M的小鼠染色结果，PMC-E/M为实验组：PMC-E/M 的小鼠染色结果，PMC-M/E为实验组：PMC-M/E的小鼠染色结果。
图6为本发明的实验例2不同实验组仓鼠感染新型冠状病毒株SA后肺组织病理评分比较图，其中，Model为模型对照组的小鼠病理评分统计结果；E为实验组：PMC-E的小鼠病理评分统计结果；M为实验组：PMC-M的小鼠病理评分统计结果；E/M为实验组： PMC-E/M的小鼠病理评分统计结果；M/E为实验组：PMC-M/E的小鼠病理评分统计结果。
图7为本发明的实验例3用新型冠状病毒株IND对30只仓鼠攻毒第5天左肺病理切片 HE染色图；其中IND-Model为模型对照组的小鼠染色结果，PMC-E为实验组：PMC-E的小鼠染色结果，PMC-M为实验组：PMC-M的小鼠染色结果，PMC-E/M为实验组：PMC-E/M 的小鼠染色结果，PMC-M/E为实验组：PMC-M/E的小鼠染色结果。
图8为本发明的实验例3不同实验组仓鼠感染新型冠状病毒株IND后肺组织病理评分比较图，其中，Model为模型对照组的小鼠病理评分统计结果；E为实验组：PMC-E的小鼠病理评分统计结果；M为实验组：PMC-M的小鼠病理评分统计结果；E/M为实验组： PMC-E/M的小鼠病理评分统计结果；M/E为实验组：PMC-M/E的小鼠病理评分统计结果。
图9为本发明的实验例3中采用信息菌素PMC-E实验组和模型对照组的仓鼠感染新型冠状病毒株IND后肺组织病理组织切片染色图的对比图，上面一排为信息菌素PMC-E 实验组的染色图，下边一排为模型对照组的染色图。
序列信息:
SEQ ID NO:1识别E蛋白之28肽抗体模拟物的氨基酸序列
SEQ ID NO:2识别M蛋白之28肽抗体模拟物的氨基酸序列
SEQ ID NO:3大肠菌素Ia的氨基酸序列
SEQ ID NO:4-7是信息菌素-covid-19。分别是信息菌素-covid-19-E,信息菌素 -covid-19-M,信息菌素-covid-19-E/M,信息菌素-covid-19-M/E的氨基酸序列。
具体实施方式
1、构建能够识别E蛋白之28肽和识别M蛋白之28肽抗体模拟物
质粒构建中的信息菌素全基因合成和质粒构建委托诺赛基因公司完成。
鉴定：对构建之质粒进行DNA测序,证实28肽抗体模拟物DNA序列位于构建之信息菌素基因序列的羧基端；制备出的信息菌素用LC-MS(液相层析-质谱)方法进行测试，证实28肽抗体模拟物的氨基酸残基位于构建之信息菌素的羧基端。
2、制备信息菌素-covid-19
全基因合成信息菌素-COVID-19的基因【在大肠菌素Ia羧基端最后一个氨基酸残基 I626之后插入28肽抗体模拟物之大肠菌素Ia和免疫蛋白基因(序列登录在Pubmed,NCBI中,编号M13819)】,插入到pET11a质粒的NdeI与BamHI之间，形成信息菌素-COVID-19 重组质粒(共四个质粒，分别具有抗体模拟物-E、抗体模拟物-M、抗体模拟物-M/E、和抗体模拟物-E/M)。
将质粒转染入大肠杆菌工程菌细胞(pET B834),将含有信息菌素-covid-19质粒的 B834工程菌置入LB液体培养基(含100μg/ml氨苄青霉素)中增殖，离心收取菌体，破菌后用pH 9 50mM硼酸缓冲液重悬浮，离心提取上清，加入硫酸链霉素沉淀DNA,再次离心提取上清，置于硼酸缓冲液中透析，DEAE琼脂糖(Sepharose,Toyopearl SP-650-M) 凝胶柱过柱，即可分别获得信息菌素-covid-19-E,信息菌素-covid-19-M,信息菌素-covid-19-M/E,,信息菌素-covid-19-E/M信息菌素。收率可达5-12mg/ml。
实验1本发明药物(信息菌素-covid-19)对三株抗新型冠状病毒SARS-CoV-2的药效学实验
1.实验目的
分别验证本发明四种信息菌素对抗三株抗新型冠状病毒SARS-CoV-2所致之急性呼吸综合症的保护作用。
2、实验材料
(1)实验动物和细胞
90只雄性仓鼠(金黄地鼠)来自于中国医学科学院昆明医学生物所。
Vero细胞来自科兴公司实验室。
(2)新型冠状病毒(SARS-CoV-2)毒株
新型冠状病毒(SARS-CoV-2)流行株：来源于广东省疾病预防控制中心(GuangdongCDC，GD108#)，简称“GD108”；
新型冠状病毒(SARS-CoV-2)南非株：来源于中国疾病预防控制中心(China CDC)，DPCC-nCoV84，简称“SA”；
新型冠状病毒(SARS-CoV-2)印度株(Delta株)：源于中国疾病预防控制中心(China CDC，IND-79#)，简称“IND”。
(3)受试药物
本发明提供的信息菌素，即大肠菌素Ia羧基端分别与本发明提供的28肽的连接所形成的融合蛋白，由北京亦科信息菌素研究院有限公司提供。共四种：
PMC-M：信息菌素-covid-19-E(大肠菌素Ia—28肽1)；
PMC-E：信息菌素-covid-19-M(大肠菌素Ia—28肽2)；
PMC-E/M：信息菌素-covid-19-M/E(大肠菌素Ia—28肽1—28肽2)；
PMC-M/E：信息菌素-covid-19-E/M(大肠菌素Ia—28肽2—28肽1)。
所述28肽1和28肽2的氨基酸序列分别如SEQ ID NO.1和SEQ ID NO.2所示。
3、实验分组
三株新型冠状病毒染毒动物分别分组进行实验，每种病毒株均分别设置空白对照组 (简称对照组)和四种药物的用药组，具体如下：
(1)金黄地鼠流行株(GD108#)攻毒评价分组：
对照组(n＝6)、PMC-M(n＝6)、PMC-E(n＝6)、PMC-E/M(n＝6)、PMC-M/E(n＝6)，共30只；
(2)金黄地鼠南非株攻毒评价分组：
对照组(n＝6)、PMC-M(n＝6)、PMC-E(n＝6)、PMC-E/M(n＝6)、PMC-M/E(n＝6)，共30只；
(3)金黄地鼠印度株(IND)攻毒评价分组：
对照组(n＝6)、PMC-M(n＝6)、PMC-E(n＝6)、PMC-E/M(n＝6)、PMC-M/E(n＝6)，共30只。
4、实验方法
(1)感染病毒的动物模型建立方法
方法是分别用三株病毒对上述各组金黄地鼠滴鼻，剂量为1×105PFU/只；
(2)给药方式和剂量：
对照组(腹腔注射生理盐水)，
给药组(腹腔注射信息菌素40mg/kg/day)；
每只金黄地鼠腹腔注射4mg信息菌素
以上各组均每日给药一次，连续给药5日后解剖；
(3)体重、体温检测：
动物染毒前3天及给药后隔日进行体重和体温检测，均在麻醉状态下进行。
体重用电子数显称称量；
体温检测使用电子体温测量仪进行测试，测试部位为腹部。
(4)样本处理：
动物染毒前及给药后第1，3，5，7天对动物进行麻醉，采集鼻拭子。
拭子样本处理：鼻拭子用800ul Trizol裂解，取其中200uL使用自动核酸提取仪提取RNA 模板，最后溶解于100uL水中，保存于-80℃备用，用一步法进行qRT-PCR。
(5)给药后第5天解剖，观察肺部大体病变情况
取左肺固定行病理切片观察；取右肺行病毒载量测定。病理观察由两位病理专家双盲阅片，根据整肺组织病理图谱综合评分。
(6)结果统计方法
使用prism graphad 8.0软件以单独数据点形式体现病理积分。不同时间点的数据对比采用paired t test统计学分析方法。不同组别动物的数据对比采用unpaired ttest统计学分析方法。
(7)肺组织病理评分标准
根据“Anti-spike IgG causes severe acute lung injury by skewingmacrophage responses during acute SARS-CoV infection”一文报道的方法，对肺部病理变化进行分级，各项指标的评分标准见下表1。
表1实验仓鼠肺部病理改变评分表
根据评分表各组每只仓鼠的肺部综合病理评分结果统计见表2。
表2实验仓鼠感染三种毒株后肺组织病理评分个体数据
5、实验结果
GD108毒株攻毒的实验组(PMC-E、PMC-M、PMC-E/M、PMC-M/E)和对照组 (GD108-Model)的肺组织病理切片染色结果如图3所示。
SA毒株攻毒的实验组(PMC-E、PMC-M、PMC-E/M、PMC-M/E)和对照组(SA-Model) 的肺组织病理切片染色结果如图5所示。
IND毒株攻毒的实验组(PMC-E和对照组(IND-Model)的肺组织病理切片染色结果如图7所示。
组织病理改变和病理评分的结果表明：
(1)SARS-CoV-2流行株感染的仓鼠模型，药物PMC-E(p<0.0001)、药物PMC-M (p<0.01)、药物PMC-E/M(p<0.0001)和药物PMC-M/E(p<0.0001)对肺部病理损伤均有显著的保护作用；
(2)SARS-CoV-2印度株(delta)感染的仓鼠模型，药物PMC-E(p<0.0001)、药物PMC-M(p<0.01)、药物PMC-E/M(p<0.001)和药物PMC-M/E(p<0.001)对肺部病理损伤均有显著的保护作用；
(3)SARS-CoV-2南非株(beta)感染的仓鼠模型，药物PMC-E(p<0.01)和药物 PMC-M/E(p<0.05)对肺部病理损伤有显著的保护作用；
(4)综合三个毒株的仓鼠模型，从通用性考虑，药物E对三个毒株感染后肺部病理损伤的保护作用相对较好。
6、实验结论
本发明提供的四种受试药物对三株株新型冠状病毒毒株均有明显对抗作用。
实验2本发明信息菌素对抗新型冠状病毒SARS-CoV-2的病毒滴度检测试验
1、实验目的：
考察本发明新药——信息菌素对新型冠状病毒SARS-CoV-2的体外抑杀作用。
2、实验材料
测试药物：PMC-M：信息菌素-covid-19-E(大肠菌素Ia—28肽1)和PMC-E：信息菌素-covid-19-M(大肠菌素Ia—28肽2)，由北京亦科信息菌素研究院有限公司提供。
以下实验材料由北京科兴中维生物技术有限公司提供：
新冠病毒流行株SARS-CoV-2epidemic strain(SARS-CoV-2/human/CHN/CN1/2020, 6.0lg CCID50/ml)。
用于测试的Vero细胞，
相应细胞培养液。
3、实验地点：
北京科兴中维生物技术有限公司实验室。
4、实验方法：
验证经信息菌素2-4小时共同孵育处理后的新冠病毒对细胞的感染力(侵袭力)降低或丧失，从而验证信息菌素对新冠病毒的抑杀作用.
以不同剂量(20、40微克/每毫升培养液)的信息菌素与新冠病毒共同孵育2-4小时，将孵育后的病毒再与易感细胞系细胞共同孵育24-72小时，观察或检测细胞的被感染情况和病毒滴度。
依据验证中对照组与其它剂量组的细胞感染情况和病毒滴度的差异，来判定信息菌素对抑杀新冠病毒是否有效。
具体操作：PMC-E、PMC-M按不同的稀释度接种细胞培养板，每个稀释度接种8孔，50μl/孔，由高稀释度向低稀释度(10-9→10-1)接种。按《检验用Vero细胞(WHO)复苏、传代及冻存标准操作规程》(DX-SOP-TM-0127)，将长成致密单层的Vero细胞支撑 1.00～2.00×105个/ml制成细胞悬液，执行《细胞计数及细胞活力检验标准操作规程》 (DX-SOP-TM-0071)进行计数，按100μl/孔加入96孔板，加入细胞后轻拍细胞板边缘，使细胞与供试品混匀，同时使细胞分散均匀。将接种后的96孔培养板放置36.5±1℃， 5％CO2培养箱内培养5天。5天观察结果并记录。
详见下表3。
表3
5、实验结果
受试药物——两种信息菌素与病毒孵育3小时后,活病毒滴度比对照组均减低了1.5 lgCCID50/ml(3小时孵育后，对照为8lgCCID50/ml)。如下表4所示。
表4
6、实验结论
本发明的信息菌素具有抑杀新型冠状病毒SARS-CoV-2的作用。
SEQUENCE LISTING
<110> 北京亦科信息菌素研究院有限公司
<120> 一种抗新冠病毒的信息菌素及其应用
<130> P210841/JJQ
<160> 7
<170> PatentIn version 3.5
<210> 1
<211> 28
<212> PRT
<213> Artificial Sequence
<220>
<223> 识别E蛋白之28肽抗体模拟物的氨基酸序列
<400> 1
Asn Tyr Tyr Ile His Trp Val Lys Gln Ala Pro Gly Lys Ser Leu Glu
1 5 10 15
Trp Ile Gly Gln His Tyr Ala Gly Tyr Ser Ala Thr
20 25
<210> 2
<211> 28
<212> PRT
<213> Artificial Sequence
<220>
<223> 识别M蛋白之28肽抗体模拟物的氨基酸序列
<400> 2
Ser Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
1 5 10 15
Trp Val Ala Trp Asp Ser Ser Leu Ser Ala Val Val
20 25
<210> 3
<211> 625
<212> PRT
<213> Artificial Sequence
<220>
<223> 大肠菌素Ia 的氨基酸序列
<400> 3
Ser Asp Pro Val Arg Ile Thr Asn Pro Gly Ala Glu Ser Leu Gly Tyr
1 5 10 15
Asp Ser Asp Gly His Glu Ile Met Ala Val Asp Ile Tyr Val Asn Pro
20 25 30
Pro Arg Val Asp Val Phe His Gly Thr Pro Pro Ala Trp Ser Ser Phe
35 40 45
Gly Asn Lys Thr Ile Trp Gly Gly Asn Glu Trp Val Asp Asp Ser Pro
50 55 60
Thr Arg Ser Asp Ile Glu Lys Arg Asp Lys Glu Ile Thr Ala Tyr Lys
65 70 75 80
Asn Thr Leu Ser Ala Gln Gln Lys Glu Asn Glu Asn Lys Arg Thr Glu
85 90 95
Ala Gly Lys Arg Leu Ser Ala Ala Ile Ala Ala Arg Glu Lys Asp Glu
100 105 110
Asn Thr Leu Lys Thr Leu Arg Ala Gly Asn Ala Asp Ala Ala Asp Ile
115 120 125
Thr Arg Gln Glu Phe Arg Leu Leu Gln Ala Glu Leu Arg Glu Tyr Gly
130 135 140
Phe Arg Thr Glu Ile Ala Gly Tyr Asp Ala Leu Arg Leu His Thr Glu
145 150 155 160
Ser Arg Met Leu Phe Ala Asp Ala Asp Ser Leu Arg Ile Ser Pro Arg
165 170 175
Glu Ala Arg Ser Leu Ile Glu Gln Ala Glu Lys Arg Gln Lys Asp Ala
180 185 190
Gln Asn Ala Asp Lys Lys Ala Ala Asp Met Leu Ala Glu Tyr Glu Arg
195 200 205
Arg Lys Gly Ile Leu Asp Thr Arg Leu Ser Glu Leu Glu Lys Asn Gly
210 215 220
Gly Ala Ala Leu Ala Val Leu Asp Ala Gln Gln Ala Arg Leu Leu Gly
225 230 235 240
Gln Gln Thr Arg Asn Asp Arg Ala Ile Ser Glu Ala Arg Asn Lys Leu
245 250 255
Ser Ser Val Thr Glu Ser Leu Asn Thr Ala Arg Asn Ala Leu Thr Arg
260 265 270
Ala Glu Gln Gln Leu Thr Gln Gln Lys Asn Thr Pro Asp Gly Lys Thr
275 280 285
Ile Val Ser Pro Glu Lys Phe Pro Gly Arg Ser Ser Thr Asn His Ser
290 295 300
Ile Val Val Ser Gly Asp Pro Arg Phe Ala Gly Thr Ile Lys Ile Thr
305 310 315 320
Thr Ser Ala Val Ile Asp Asn Arg Ala Asn Leu Asn Tyr Leu Leu Ser
325 330 335
His Ser Gly Leu Asp Tyr Lys Arg Asn Ile Leu Asn Asp Arg Asn Pro
340 345 350
Val Val Thr Glu Asp Val Glu Gly Asp Lys Lys Ile Tyr Asn Ala Glu
355 360 365
Val Ala Glu Trp Asp Lys Leu Arg Gln Arg Leu Leu Asp Ala Arg Asn
370 375 380
Lys Ile Thr Ser Ala Glu Ser Ala Val Asn Ser Ala Arg Asn Asn Leu
385 390 395 400
Ser Ala Arg Thr Asn Glu Gln Lys His Ala Asn Asp Ala Leu Asn Ala
405 410 415
Leu Leu Lys Glu Lys Glu Asn Ile Arg Asn Gln Leu Ser Gly Ile Asn
420 425 430
Gln Lys Ile Ala Glu Glu Lys Arg Lys Gln Asp Glu Leu Lys Ala Thr
435 440 445
Lys Asp Ala Ile Asn Phe Thr Thr Glu Phe Leu Lys Ser Val Ser Glu
450 455 460
Lys Tyr Gly Ala Lys Ala Glu Gln Leu Ala Arg Glu Met Ala Gly Gln
465 470 475 480
Ala Lys Gly Lys Lys Ile Arg Asn Val Glu Glu Ala Leu Lys Thr Tyr
485 490 495
Glu Lys Tyr Arg Ala Asp Ile Asn Lys Lys Ile Asn Ala Lys Asp Arg
500 505 510
Ala Ala Ile Ala Ala Ala Leu Glu Ser Val Lys Leu Ser Asp Ile Ser
515 520 525
Ser Asn Leu Asn Arg Phe Ser Arg Gly Leu Gly Tyr Ala Gly Lys Phe
530 535 540
Thr Ser Leu Ala Asp Trp Ile Thr Glu Phe Gly Lys Ala Val Arg Thr
545 550 555 560
Glu Asn Trp Arg Pro Leu Phe Val Lys Thr Glu Thr Ile Ile Ala Gly
565 570 575
Asn Ala Ala Thr Ala Leu Val Ala Leu Val Phe Ser Ile Leu Thr Gly
580 585 590
Ser Ala Leu Gly Ile Ile Gly Tyr Gly Leu Leu Met Ala Val Thr Gly
595 600 605
Ala Leu Ile Asp Glu Ser Leu Val Glu Lys Ala Asn Lys Phe Trp Gly
610 615 620
Ile
625
<210> 4
<211> 653
<212> PRT
<213> Artificial Sequence
<220>
<223> 信息菌素-covid-19-E
<400> 4
Ser Asp Pro Val Arg Ile Thr Asn Pro Gly Ala Glu Ser Leu Gly Tyr
1 5 10 15
Asp Ser Asp Gly His Glu Ile Met Ala Val Asp Ile Tyr Val Asn Pro
20 25 30
Pro Arg Val Asp Val Phe His Gly Thr Pro Pro Ala Trp Ser Ser Phe
35 40 45
Gly Asn Lys Thr Ile Trp Gly Gly Asn Glu Trp Val Asp Asp Ser Pro
50 55 60
Thr Arg Ser Asp Ile Glu Lys Arg Asp Lys Glu Ile Thr Ala Tyr Lys
65 70 75 80
Asn Thr Leu Ser Ala Gln Gln Lys Glu Asn Glu Asn Lys Arg Thr Glu
85 90 95
Ala Gly Lys Arg Leu Ser Ala Ala Ile Ala Ala Arg Glu Lys Asp Glu
100 105 110
Asn Thr Leu Lys Thr Leu Arg Ala Gly Asn Ala Asp Ala Ala Asp Ile
115 120 125
Thr Arg Gln Glu Phe Arg Leu Leu Gln Ala Glu Leu Arg Glu Tyr Gly
130 135 140
Phe Arg Thr Glu Ile Ala Gly Tyr Asp Ala Leu Arg Leu His Thr Glu
145 150 155 160
Ser Arg Met Leu Phe Ala Asp Ala Asp Ser Leu Arg Ile Ser Pro Arg
165 170 175
Glu Ala Arg Ser Leu Ile Glu Gln Ala Glu Lys Arg Gln Lys Asp Ala
180 185 190
Gln Asn Ala Asp Lys Lys Ala Ala Asp Met Leu Ala Glu Tyr Glu Arg
195 200 205
Arg Lys Gly Ile Leu Asp Thr Arg Leu Ser Glu Leu Glu Lys Asn Gly
210 215 220
Gly Ala Ala Leu Ala Val Leu Asp Ala Gln Gln Ala Arg Leu Leu Gly
225 230 235 240
Gln Gln Thr Arg Asn Asp Arg Ala Ile Ser Glu Ala Arg Asn Lys Leu
245 250 255
Ser Ser Val Thr Glu Ser Leu Asn Thr Ala Arg Asn Ala Leu Thr Arg
260 265 270
Ala Glu Gln Gln Leu Thr Gln Gln Lys Asn Thr Pro Asp Gly Lys Thr
275 280 285
Ile Val Ser Pro Glu Lys Phe Pro Gly Arg Ser Ser Thr Asn His Ser
290 295 300
Ile Val Val Ser Gly Asp Pro Arg Phe Ala Gly Thr Ile Lys Ile Thr
305 310 315 320
Thr Ser Ala Val Ile Asp Asn Arg Ala Asn Leu Asn Tyr Leu Leu Ser
325 330 335
His Ser Gly Leu Asp Tyr Lys Arg Asn Ile Leu Asn Asp Arg Asn Pro
340 345 350
Val Val Thr Glu Asp Val Glu Gly Asp Lys Lys Ile Tyr Asn Ala Glu
355 360 365
Val Ala Glu Trp Asp Lys Leu Arg Gln Arg Leu Leu Asp Ala Arg Asn
370 375 380
Lys Ile Thr Ser Ala Glu Ser Ala Val Asn Ser Ala Arg Asn Asn Leu
385 390 395 400
Ser Ala Arg Thr Asn Glu Gln Lys His Ala Asn Asp Ala Leu Asn Ala
405 410 415
Leu Leu Lys Glu Lys Glu Asn Ile Arg Asn Gln Leu Ser Gly Ile Asn
420 425 430
Gln Lys Ile Ala Glu Glu Lys Arg Lys Gln Asp Glu Leu Lys Ala Thr
435 440 445
Lys Asp Ala Ile Asn Phe Thr Thr Glu Phe Leu Lys Ser Val Ser Glu
450 455 460
Lys Tyr Gly Ala Lys Ala Glu Gln Leu Ala Arg Glu Met Ala Gly Gln
465 470 475 480
Ala Lys Gly Lys Lys Ile Arg Asn Val Glu Glu Ala Leu Lys Thr Tyr
485 490 495
Glu Lys Tyr Arg Ala Asp Ile Asn Lys Lys Ile Asn Ala Lys Asp Arg
500 505 510
Ala Ala Ile Ala Ala Ala Leu Glu Ser Val Lys Leu Ser Asp Ile Ser
515 520 525
Ser Asn Leu Asn Arg Phe Ser Arg Gly Leu Gly Tyr Ala Gly Lys Phe
530 535 540
Thr Ser Leu Ala Asp Trp Ile Thr Glu Phe Gly Lys Ala Val Arg Thr
545 550 555 560
Glu Asn Trp Arg Pro Leu Phe Val Lys Thr Glu Thr Ile Ile Ala Gly
565 570 575
Asn Ala Ala Thr Ala Leu Val Ala Leu Val Phe Ser Ile Leu Thr Gly
580 585 590
Ser Ala Leu Gly Ile Ile Gly Tyr Gly Leu Leu Met Ala Val Thr Gly
595 600 605
Ala Leu Ile Asp Glu Ser Leu Val Glu Lys Ala Asn Lys Phe Trp Gly
610 615 620
Ile Asn Tyr Tyr Ile His Trp Val Lys Gln Ala Pro Gly Lys Ser Leu
625 630 635 640
Glu Trp Ile Gly Gln His Tyr Ala Gly Tyr Ser Ala Thr
645 650
<210> 5
<211> 653
<212> PRT
<213> Artificial Sequence
<220>
<223> 信息菌素-covid-19-M
<400> 5
Ser Asp Pro Val Arg Ile Thr Asn Pro Gly Ala Glu Ser Leu Gly Tyr
1 5 10 15
Asp Ser Asp Gly His Glu Ile Met Ala Val Asp Ile Tyr Val Asn Pro
20 25 30
Pro Arg Val Asp Val Phe His Gly Thr Pro Pro Ala Trp Ser Ser Phe
35 40 45
Gly Asn Lys Thr Ile Trp Gly Gly Asn Glu Trp Val Asp Asp Ser Pro
50 55 60
Thr Arg Ser Asp Ile Glu Lys Arg Asp Lys Glu Ile Thr Ala Tyr Lys
65 70 75 80
Asn Thr Leu Ser Ala Gln Gln Lys Glu Asn Glu Asn Lys Arg Thr Glu
85 90 95
Ala Gly Lys Arg Leu Ser Ala Ala Ile Ala Ala Arg Glu Lys Asp Glu
100 105 110
Asn Thr Leu Lys Thr Leu Arg Ala Gly Asn Ala Asp Ala Ala Asp Ile
115 120 125
Thr Arg Gln Glu Phe Arg Leu Leu Gln Ala Glu Leu Arg Glu Tyr Gly
130 135 140
Phe Arg Thr Glu Ile Ala Gly Tyr Asp Ala Leu Arg Leu His Thr Glu
145 150 155 160
Ser Arg Met Leu Phe Ala Asp Ala Asp Ser Leu Arg Ile Ser Pro Arg
165 170 175
Glu Ala Arg Ser Leu Ile Glu Gln Ala Glu Lys Arg Gln Lys Asp Ala
180 185 190
Gln Asn Ala Asp Lys Lys Ala Ala Asp Met Leu Ala Glu Tyr Glu Arg
195 200 205
Arg Lys Gly Ile Leu Asp Thr Arg Leu Ser Glu Leu Glu Lys Asn Gly
210 215 220
Gly Ala Ala Leu Ala Val Leu Asp Ala Gln Gln Ala Arg Leu Leu Gly
225 230 235 240
Gln Gln Thr Arg Asn Asp Arg Ala Ile Ser Glu Ala Arg Asn Lys Leu
245 250 255
Ser Ser Val Thr Glu Ser Leu Asn Thr Ala Arg Asn Ala Leu Thr Arg
260 265 270
Ala Glu Gln Gln Leu Thr Gln Gln Lys Asn Thr Pro Asp Gly Lys Thr
275 280 285
Ile Val Ser Pro Glu Lys Phe Pro Gly Arg Ser Ser Thr Asn His Ser
290 295 300
Ile Val Val Ser Gly Asp Pro Arg Phe Ala Gly Thr Ile Lys Ile Thr
305 310 315 320
Thr Ser Ala Val Ile Asp Asn Arg Ala Asn Leu Asn Tyr Leu Leu Ser
325 330 335
His Ser Gly Leu Asp Tyr Lys Arg Asn Ile Leu Asn Asp Arg Asn Pro
340 345 350
Val Val Thr Glu Asp Val Glu Gly Asp Lys Lys Ile Tyr Asn Ala Glu
355 360 365
Val Ala Glu Trp Asp Lys Leu Arg Gln Arg Leu Leu Asp Ala Arg Asn
370 375 380
Lys Ile Thr Ser Ala Glu Ser Ala Val Asn Ser Ala Arg Asn Asn Leu
385 390 395 400
Ser Ala Arg Thr Asn Glu Gln Lys His Ala Asn Asp Ala Leu Asn Ala
405 410 415
Leu Leu Lys Glu Lys Glu Asn Ile Arg Asn Gln Leu Ser Gly Ile Asn
420 425 430
Gln Lys Ile Ala Glu Glu Lys Arg Lys Gln Asp Glu Leu Lys Ala Thr
435 440 445
Lys Asp Ala Ile Asn Phe Thr Thr Glu Phe Leu Lys Ser Val Ser Glu
450 455 460
Lys Tyr Gly Ala Lys Ala Glu Gln Leu Ala Arg Glu Met Ala Gly Gln
465 470 475 480
Ala Lys Gly Lys Lys Ile Arg Asn Val Glu Glu Ala Leu Lys Thr Tyr
485 490 495
Glu Lys Tyr Arg Ala Asp Ile Asn Lys Lys Ile Asn Ala Lys Asp Arg
500 505 510
Ala Ala Ile Ala Ala Ala Leu Glu Ser Val Lys Leu Ser Asp Ile Ser
515 520 525
Ser Asn Leu Asn Arg Phe Ser Arg Gly Leu Gly Tyr Ala Gly Lys Phe
530 535 540
Thr Ser Leu Ala Asp Trp Ile Thr Glu Phe Gly Lys Ala Val Arg Thr
545 550 555 560
Glu Asn Trp Arg Pro Leu Phe Val Lys Thr Glu Thr Ile Ile Ala Gly
565 570 575
Asn Ala Ala Thr Ala Leu Val Ala Leu Val Phe Ser Ile Leu Thr Gly
580 585 590
Ser Ala Leu Gly Ile Ile Gly Tyr Gly Leu Leu Met Ala Val Thr Gly
595 600 605
Ala Leu Ile Asp Glu Ser Leu Val Glu Lys Ala Asn Lys Phe Trp Gly
610 615 620
Ile Ser Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
625 630 635 640
Glu Trp Val Ala Trp Asp Ser Ser Leu Ser Ala Val Val
645 650
<210> 6
<211> 681
<212> PRT
<213> Artificial Sequence
<220>
<223> 信息菌素-covid-19-E/M
<400> 6
Ser Asp Pro Val Arg Ile Thr Asn Pro Gly Ala Glu Ser Leu Gly Tyr
1 5 10 15
Asp Ser Asp Gly His Glu Ile Met Ala Val Asp Ile Tyr Val Asn Pro
20 25 30
Pro Arg Val Asp Val Phe His Gly Thr Pro Pro Ala Trp Ser Ser Phe
35 40 45
Gly Asn Lys Thr Ile Trp Gly Gly Asn Glu Trp Val Asp Asp Ser Pro
50 55 60
Thr Arg Ser Asp Ile Glu Lys Arg Asp Lys Glu Ile Thr Ala Tyr Lys
65 70 75 80
Asn Thr Leu Ser Ala Gln Gln Lys Glu Asn Glu Asn Lys Arg Thr Glu
85 90 95
Ala Gly Lys Arg Leu Ser Ala Ala Ile Ala Ala Arg Glu Lys Asp Glu
100 105 110
Asn Thr Leu Lys Thr Leu Arg Ala Gly Asn Ala Asp Ala Ala Asp Ile
115 120 125
Thr Arg Gln Glu Phe Arg Leu Leu Gln Ala Glu Leu Arg Glu Tyr Gly
130 135 140
Phe Arg Thr Glu Ile Ala Gly Tyr Asp Ala Leu Arg Leu His Thr Glu
145 150 155 160
Ser Arg Met Leu Phe Ala Asp Ala Asp Ser Leu Arg Ile Ser Pro Arg
165 170 175
Glu Ala Arg Ser Leu Ile Glu Gln Ala Glu Lys Arg Gln Lys Asp Ala
180 185 190
Gln Asn Ala Asp Lys Lys Ala Ala Asp Met Leu Ala Glu Tyr Glu Arg
195 200 205
Arg Lys Gly Ile Leu Asp Thr Arg Leu Ser Glu Leu Glu Lys Asn Gly
210 215 220
Gly Ala Ala Leu Ala Val Leu Asp Ala Gln Gln Ala Arg Leu Leu Gly
225 230 235 240
Gln Gln Thr Arg Asn Asp Arg Ala Ile Ser Glu Ala Arg Asn Lys Leu
245 250 255
Ser Ser Val Thr Glu Ser Leu Asn Thr Ala Arg Asn Ala Leu Thr Arg
260 265 270
Ala Glu Gln Gln Leu Thr Gln Gln Lys Asn Thr Pro Asp Gly Lys Thr
275 280 285
Ile Val Ser Pro Glu Lys Phe Pro Gly Arg Ser Ser Thr Asn His Ser
290 295 300
Ile Val Val Ser Gly Asp Pro Arg Phe Ala Gly Thr Ile Lys Ile Thr
305 310 315 320
Thr Ser Ala Val Ile Asp Asn Arg Ala Asn Leu Asn Tyr Leu Leu Ser
325 330 335
His Ser Gly Leu Asp Tyr Lys Arg Asn Ile Leu Asn Asp Arg Asn Pro
340 345 350
Val Val Thr Glu Asp Val Glu Gly Asp Lys Lys Ile Tyr Asn Ala Glu
355 360 365
Val Ala Glu Trp Asp Lys Leu Arg Gln Arg Leu Leu Asp Ala Arg Asn
370 375 380
Lys Ile Thr Ser Ala Glu Ser Ala Val Asn Ser Ala Arg Asn Asn Leu
385 390 395 400
Ser Ala Arg Thr Asn Glu Gln Lys His Ala Asn Asp Ala Leu Asn Ala
405 410 415
Leu Leu Lys Glu Lys Glu Asn Ile Arg Asn Gln Leu Ser Gly Ile Asn
420 425 430
Gln Lys Ile Ala Glu Glu Lys Arg Lys Gln Asp Glu Leu Lys Ala Thr
435 440 445
Lys Asp Ala Ile Asn Phe Thr Thr Glu Phe Leu Lys Ser Val Ser Glu
450 455 460
Lys Tyr Gly Ala Lys Ala Glu Gln Leu Ala Arg Glu Met Ala Gly Gln
465 470 475 480
Ala Lys Gly Lys Lys Ile Arg Asn Val Glu Glu Ala Leu Lys Thr Tyr
485 490 495
Glu Lys Tyr Arg Ala Asp Ile Asn Lys Lys Ile Asn Ala Lys Asp Arg
500 505 510
Ala Ala Ile Ala Ala Ala Leu Glu Ser Val Lys Leu Ser Asp Ile Ser
515 520 525
Ser Asn Leu Asn Arg Phe Ser Arg Gly Leu Gly Tyr Ala Gly Lys Phe
530 535 540
Thr Ser Leu Ala Asp Trp Ile Thr Glu Phe Gly Lys Ala Val Arg Thr
545 550 555 560
Glu Asn Trp Arg Pro Leu Phe Val Lys Thr Glu Thr Ile Ile Ala Gly
565 570 575
Asn Ala Ala Thr Ala Leu Val Ala Leu Val Phe Ser Ile Leu Thr Gly
580 585 590
Ser Ala Leu Gly Ile Ile Gly Tyr Gly Leu Leu Met Ala Val Thr Gly
595 600 605
Ala Leu Ile Asp Glu Ser Leu Val Glu Lys Ala Asn Lys Phe Trp Gly
610 615 620
Ile Asn Tyr Tyr Ile His Trp Val Lys Gln Ala Pro Gly Lys Ser Leu
625 630 635 640
Glu Trp Ile Gly Gln His Tyr Ala Gly Tyr Ser Ala Thr Ser Tyr Ala
645 650 655
Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala
660 665 670
Trp Asp Ser Ser Leu Ser Ala Val Val
675 680
<210> 7
<211> 681
<212> PRT
<213> Artificial Sequence
<220>
<223> 信息菌素-covid-19-M/E
<400> 7
Ser Asp Pro Val Arg Ile Thr Asn Pro Gly Ala Glu Ser Leu Gly Tyr
1 5 10 15
Asp Ser Asp Gly His Glu Ile Met Ala Val Asp Ile Tyr Val Asn Pro
20 25 30
Pro Arg Val Asp Val Phe His Gly Thr Pro Pro Ala Trp Ser Ser Phe
35 40 45
Gly Asn Lys Thr Ile Trp Gly Gly Asn Glu Trp Val Asp Asp Ser Pro
50 55 60
Thr Arg Ser Asp Ile Glu Lys Arg Asp Lys Glu Ile Thr Ala Tyr Lys
65 70 75 80
Asn Thr Leu Ser Ala Gln Gln Lys Glu Asn Glu Asn Lys Arg Thr Glu
85 90 95
Ala Gly Lys Arg Leu Ser Ala Ala Ile Ala Ala Arg Glu Lys Asp Glu
100 105 110
Asn Thr Leu Lys Thr Leu Arg Ala Gly Asn Ala Asp Ala Ala Asp Ile
115 120 125
Thr Arg Gln Glu Phe Arg Leu Leu Gln Ala Glu Leu Arg Glu Tyr Gly
130 135 140
Phe Arg Thr Glu Ile Ala Gly Tyr Asp Ala Leu Arg Leu His Thr Glu
145 150 155 160
Ser Arg Met Leu Phe Ala Asp Ala Asp Ser Leu Arg Ile Ser Pro Arg
165 170 175
Glu Ala Arg Ser Leu Ile Glu Gln Ala Glu Lys Arg Gln Lys Asp Ala
180 185 190
Gln Asn Ala Asp Lys Lys Ala Ala Asp Met Leu Ala Glu Tyr Glu Arg
195 200 205
Arg Lys Gly Ile Leu Asp Thr Arg Leu Ser Glu Leu Glu Lys Asn Gly
210 215 220
Gly Ala Ala Leu Ala Val Leu Asp Ala Gln Gln Ala Arg Leu Leu Gly
225 230 235 240
Gln Gln Thr Arg Asn Asp Arg Ala Ile Ser Glu Ala Arg Asn Lys Leu
245 250 255
Ser Ser Val Thr Glu Ser Leu Asn Thr Ala Arg Asn Ala Leu Thr Arg
260 265 270
Ala Glu Gln Gln Leu Thr Gln Gln Lys Asn Thr Pro Asp Gly Lys Thr
275 280 285
Ile Val Ser Pro Glu Lys Phe Pro Gly Arg Ser Ser Thr Asn His Ser
290 295 300
Ile Val Val Ser Gly Asp Pro Arg Phe Ala Gly Thr Ile Lys Ile Thr
305 310 315 320
Thr Ser Ala Val Ile Asp Asn Arg Ala Asn Leu Asn Tyr Leu Leu Ser
325 330 335
His Ser Gly Leu Asp Tyr Lys Arg Asn Ile Leu Asn Asp Arg Asn Pro
340 345 350
Val Val Thr Glu Asp Val Glu Gly Asp Lys Lys Ile Tyr Asn Ala Glu
355 360 365
Val Ala Glu Trp Asp Lys Leu Arg Gln Arg Leu Leu Asp Ala Arg Asn
370 375 380
Lys Ile Thr Ser Ala Glu Ser Ala Val Asn Ser Ala Arg Asn Asn Leu
385 390 395 400
Ser Ala Arg Thr Asn Glu Gln Lys His Ala Asn Asp Ala Leu Asn Ala
405 410 415
Leu Leu Lys Glu Lys Glu Asn Ile Arg Asn Gln Leu Ser Gly Ile Asn
420 425 430
Gln Lys Ile Ala Glu Glu Lys Arg Lys Gln Asp Glu Leu Lys Ala Thr
435 440 445
Lys Asp Ala Ile Asn Phe Thr Thr Glu Phe Leu Lys Ser Val Ser Glu
450 455 460
Lys Tyr Gly Ala Lys Ala Glu Gln Leu Ala Arg Glu Met Ala Gly Gln
465 470 475 480
Ala Lys Gly Lys Lys Ile Arg Asn Val Glu Glu Ala Leu Lys Thr Tyr
485 490 495
Glu Lys Tyr Arg Ala Asp Ile Asn Lys Lys Ile Asn Ala Lys Asp Arg
500 505 510
Ala Ala Ile Ala Ala Ala Leu Glu Ser Val Lys Leu Ser Asp Ile Ser
515 520 525
Ser Asn Leu Asn Arg Phe Ser Arg Gly Leu Gly Tyr Ala Gly Lys Phe
530 535 540
Thr Ser Leu Ala Asp Trp Ile Thr Glu Phe Gly Lys Ala Val Arg Thr
545 550 555 560
Glu Asn Trp Arg Pro Leu Phe Val Lys Thr Glu Thr Ile Ile Ala Gly
565 570 575
Asn Ala Ala Thr Ala Leu Val Ala Leu Val Phe Ser Ile Leu Thr Gly
580 585 590
Ser Ala Leu Gly Ile Ile Gly Tyr Gly Leu Leu Met Ala Val Thr Gly
595 600 605
Ala Leu Ile Asp Glu Ser Leu Val Glu Lys Ala Asn Lys Phe Trp Gly
610 615 620
Ile Ser Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
625 630 635 640
Glu Trp Val Ala Trp Asp Ser Ser Leu Ser Ala Val Val Asn Tyr Tyr
645 650 655
Ile His Trp Val Lys Gln Ala Pro Gly Lys Ser Leu Glu Trp Ile Gly
660 665 670
Gln His Tyr Ala Gly Tyr Ser Ala Thr
675 680
Claims (10)
1.SEQ ID NO.1和/或SEQ ID NO.2所示氨基酸序列的多肽。
2.SEQ ID NO.1和/或SEQ ID NO.2所示氨基酸序列的多肽在制备抗新型冠状病毒SARS-CoV-2的药物中的用途。
3.权利要求2所述的用途，其中所述药物，包括预防、治疗和诊断新型冠状病毒SARS-CoV-2的制剂。
4.一种抗新型冠状病毒SARS-CoV-2的药物，是可形成离子通道的E1族大肠菌素与SEQID NO.1和/或SEQ ID NO.2所示序列的多肽相连接得到的融合蛋白。
5.权利要求4所述的药物，所述可形成离子通道的E1族大肠菌素选自大肠菌素E1、Ia、Ib、A、B或大肠菌素N。
6.权利要求5所述的药物，所述可形成离子通道的E1族大肠菌素是大肠菌素Ia，其氨基酸序列如SEQ ID NO.3所示。
7.权利要求4-6中任一所述的药物，所述连接，是将SEQ ID NO.1和/或SEQ ID NO.2所示序列的多肽连接到大肠菌素的羧基端和/或氨基端。
8.权利要求7所述的药物，所述连接，是将SEQ ID NO.1和/或SEQ ID NO.2所示序列的多肽连接到大肠菌素的羧基端。
9.权利要求8所述的药物，是多肽的排列方式选自以下顺序的融合蛋白：
SEQ ID NO.3—SEQ ID NO.1；
SEQ ID NO.3—SEQ ID NO.2；
SEQ ID NO.3—SEQ ID NO.1—SEQ ID NO.2；
或者，SEQ ID NO.3—SEQ ID NO.2—SEQ ID NO.1。
10.一种抗新型冠状病毒SARS-CoV-2的药物的制备方法，其特征在于，将SEQ ID NO.1和/或SEQ ID NO.2所示氨基酸序列的蛋白与大肠菌素连接。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CN2022/073668 WO2023050661A1 (zh) | 2021-09-28 | 2022-01-25 | 一种抗新冠病毒的信息菌素及其应用 |
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| CN202111141279 | 2021-09-28 | ||
| CN2021111412791 | 2021-09-28 |
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| Publication Number | Publication Date |
|---|---|
| CN114369158A true CN114369158A (zh) | 2022-04-19 |
| CN114369158B CN114369158B (zh) | 2024-04-19 |
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| WO2004083438A1 (fr) * | 2003-03-19 | 2004-09-30 | Chengdu Photon Biotechnology Limited | Nouveau peptide utilise contre enterococcus faecalis, et son procede de production |
| CN101633699A (zh) * | 2009-09-02 | 2010-01-27 | 畿晋庆三联（北京）生物技术有限公司 | 一种含抗体模拟物的新型抗生素及其制备方法与应用 |
| CN101797393A (zh) * | 2009-04-03 | 2010-08-11 | 四川大学华西医院 | 一种恶性淋巴瘤放射性靶向分子显像剂或/和靶向治疗剂 |
| US20120190826A1 (en) * | 2011-01-25 | 2012-07-26 | Protein Design Lab, Ltd. | Novel antibiotic comprising an antibody mimetic, its preparation methods and uses thereof |
| CN107722122A (zh) * | 2011-09-23 | 2018-02-23 | 昂考梅德药品有限公司 | Vegf/dll4结合剂及其应用 |
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| CN1532283A (zh) * | 2003-03-19 | 2004-09-29 | 成都阳辉生物科技有限责任公司 | 一种新型抗肺炎链球菌多肽及其制备方法 |
| CN102101888B (zh) * | 2009-12-17 | 2013-03-20 | 畿晋庆三联（北京）生物技术有限公司 | 一种新型抗eb病毒所致肿瘤多肽及其应用与制备方法 |
| CN104072592B (zh) * | 2013-03-26 | 2016-12-28 | 复旦大学 | 对新型冠状病毒HCoV-EMC 2012感染具有抑制作用的多肽及其应用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2004083438A1 (fr) * | 2003-03-19 | 2004-09-30 | Chengdu Photon Biotechnology Limited | Nouveau peptide utilise contre enterococcus faecalis, et son procede de production |
| CN101797393A (zh) * | 2009-04-03 | 2010-08-11 | 四川大学华西医院 | 一种恶性淋巴瘤放射性靶向分子显像剂或/和靶向治疗剂 |
| CN101633699A (zh) * | 2009-09-02 | 2010-01-27 | 畿晋庆三联（北京）生物技术有限公司 | 一种含抗体模拟物的新型抗生素及其制备方法与应用 |
| US20120190826A1 (en) * | 2011-01-25 | 2012-07-26 | Protein Design Lab, Ltd. | Novel antibiotic comprising an antibody mimetic, its preparation methods and uses thereof |
| CN107722122A (zh) * | 2011-09-23 | 2018-02-23 | 昂考梅德药品有限公司 | Vegf/dll4结合剂及其应用 |
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