CN114957409A - 基于s蛋白r815位点的冠状病毒干预的方法和产品 - Google Patents
基于s蛋白r815位点的冠状病毒干预的方法和产品 Download PDFInfo
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Abstract
本发明提供了基于S蛋白R815位点的冠状病毒干预方法和产品,具体地,本发明提供了抗原肽和新型冠状病毒的疫苗多肽,本发明还提供含有所述抗原肽或疫苗多肽的疫苗组合物及其应用。实验表明,本发明的抗原肽或疫苗多肽可有效防止S蛋白产生细胞融合和感染效应,从而有效防止新型冠状病毒的感染。
Description
技术领域
本发明属于生物医药领域,具体地说,本发明涉及基于S蛋白R815位点的冠状病毒干预的方法和产品。
背景技术
新型冠状病毒(severe acute respiratory syndrome coronavirus-2, SARS-CoV-2)属于冠状病毒β属的一成员,是造成COVID19的病原。COVID19疫情已蔓延至超过80个国家和地区,超过1亿人口确诊,并造成全球超过200万人死亡;除此之外还导致国际社会运行瘫痪,以及前所未有的经济财产损失。受感染人群不光肺部功能受阻,同时产生的系统性炎症也造成多种并发症在高危人群中发病。
然而目前市面上没有任何一款直接针对病毒或宿主病症反应的特效药,因此新的药物开发、运用与普及都迫在眉睫。
因此,本领域迫切需要开发一种能有效抑制新型冠状病毒所诱导的细胞融合效果,从而防止病毒感染的抗新型冠状病毒疫苗。
发明内容
本发明的目的在于提供一种能有效抑制新型冠状病毒所诱导的细胞融合效果,从而防止病毒感染的抗新型冠状病毒疫苗。
本发明的另一目的在于,发现新冠S蛋白的最重要氨基酸功能位点;单点突变最大化保留原有S蛋白结构;本发明包含对突变株有效的功能位点;有效避免、减少野生型新冠S蛋白促使的细胞融合和副作用;一种可针对野生型S 蛋白进行干预的方案。
本发明的第一方面,提供了一种抗原肽,所述抗原肽衍生自新型冠状病毒 S蛋白,并且所述抗原肽在对应于新型冠状病毒S蛋白氨基酸序列的SEQ ID NO.: 1的第815位的精氨酸发生突变。
在另一优选例中,所述突变包括氨基酸的插入、缺失或替换。
在另一优选例中,所述第815位的精氨酸突变为任何氨基酸。
在另一优选例中,所述第815位的精氨酸突变为选自下组的一种或多种氨基酸:丙氨酸(A)、天冬酰胺(N)、赖氨酸(K)、天冬氨酸(D)和谷氨酸 (E)。
在另一优选例中,所述第815位的精氨酸突变为选自下组的一种或多种氨基酸:丙氨酸(A)、天冬酰胺(N)。
在另一优选例中,所述的突变选自下组:R815A、R815N、或其组合。
在另一优选例中,所述新型冠状病毒S蛋白包括新冠病毒突变株(比如英国、南非或南美株)的S蛋白。
在另一优选例中,所述抗原肽的氨基酸序列如SEQ ID NO.3-5中任一所示。
在另一优选例中,所述的抗原肽为具有SEQ ID NO.3-5中任一所示氨基酸序列的多肽、其活性片段、或其保守性变异多肽。
在另一优选例中,所述的抗原肽除所述突变(如815位)外,其余的氨基酸序列与SEQ ID NO.:1所示的序列相同或基本相同。
在另一优选例中,所述抗原肽除所述突变(如815位)外,其余的氨基酸序列包括C端19氨基酸截短(ΔCT19)型、C端TM截短(ΔTM)型、以及第815位的精氨酸后的截短型S蛋白。
在另一优选例中,所述的基本相同是至多有50个(较佳地为1-20个,更佳地为1-10个、更佳地1-5个)氨基酸不相同,其中,所述的不相同包括氨基酸的取代、缺失或添加,且所述的抗原肽具有抑制新型冠状病毒S蛋白的细胞融合和感染效应的活性。
在另一优选例中,所述抗原肽与SEQ ID NO.:1所示序列的同源性至少为80%,较佳地至少为85%或90%,更佳地至少为95%,最佳地至少为98%或99%。
在另一优选例中,所述的抗原肽与新型冠状病毒的S蛋白竞争性结合人ACE2 受体(包括其发挥作用所必须的已知或未知的辅助受体)。
在另一优选例中,所述的“竞争性结合”指所述的抗原肽与新型冠状病毒的S 蛋白结合于相同或基本相同的人ACE2蛋白的结合域(或氨基酸区段)。
在另一优选例中,所述的抗原肽与新型冠状病毒的S蛋白结合于人ACE2蛋白上的相同的结合区段。
在另一优选例中,所述的竞争性结合包括阻断性或非阻断性的竞争性结合。
在另一优选例中,所述的抗原肽为人工合成的或重组的抗原肽。
在另一优选例中,所述抗原肽为酵母细胞表达的重组蛋白。
在另一优选例中,所述抗原肽为昆虫细胞表达的重组蛋白。
在另一优选例中,所述昆虫细胞选自下组:Sf9、Sf21、Tni、Hi5-Sf细胞、或其组合。
在另一优选例中,所述酵母包括毕赤酵母。
在另一优选例中,所述的抗原肽选自下组:
(a)具有SEQ ID NO.:3-5中任一所示的多肽;
(b)对(a)中多肽的氨基酸序列进行一个或多个氨基酸添加、一个或多个氨基酸的取代或1-3个氨基酸缺失所形成的衍生多肽,所述衍生多肽与衍生前的原始多肽具有基本相同的功能。
在另一优选例中,所述的“基本相同的功能”指所述的衍生多肽具有抑制新型冠状病毒S蛋白的细胞融合和感染效应的活性。
本发明第二方面提供了一种疫苗多肽,所述疫苗多肽包括本发明第一方面所述的抗原肽。
在另一优选例中,所述的疫苗多肽可激发灵长动物和啮齿动物产生阻断RBD 与ACE2结合,且抑制新型冠状病毒S蛋白的细胞融合和感染效应的中和抗体。
在另一优选例中,所述的疫苗多肽可激发灵长动物产生细胞免疫和体液免疫。
在另一优选例中,所述的灵长动物包括人、非人灵长类动物。
本发明第三方面提供了一种mRNA疫苗,所述的疫苗含有用于表达本发明第一方面所述抗原肽的编码mRNA、以及DNA表达载体。
在另一优选例中,所述的mRNA疫苗的包装载体为含有Toll样受体结合剂的鱼精蛋白、纳米颗粒人工膜、化学合成多聚体、以及脂质体。
本发明第四方面提供了一种分离的多核苷酸,所述的多核苷酸编码本发明第一方面所述的抗原肽或本发明第二方面所述的疫苗多肽。
本发明第五方面提供了一种表达载体,所述表达载体含有本发明第四方面所述的多核苷酸。
本发明第六方面提供了一种宿主细胞,所述的宿主细胞含有本发明第五方面所述的表达载体,或者在基因组中整合有本发明第四方面所述的多核苷酸。
在另一优选例中,所述的宿主细胞包括原核细胞和真核细胞。
在另一优选例中,所述的宿主细胞包括酵母、果蝇S2细胞、昆虫Hi5-Sf 细胞、大肠杆菌、猴来源Vero E6细胞、仓鼠CHO细胞、DC细胞、或其组合。
本发明第七方面提供了一种丧失新型冠状病毒S蛋白细胞融合效应的抗原病毒株,所述病毒株的基因组中的对应于新型冠状病毒S蛋白氨基酸序列的SEQ ID NO.:1的第815位的精氨酸发生突变。
在另一优选例中,所述突变包括氨基酸的插入、缺失或替换。
在另一优选例中,所述病毒株的基因组中的基于SEQ ID NO.:2的编码对应于SEQID NO.:1的第815位精氨酸的核苷酸发生突变。
在另一优选例中,所述核苷酸发生突变指:核苷酸突变为编码精氨酸以外的任何氨基酸的核苷酸。
在另一优选例中,所述核苷酸发生突变指:所述核苷酸突变为编码选自下组的一种或多种氨基酸的核苷酸:丙氨酸(A)、天冬酰胺(N)、赖氨酸(K)、天冬氨酸(D)和谷氨酸(E)。
在另一优选例中,所述核苷酸发生突变指:所述核苷酸突变为编码选自下组的一种或多种氨基酸的核苷酸:丙氨酸(A)、天冬酰胺(N)。
本发明第八方面提供了一种药物组合物,所述的组合物含有本发明第一方面所述的抗原肽、本发明第二方面所述的疫苗多肽或本发明第三方面所述的 mRNA疫苗或本发明第四方面所述的多核苷酸或者本发明第五方面所述的表达载体或者本发明第六方面所述的宿主细胞或本发明第七方面所述的病毒株,以及药学上可接受的载体和/或辅料。
在另一优选例中,所述的药物组合物为疫苗组合物。
在另一优选例中,所述疫苗组合物为单价或多价。
在另一优选例中,所述的药物组合物还含有佐剂,首选各种铝佐剂。
在另一优选例中,所述的药物为针对新型冠状病毒S蛋白氨基酸序列的SEQ IDNO.:1的第815位精氨酸的抑制剂。
在另一优选例中,所述药物组合物中的抗原肽、免疫多肽、mRNA疫苗或病毒株、和佐剂(如铝)的摩尔数或重量比在1:100之间,优选为1:40到1:60之间。
在另一优选例中,所述的药物组合物包括单方药物、复方药物、或协同药物。
在另一优选例中,所述的药物组合物的剂型为液态、固体、或凝胶态。
在另一优选例中,所述的药物组合物用选自下组的方式施用:皮下注射、皮内注射、肌肉注射、静脉注射、腹腔注射、微针注射、口服、或口鼻腔喷入和雾化吸入。
本发明第九方面提供了一种疫苗组合物,所述的组合物含有本发明第一方面所述的抗原肽、本发明第二方面所述的疫苗多肽或本发明第三方面所述的 mRNA疫苗或本发明第四方面所述的多核苷酸或者本发明第五方面所述的表达载体或者本发明第六方面所述的宿主细胞或本发明第七方面所述的病毒株,以及免疫学上可接受的载体和/或辅料。
在另一优选例中,所述的疫苗组合物还含有佐剂。
在另一优选例中,所述佐剂包括:颗粒型和非颗粒型佐剂。
在另一优选例中,所述颗粒型佐剂选自下组:铝盐、油包水乳剂、水包油乳剂、纳米颗粒、微小颗粒、脂质体、免疫刺激复合物,或其组合。
另一优选例中,所述非颗粒型佐剂选自下组:胞壁酰二肽及其衍生物、皂苷、脂质A、细胞因子、衍生多糖、细菌毒素,微生物及其产物如分枝杆菌(结核杆菌、卡介苗)、短小杆菌、百日咳杆菌、蜂胶、或其组合。
在另一优选例中,所述的佐剂包括氧化铝、皂苷、quil A、胞壁酰二肽、矿物油或植物油、基于囊泡的佐剂、非离子嵌段共聚物或DEAE葡聚糖、细胞因子(包括IL-1、IL-2、IFN-r、GM-CSF、IL-6、IL-12、和CpG)。
在另一优选例中,所述的疫苗组合物包括注射剂型。
本发明第十方面提供了如本发明第一方面所述的抗原肽或本发明第二方面所述的疫苗多肽或本发明第三方面所述的mRNA疫苗或本发明第七方面所述的病毒株或本发明第八方面所述的药物组合物或本发明第九方面所述的疫苗组合物的用途,(a)用于制备针对新型冠状病毒的抗体;和/或(b)用于制备预防和/或治疗冠状病毒感染或其相关疾病的药物。
在另一优选例中,所述抗体包括针对新型冠状病毒S蛋白第815位精氨酸位点突变的封闭型抗体。
在另一优选例中,所述的冠状病毒感染或其相关疾病选自下组:呼吸道感染、肺炎及其并发症、中东呼吸综合症、人类呼吸系统疾病新冠肺炎、猪肠胃疾病及其并发症、或其组合。
在另一优选例中,所述的冠状病毒相关疾病包括新型冠状病毒肺炎(COVID-19)。
在另一优选例中,所述冠状病毒选自下组:SARS-CoV-2、SARS-CoV、MERS-CoV、SADS-CoV、或其组合。
在另一优选例中,所述治疗包括用基因治疗的方法进行的治疗。
本发明第十一方面提供了一种制备本发明第一方面所述的抗原肽的方法,包括步骤:
(i)在适宜条件下培养本发明第六方面所述的宿主细胞,从而表达本发明第一方面所述的抗原肽;
(ii)纯化所述抗原肽。
在另一优选例中,所述方法步骤(i)中将转化的酵母单菌落分别接种到 BMGY培养基中,培养后离心去除上清,用BMMY培养基重悬菌体,28-30℃(优选为29.5℃),诱导培养36-48小时(优选为48小时)。
本发明第十二方面提供了一种产生针对冠状病毒SARS-CoV-2的免疫反应的方法,其特征在于,包括步骤:给需要的对象施用本发明第一方面所述的抗原肽、本发明第二方面所述的疫苗多肽、本发明第三方面所述的mRNA疫苗或本发明第七方面所述的病毒株或本发明第八方面所述的药物组合物或本发明第九方面所述的疫苗组合物。
在另一优选例中,所述的对象包括人或非人哺乳动物。
在另一优选例中,所述的非人哺乳动物包括非人灵长动物(如猴)。
在另一优选例中,所述方法在所述对象中诱导产生针对冠状病毒SARS-CoV-2 的中和抗体。
在另一优选例中,所述中和抗体能抑制新型冠状病毒S蛋白的细胞融合和感染效应。
本发明第十三方面提供了一种抑制新型冠状病毒S蛋白的细胞融合效应的方法,包括步骤:在本发明第一方面所述的抗原肽、本发明第二方面所述的疫苗多肽、本发明第三方面所述的mRNA疫苗或本发明第七方面所述的病毒株或本发明第八方面所述的药物组合物或本发明第九方面所述的疫苗组合物存在下,培养表达ACE2 蛋白的细胞,从而抑制新型冠状病毒S蛋白的细胞融合和感染效应。
在另一优选例中,所述细胞为体外培养的细胞。
在另一优选例中,所述方法为体外的方法。
在另一优选例中,所述细胞选自下组:肺部上皮细胞、肠上皮细胞、肝与肾上皮细胞、或其组合。
在另一优选例中,所述细胞选自下组:HEK293T-ACE2、Vero E6-ACE2、Caco2、Calu3细胞、或其组合。
本发明第十四方面提供了一种治疗方法,给需要的对象施用本发明第一方面所述的抗原肽、本发明第二方面所述的疫苗多肽、本发明第三方面所述mRNA 疫苗、本发明第四方面所述的多核苷酸或者本发明第五方面所述的表达载体或者本发明第六方面所述的宿主细胞或本发明第七方面所述的病毒株或本发明第八方面所述的药物组合物或本发明第九方面所述的疫苗组合物。
在另一优选例中,所述治疗方法包括基因治疗方法。
在另一优选例中,所示治疗方法包括体外使用电穿孔技术转染的人类DC 细胞移植,淋巴mRNA疫苗注射。
本发明第十五方面提供了一种特异性结合剂,所述特异性结合剂特异性识别或结合本发明第一方面所述的抗原肽。
在另一优选例中,所述特异性结合剂特异性识别所述抗原肽中包含第815位的精氨酸突变位点(R815)的突变位点。
在另一优选例中,所述特异性结合剂特异性识别所述抗原肽中第815位的精氨酸突变位点(R815)。
在另一优选例中,所述特异性结合剂识别序列性表位。
在另一优选例中,所述特异性结合剂识别构象性表位。
在另一优选例中,所述特异性结合剂选自下组:多肽、抗体、小分子化合物、或其组合。
在另一优选例中,所述抗体包括单克隆抗体或多克隆抗体。
在另一优选例中,所述抗体包括抗体片段,例如骆驼类VHH纳米抗体。
本发明第十六方面提供了一种筛选预防和/或治疗冠状病毒SARS-CoV-2感染或其相关疾病的候选化合物的方法,包括:
(a)将权利要求1所述的抗原肽与化合物库混合,用模拟及筛选方法测定化合物库中的化合物与本发明第一方面所述的抗原肽的结合情况;其中所述模拟及筛选方法包括化学结构信息学、系统细胞生物学、分子蛋白组学;
其中,如果所述测试化合物库中的化合物与本发明第一方面所述的抗原肽有结合,则表明所述与本发明第一方面所述的抗原肽结合的化合物为所述的候选化合物。
在另一优选例中,所述结合包括所述测试化合物库中的化合物与所述的抗原肽中第815位的精氨酸突变位点(R815)的结合。
在另一优选例中,所述方法包括步骤(b):将步骤(a)中所确定的候选化合物施用于体外表达ACE2的细胞,测定其对细胞融合和新冠病毒感染的效果。
在另一优选例中,所述方法包括步骤(b):将步骤(a)中所确定的候选化合物施用于哺乳动物模型,测定其对哺乳动物的影响。
在另一优选例中,所述哺乳动物为患有冠状病毒SARS-CoV-2感染或其相关疾病的哺乳动物。
在另一优选例中,所述的方法是非诊断和非治疗性的。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1显示了新冠S蛋白与宿主ACE2细胞的细胞融合效应。通过光学显微镜拍摄到表达SARS-CoV-2S蛋白的HEK293T单细胞(A);或与ACE2细胞融合后的细胞复合体(B)。通过蛋白质印迹法,我们发现S蛋白诱导的细胞融合后产生S2’蛋白条带(C)。(D)4种已知冠状病毒S蛋白氨基酸位点的序列比对及SARS-CoV-2S蛋白S2’位置及切割位点的结构图。标尺距离代表 20μm。
图2显示了R815位点突变S蛋白的融合效应缺失。蛋白质印迹法展示了野生型(WT)S、R815N及R815A突变型S蛋白大小(A);后三排加入ACE2细胞的情况下,野生型S蛋白产生了S2’条带,而R815N和R815A突变均抑制了 S2’的产生(A)。光学显微镜照片拍摄到的野生型(WT)S与ACE2细胞融合效应,并且能够完全被R815N和R815A突变抑制(B)。标尺距离代表20μm。
图3显示了R815位点有效防止其它突变株S蛋白的融合效应。光学显微镜照片拍摄到的天然D614G S蛋白突变株融合效应,能够完全受R815N及R815A 突变抑制(A);人工制作的C端19氨基酸(S-CTΔ19)截短的功能增强突变也能够完全被R815N和R815A突变抑制(B)。标尺距离代表20μm。
图4显示了R815位点突变有效防止假病毒感染ACE2细胞。荧光显微镜图片(A)、及蛋白质印迹法展示的绿色荧光体(B),只在受野生型(WT)S蛋白逆转录病毒感染的ACE2-HEK293T细胞中表达;R815N和R815A突变型逆转录病毒颗粒均不具有感染力。标尺距离代表20μm。
图5显示了R815位点突变减少野生型S蛋白发挥细胞融合功能。HA-蛋白标签免疫共沉淀后,蛋白质印迹法显示野生型与R815A突变型,均能与含有Myc 标签的野生型S蛋白结合(A);蛋白质印迹法显示共同表达的R815A突变型S 蛋白,能有效减少野生型S蛋白与ACE2细胞的细胞融合现象和S2’的产生(B)。
具体实施方式
本发明人通过广泛而深入的研究,意外地发现,新型冠状病毒S蛋白氨基酸序列的SEQ ID NO.:1的第815位的精氨酸突变后,可有效防止S蛋白产生细胞融合和感染效应,并且R815的位点突变还可有效阻止各种S蛋白突变株发挥融合效应,从而有效防止新型冠状病毒的感染,此外本发明人还首次发现,含有R815的位点突变的蛋白还可有效治疗冠状病毒SARS-CoV-2感染或其相关疾病。在此基础上,本发明人完成了本发明。
术语
如本文所用,术语“AxxB”表示第xx位的氨基酸A变为氨基酸B,例如“L87I”表示第87位的氨基酸L突变为I,以此类推。
冠状病毒SARS-CoV-2
冠状病毒(Coronavirus,CoV)属于套式病毒目(Nidovirales)冠状病毒科(Coronaviridae),是一种有包膜的正链RNA病毒,其亚科包含α、β、δ及γ四属。
目前已知的感染人的冠状病毒中,HCoV-229E和HCoV-NL63属于α属冠状病毒,HCoV-OC43、SARS-CoV、HCoV-HKU1、MERS-CoV和SARS-CoV-2均为β属冠状病毒。
2019年年底爆发的新型冠状病毒(SARS-CoV-2)与SARS-CoV有约80%相似性、与MERS-CoV有40%的相似性,也属于β属冠状病毒。
该类病毒的基因组是一条单股正链RNA,是基因组最大的RNA病毒之一,编码包括复制酶、刺突蛋白、囊膜蛋白、包膜蛋白和核壳蛋白等。在病毒复制的初始阶段,基因组被翻译成两条长达几千个氨基酸的肽链即前体多聚蛋白(Polyprotein),随后前体蛋白被蛋白酶切割生成非结构蛋白(如RNA聚合酶和解旋酶)和结构蛋白 (如刺突蛋白)及辅助蛋白。
S蛋白是冠状病毒SARS-CoV-2的一种主要的结构蛋白,其中,RBD负责与人 ACE2受体结合。
>全长Spike蛋白的氨基酸序列(S蛋白,YP_009724390.1)
MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFH AIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCN DPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHT PINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKY NENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASV YAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADY NYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPL QSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQ QFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWR VYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSV AYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDK NTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAAR DLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYE NQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEA EVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGV VFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIG IVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQE LGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT (SEQ ID NO.1)
编码全长Spike蛋白(S蛋白,YP_009724390.1)的核苷酸序列如SEQ ID NO.:2 所示:
ATGTTCGTGTTTCTGGTGCTGCTGCCTCTGGTGAGCTCCCAGTGCGTGAATCTGACCACAAGGACC CAGCTGCCCCCTGCCTATACCAACTCCTTCACACGGGGCGTGTACTATCCCGACAAGGTGTTCCGGAGCAG CGTGCTGCACTCCACACAGGATCTGTTTCTGCCTTTCTTTTCTAACGTGACCTGGTTCCACGCCATCCACG TGAGCGGCACCAATGGCACAAAGAGGTTCGACAACCCAGTGCTGCCCTTCAATGATGGCGTGTACTTCGCC TCCACCGAGAAGTCTAATATCATCCGCGGCTGGATCTTTGGCACCACACTGGACAGCAAGACACAGTCCCT GCTGATCGTGAACAATGCCACCAACGTGGTCATCAAGGTGTGCGAGTTCCAGTTTTGTAACGATCCATTCC TGGGCGTGTACTATCACAAGAACAATAAGTCTTGGATGGAGAGCGAGTTTCGCGTGTATTCCTCTGCCAAC AATTGCACATTTGAGTACGTGTCCCAGCCCTTCCTGATGGACCTGGAGGGCAAGCAGGGCAATTTCAAGAA CCTGCGGGAGTTCGTGTTTAAGAACATCGATGGCTACTTCAAAATCTACTCCAAGCACACCCCAATCAATC TGGTGAGAGACCTGCCACAGGGCTTCTCTGCCCTGGAGCCACTGGTGGATCTGCCCATCGGCATCAACATC ACCCGGTTTCAGACACTGCTGGCCCTGCACAGAAGCTACCTGACACCAGGCGACAGCTCCTCTGGATGGAC CGCAGGAGCAGCAGCCTACTATGTGGGCTATCTGCAGCCCAGGACCTTCCTGCTGAAGTACAACGAGAATG GCACCATCACAGACGCAGTGGATTGCGCACTGGACCCCCTGTCTGAGACCAAGTGTACACTGAAGAGCTTT ACCGTGGAGAAGGGCATCTATCAGACAAGCAACTTCAGGGTGCAGCCTACCGAGTCCATCGTGCGCTTTCC CAATATCACAAACCTGTGCCCTTTTGGCGAGGTGTTCAATGCAACCAGGTTCGCAAGCGTGTACGCATGGA ATAGGAAGCGCATCTCCAACTGCGTGGCCGACTATTCTGTGCTGTACAATAGCGCCTCCTTCTCTACCTTT AAGTGCTACGGCGTGAGCCCCACAAAGCTGAATGACCTGTGCTTTACCAACGTGTACGCCGATTCCTTCGT GATCAGGGGCGACGAGGTGCGCCAGATCGCACCAGGACAGACAGGCAAGATCGCAGACTACAACTATAAGC TGCCTGACGATTTCACCGGCTGCGTGATCGCCTGGAACAGCAACAATCTGGATAGCAAAGTGGGCGGCAAC TACAATTATCTGTACCGGCTGTTTAGAAAGTCTAACCTGAAGCCATTCGAGAGGGACATCTCCACAGAAAT CTACCAGGCCGGCTCTACCCCCTGCAATGGCGTGGAGGGCTTTAACTGTTATTTCCCTCTGCAGAGCTACG GCTTCCAGCCAACAAATGGCGTGGGCTATCAGCCCTACCGCGTGGTGGTGCTGTCTTTTGAGCTGCTGCAC GCCCCTGCAACAGTGTGCGGACCAAAGAAGAGCACCAATCTGGTGAAGAACAAGTGCGTGAACTTCAACTT CAACGGACTGACCGGCACAGGCGTGCTGACCGAGTCCAACAAGAAGTTCCTGCCTTTTCAGCAGTTCGGCA GGGACATCGCAGATACCACAGACGCCGTGCGCGACCCTCAGACCCTGGAGATCCTGGATATCACACCATGC TCCTTCGGCGGCGTGTCTGTGATCACACCAGGCACCAATACAAGCAACCAGGTGGCCGTGCTGTATCAGGA CGTGAACTGTACCGAGGTGCCCGTGGCAATCCACGCAGATCAGCTGACCCCTACATGGCGGGTGTACTCTA CCGGCAGCAACGTGTTCCAGACAAGAGCCGGATGCCTGATCGGAGCAGAGCACGTGAACAATAGCTATGAG TGCGACATCCCTATCGGCGCCGGCATCTGTGCCTCCTACCAGACCCAGACAAACTCCCCAAGGAGAGCACG GTCTGTGGCAAGCCAGTCCATCATCGCCTATACCATGAGCCTGGGCGCCGAGAACTCCGTGGCCTACTCCA ACAATTCTATCGCCATCCCTACCAATTTCACAATCTCCGTGACCACAGAGATCCTGCCAGTGAGCATGACC AAGACATCCGTGGACTGCACAATGTATATCTGTGGCGATTCCACCGAGTGCTCTAATCTGCTGCTGCAGTA CGGCTCTTTTTGTACCCAGCTGAACAGAGCCCTGACAGGCATCGCCGTGGAGCAGGACAAGAATACACAGG AGGTGTTCGCCCAGGTGAAGCAAATCTACAAGACCCCACCCATCAAGGACTTTGGCGGCTTCAACTTTAGC CAGATCCTGCCCGATCCTAGCAAGCCATCCAAGCGGTCTTTTATCGAGGACCTGCTGTTCAATAAGGTGAC CCTGGCCGATGCCGGCTTCATCAAGCAGTATGGCGATTGCCTGGGCGACATCGCCGCCAGAGACCTGATCT GTGCCCAGAAGTTTAACGGCCTGACCGTGCTGCCTCCACTGCTGACAGATGAGATGATCGCCCAGTACACA TCTGCCCTGCTGGCAGGCACCATCACAAGCGGATGGACCTTCGGCGCAGGAGCCGCCCTGCAGATCCCCTT TGCCATGCAGATGGCCTATCGGTTCAATGGCATCGGCGTGACCCAGAATGTGCTGTACGAGAACCAGAAGC TGATCGCCAATCAGTTTAACTCCGCCATCGGCAAGATCCAGGACTCTCTGAGCTCCACAGCAAGCGCCCTG GGCAAGCTGCAGGATGTGGTGAATCAGAACGCCCAGGCCCTGAACACCCTGGTGAAGCAGCTGTCTAGCAA TTTCGGCGCCATCTCCTCTGTGCTGAACGATATCCTGAGCCGGCTGGACAAGGTGGAGGCAGAGGTGCAGA TCGACCGGCTGATCACAGGCAGACTGCAGTCCCTGCAGACCTACGTGACACAGCAGCTGATCAGGGCAGCA GAGATCAGGGCATCTGCCAACCTGGCAGCAACCAAGATGAGCGAGTGCGTGCTGGGCCAGTCCAAGAGAGT GGACTTTTGTGGCAAGGGCTATCACCTGATGAGCTTCCCACAGTCCGCCCCTCACGGAGTGGTGTTTCTGC ACGTGACCTACGTGCCAGCCCAGGAGAAGAACTTCACCACAGCACCAGCAATCTGCCACGATGGCAAGGCA CACTTTCCTAGGGAGGGCGTGTTCGTGAGCAATGGCACCCACTGGTTTGTGACACAGCGCAACTTCTACGA GCCACAGATCATCACCACAGACAATACATTCGTGTCCGGCAACTGTGACGTGGTCATCGGCATCGTGAACA ATACCGTGTATGATCCTCTGCAGCCAGAGCTGGACTCTTTTAAGGAGGAGCTGGATAAGTACTTCAAGAAC CACACCAGCCCCGACGTGGATCTGGGCGACATCTCTGGCATCAATGCCAGCGTGGTGAACATCCAGAAGGA GATCGACAGGCTGAATGAGGTGGCCAAGAATCTGAACGAGTCCCTGATCGATCTGCAGGAGCTGGGCAAGT ATGAGCAGTACATCAAGTGGCCCTGGTATATCTGGCTGGGCTTCATCGCCGGCCTGATCGCCATCGTGATG GTGACCATCATGCTGTGCTGTATGACAAGCTGCTGTTCCTGCCTGAAGGGCTGCTGTTCTTGTGGCAGCTG CTGTAAGTTTGATGAGGACGATAGCGAGCCTGTGCTGAAGGGCGTGAAGCTGCACTACACCTGA(SEQ ID NO.:2)
应理解,在本发明中,S蛋白包括野生型和突变型。
本发明主要目标是研发出一种能诱导机体产生靶向冠状病毒SARS-CoV-2的中和抗体的疫苗,用于防止新型突变株新冠病毒的融合效应,从而预防新型冠状病毒的感染,并可有效阻断因新冠病毒突变株导致的感染。
此外,本发明的另一目标是研发出能够有效治疗冠状病毒SARS-CoV-2感染或其相关疾病的含有S蛋白突变体的药物。
抗原肽
本发明提供了一种衍生自新型冠状病毒S蛋白的抗原肽,并且所述抗原肽在对应于新型冠状病毒S蛋白氨基酸序列的SEQ ID NO.:1的第815位的精氨酸发生突变。
在一优选实施方式中,所述第815位的精氨酸突变为选自下组的一种或多种氨基酸:丙氨酸(A)、天冬酰胺(N)、赖氨酸(K)、天冬氨酸(D)和谷氨酸(E)。
应理解,本发明抗原肽中的氨基酸编号基于SEQ ID NO.:1作出,当某一具体抗原肽与SEQ ID NO.:1所示序列的同源性达到80%或以上时,抗原肽的氨基酸编号可能会有相对于SEQ ID NO.:1)的氨基酸编号的错位,如向氨基酸的N末端或C末端错位1-5位,而采用本领域常规的序列比对技术,本领域技术人员通常可以理解这样的错位是在合理范围内的,且不应当由于氨基酸编号的错位而使同源性达80%(如90%、95%、98%)的、具有相同或相似的具有抑制新型冠状病毒S蛋白的细胞融合和感染效应的活性的抗原肽不在本发明抗原肽的范围内。
本发明抗原肽是合成蛋白或重组蛋白,即可以是化学合成的产物,或使用重组技术从原核或真核宿主(例如,细菌、酵母、植物)中产生。根据重组生产方案所用的宿主,本发明的突变蛋白可以是糖基化的,或可以是非糖基化的。本发明的突变蛋白还可包括或不包括起始的甲硫氨酸残基。
本发明还包括所述抗原肽的片段、衍生物和类似物。如本文所用,术语“片段”、“衍生物”和“类似物”是指基本上保持所述抗原肽相同的生物学功能或活性的蛋白。
本发明的抗原肽片段、衍生物或类似物可以是(i)有一个或多个保守或非保守性氨基酸残基(优选保守性氨基酸残基)被取代的突变蛋白,而这样的取代的氨基酸残基可以是也可以不是由遗传密码编码的,或(ii)在一个或多个氨基酸残基中具有取代基团的抗原肽,或(iii)成熟突变蛋白与另一个化合物(比如延长突变蛋白半衰期的化合物,例如聚乙二醇)融合所形成的抗原肽,或(iv) 附加的氨基酸序列融合到此抗原肽序列而形成的抗原肽(如前导序列或分泌序列或用来纯化此抗原肽的序列或蛋白原序列,或与抗原IgG片段的形成的融合蛋白)。根据本文的教导,这些片段、衍生物和类似物属于本领域熟练技术人员公知的范围。本发明中,保守性替换的氨基酸最好根据表I进行氨基酸替换而产生。
表I
本发明的活性抗原肽具有基本相同的激发免疫反应的免疫原性,与新型冠状病毒的S蛋白具有竞争性结合人ACE2蛋白的活性,且具有完全抑制新型冠状病毒 S蛋白的细胞融合和感染效应的活性。
优选地,所述抗原肽如SEQ ID NO.3-5中任一所示。
R815A突变型全长S蛋白序列(SEQ ID NO.3):
MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFH AIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCN DPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHT PINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKY NENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASV YAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADY NYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPL QSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQ QFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWR VYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSV AYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDK NTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKASFIEDLLFNKVTLADAGFIKQYGDCLGDIAAR DLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYE NQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEA EVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGV VFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIG IVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQE LGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT (SEQ ID NO.3)
R815N突变型全长S蛋白序列(SEQ ID NO.:4)
MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFH AIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCN DPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHT PINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKY NENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASV YAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADY NYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPL QSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQ QFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWR VYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSV AYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDK NTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKNSFIEDLLFNKVTLADAGFIKQYGDCLGDIAAR DLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYE NQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEA EVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGV VFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIG IVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQE LGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT (SEQ ID NO.4)
R815K突变型全长S蛋白序列(SEQ ID NO.5)
MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFH AIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCN DPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHT PINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKY NENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASV YAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADY NYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPL QSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQ QFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWR VYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSV AYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDK NTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKKSFIEDLLFNKVTLADAGFIKQYGDCLGDIAAR DLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYE NQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEA EVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGV VFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIG IVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQE LGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT (SEQ ID NO.5)
应理解,本发明突变蛋白与SEQ ID NO.:3-5中任一所示的序列相比,通常具有较高的同源性(相同性),优选地,所述的突变蛋白与SEQ ID NO.:3-5 中任一所示序列的同源性至少为80%,较佳地至少为85%-90%,更佳地至少为95%,最佳地至少为98%,最佳地,≥99%。
此外,还可以对本发明的抗原肽进行修饰。修饰(通常不改变一级结构)形式包括:体内或体外的抗原肽的化学衍生形式如乙酰化或羧基化。修饰还包括糖基化,如那些在抗原肽的合成和加工中或进一步加工步骤中进行糖基化修饰而产生的抗原肽。这种修饰可以通过将抗原肽暴露于进行糖基化的酶(如哺乳动物的糖基化酶或去糖基化酶)而完成。修饰形式还包括具有磷酸化氨基酸残基(如磷酸酪氨酸,磷酸丝氨酸,磷酸苏氨酸)的序列。还包括被修饰从而提高了其抗蛋白水解性能或优化了溶解性能的抗原肽。
术语“编码抗原肽的多核苷酸”可以是包括编码本发明抗原肽的多核苷酸,也可以是还包括附加编码和/或非编码序列的多核苷酸;核苷酸包括核糖核酸(RNA, RibonucleicAcid),和脱氧核糖核酸(DNA,Deoxyribonucleic Acid)。
本发明还涉及上述多核苷酸的变异体,其编码与本发明有相同的氨基酸序列的多肽或抗原肽的片段、类似物和衍生物。这些核苷酸变异体包括取代变异体、缺失变异体和插入变异体。如本领域所知的,等位变异体是一个多核苷酸的替换形式,它可能是一个或多个核苷酸的取代、缺失或插入,但不会从实质上改变其编码的突变蛋白的功能。
本发明还涉及与上述的序列杂交且两个序列之间具有至少50%,较佳地至少70%,更佳地至少80%相同性的多核苷酸。本发明特别涉及在严格条件(或严紧条件) 下与本发明所述多核苷酸可杂交的多核苷酸。在本发明中,“严格条件”是指:(1) 在较低离子强度和较高温度下的杂交和洗脱,如0.2×SSC,0.1%SDS,60℃;或(2) 杂交时加有变性剂,如50%(v/v)甲酰胺,0.1%小牛血清/0.1%Ficoll,42℃等;或(3)仅在两条序列之间的相同性至少在90%以上,更好是95%以上时才发生杂交。
本发明的抗原肽和多核苷酸优选以分离的形式提供,更佳地,被纯化至均质。
本发明多核苷酸全长序列通常可以通过PCR扩增法、重组法或人工合成的方法获得。对于PCR扩增法,可根据本发明所公开的有关核苷酸序列,尤其是开放阅读框序列来设计引物,并用市售的cDNA库或按本领域技术人员已知的常规方法所制备的cDNA库作为模板,扩增而得有关序列。当序列较长时,常常需要进行两次或多次PCR扩增,然后再将各次扩增出的片段按正确次序拼接在一起。
一旦获得了有关的序列,就可以用重组法来大批量地获得有关序列。这通常是将其克隆入载体,再转入细胞,然后通过常规方法从增殖后的宿主细胞中分离得到有关序列。
此外,还可用人工合成的方法来合成有关序列,尤其是片段长度较短时。通常,通过先合成多个小片段,然后再进行连接可获得序列很长的片段。
目前,已经可以完全通过化学合成来得到编码本发明蛋白(或其片段,或其衍生物)的DNA序列。然后可将该DNA序列引入本领域中已知的各种现有的DNA分子 (或如载体)和细胞中。此外,还可通过化学合成将突变引入本发明蛋白序列中。
应用PCR技术扩增DNA/RNA的方法被优选用于获得本发明的多核苷酸。特别是很难从文库中得到全长的cDNA时,可优选使用RACE法(RACE-cDNA末端快速扩增法),用于PCR的引物可根据本文所公开的本发明的序列信息适当地选择,并可用常规方法合成。可用常规方法如通过凝胶电泳分离和纯化扩增的DNA/RNA片段。
疫苗多肽
在本发明中,“本发明表位肽”、“本发明疫苗多肽”、“本发明多肽”可互换使用,指符合本发明第二方面中所述的疫苗多肽。
在本发明中,疫苗多肽还包括其他形式,例如药学上可接受的盐、偶联物、或融合蛋白。
在本发明中,疫苗多肽包括对SEQ ID No:3-5中任一所示的序列进行一个或多个(如1-5个,优选地1-3个)氨基酸添加、一个或多个(如1-5个,优选地1-3 个)氨基酸的取代和/或1-3个氨基酸缺失所形成的衍生多肽,所述衍生多肽与衍生前的原始多肽具有基本相同的功能。
优选地,疫苗多肽包括对SEQ ID No:3-5中任一所示的序列经过1-3个氨基酸添加(优选添加在N端或C端)、和/或1-2个氨基酸的取代(优选保守性氨基酸替换)并仍具有与衍生前的原始多肽具有基本相同的功能。
优选地,所述的保守性氨基酸替换根据表II进行氨基酸替换。
表II
最初的残基 | 代表性的取代 | 优选的取代 |
Ala(A) | Val;Leu;Ile | Val |
Arg(R) | Lys;Gln;Asn | Lys |
Asn(N) | Gln;His;Lys;Arg | Gln |
Asp(D) | Glu | Glu |
Cys(C) | Ser | Ser |
Gln(Q) | Asn | Asn |
Glu(E) | Asp | Asp |
Gly(G) | Pro;Ala | Ala |
His(H) | Asn;Gln;Lys;Arg | Arg |
Ile(I) | Leu;Val;Met;Ala;Phe | Leu |
Leu(L) | Ile;Val;Met;Ala;Phe | Ile |
Lys(K) | Arg;Gln;Asn | Arg |
Met(M) | Leu;Phe;Ile | Leu |
Phe(F) | Leu;Val;Ile;Ala;Tyr | Leu |
Pro(P) | Ala | Ala |
Ser(S) | Thr | Thr |
Thr(T) | Ser | Ser |
Trp(W) | Tyr;Phe | Tyr |
Tyr(Y) | Trp;Phe;Thr;Ser | Phe |
Val(V) | Ile;Leu;Met;Phe;Ala | Leu |
如本文所用,“分离的”是指物质从其原始环境中分离出来(如果是天然的物质,原始环境即是天然环境)。如活体细胞内的天然状态下的多肽是没有分离纯化的,但同样的多肽如从天然状态中同存在的其他物质中分开,则为分离纯化的。
如本文所用,“分离的肽”是指本发明多肽基本上不含天然与其相关的其它蛋白、脂类、糖类或其它物质。本领域的技术人员能用标准的蛋白质纯化技术纯化本发明多肽。基本上纯化的多肽(融合蛋白)在非还原聚丙烯酰胺凝胶上能产生单一的主带。
本发明的多肽可以是重组多肽、或合成多肽,优选合成多肽。
在本发明中,当疫苗多肽的序列较短(如≤70aa,更佳地≤60aa时),可用化学方法直接合成相关肽序列。
当疫苗多肽的序列较长或以融合蛋白形式提供疫苗多肽时,也可以用重组法来大批量地获得相关肽序列。这通常是将编码所述抗原多肽或其融合蛋白的编码序列克隆入载体,再转入细胞,然后通过常规方法从增殖后的宿主细胞中分离得到相关的抗原肽或融合蛋白。
mRNA疫苗
本发明还提供了用于预防新型冠状病毒的mRNA疫苗。
典型地,本发明方法包括:首先通过PCR方法获得抗原蛋白的表达基因(或编码序列),之后利用体外转录技术获得相应的mRNA,从而获得高效的mRNA疫苗。
mRNA疫苗是一种体外制备的具有表达活性的mRNA,其主要结构包括5'和 3'UTR以及含有表达抗原的开放读码框。相比于DNA疫苗,它不需要任何核定位信号,并且无整合到基因组上的风险。
在本发明的mRNA疫苗中,是编码本发明第一方面所述抗原肽的mRNA。
载体和宿主细胞
本发明还提供了一种包含本发明的抗原肽编码序列的载体,以及含所述载体的宿主细胞。
在本发明的一个优选例中,所述载体具有表达所述抗原肽基因的表达盒,所述表达盒从5’-3’依次具有下述元件:启动子,抗原肽基因,和终止子。
本领域的普通技术人员可以使用的常规方法获得所述抗原肽的上述优化基因序列,例如全人工合成或PCR法合成。一种优选的合成法为不对称PCR法。用于PCR的引物可根据本文所公开的本发明的序列信息适当地选择,并可用常规方法合成。可用常规方法如通过凝胶电泳分离和纯化扩增的DNA/RNA片段。
本发明的多核苷酸序列可以通过常规的重组DNA技术,表达或生产目的蛋白(抗原肽),包括步骤:
(1)用编码本发明蛋白的多核苷酸(或变异体),或用含有该多核苷酸的重组表达载体转化或转导合适的宿主细胞,较佳地为酵母或果蝇S2细胞;
(2)在合适的培养基中培养宿主细胞;
(3)从培养基或细胞中分离、纯化蛋白质。
本领域的技术人员熟知的方法能用于构建含本发明蛋白的编码DNA序列和合适的转录/翻译控制信号的表达载体,优选市售的载体如pPinkαHC或pMT/BiP/V5-HisA。这些方法包括体外重组DNA技术、DNA合成技术、体内重组技术等。所述的DNA序列可有效连接到表达载体中的适当启动子上,以指导mRNA 合成。表达载体还包括翻译起始用的核糖体结合位点和转录终止子。此外,表达载体优选包含一个或多个选择性标记基因,以提供用于选择转化的宿主细胞的表型性状。
包含上述DNA序列以及适当启动子或者控制序列的载体,可以用于转化适当的宿主细胞,表达目的蛋白。能够表达本发明抗原肽的宿主细胞可以是原核细胞,如大肠杆菌;或是低等真核细胞,如酵母细胞(毕赤酵母、酿酒酵母);或是高等真核细胞,如昆虫细胞;优选为酵母细胞。用重组DNA转化宿主细胞可用本领域技术人员熟知的常规技术进行。工程细胞可以是快速利用甲醇型 (Mut+)或慢速利用甲醇型(Muts)。
工程细胞的培养和目的蛋白发酵生产
在获得工程细胞后,便可在适合的条件下培养工程细胞,表达本发明的基因序列所编码的蛋白。根据宿主细胞的不同,培养中所用的培养基可选自各种常规培养基,在适于宿主细胞生长的条件下进行培养。当宿主细胞生长到适当的细胞密度后,用合适的方法(如温度转换或化学诱导)诱导选择的启动子,将细胞再培养一段时间。
在本发明中,可采用常规的发酵条件。代表性的条件包括(但并不限于):
(a)就温度而言,本发明的抗原肽的发酵及诱导温度保持在28-30℃;
(b)就诱导期的pH值而言,诱导期pH控制在3-9;
(c)就溶氧(DO)而言,DO控制在20-90%,溶氧的维持可以用氧气/空气混合气体的通入来解决;
(d)就补料而言,补料种类宜包括甘油、甲醇、葡萄糖等碳源,可单独补料或混合补料。
工程细胞表达目的蛋白可以采用层析技术进行纯化。层析技术包括阳离子交换层析、阴离子交换层析、凝胶过滤层析、疏水层析、亲和层析等技术。常用的层析方法包括:
1.阴离子交换层析
阴离子交换层析介质包括(但不限于):Q-Sepharose、DEAE-Sepharose。如果发酵样品的盐浓度较高,影响与离子交换介质的结合,则在进行离子交换层析前需降低盐浓度。样品可以用稀释、超滤、透析、凝胶过滤层析等手段进行平衡缓冲液的更换,直至与对应的离子交换柱平衡液系统相似,然后上样,进行盐浓度或pH的梯度洗脱。
2.疏水层析
疏水层析介质包括(但不限于):Phenyl-Sepharose、Butyl-Sepharose、 Octyle-Sepharose。样品通过添加NaCl、(NH4)2SO4等方式提高盐浓度,然后上样,通过降低盐浓度方法洗脱。通过疏水层析除去疏水性有较大差异的杂蛋白。
3.凝胶过滤层析
疏水层析介质包括(但不限于):Sephacryl、Superdex、Sephadex类。通过凝胶过滤层析更换缓冲体系,或进一步精纯。
4.亲和层析
亲和层析介质包括(但不限于):HiTrapTMHeparin HP Columns。
制备方法
本发明的抗原肽(多肽)可以是重组多肽或合成多肽。本发明的多肽可以是化学合成的,或重组的。相应地,本发明多肽可用常规方法人工合成,也可用重组方法生产。
一种优选的方法是使用液相合成技术或固相合成技术,如Boc固相法、Fmoc 固相法或是两种方法联合使用。固相合成可快速获得样品,可根据目的肽的序列特征选用适当的树脂载体及合成系统。例如,Fmoc系统中优选的固相载体如连接有肽中C端氨基酸的Wang树脂,Wang树脂结构为聚苯乙烯,与氨基酸间的手臂是4-烷氧基苄醇;用25%六氢吡啶/二甲基甲酰胺室温处理20分钟,以除去Fmoc保护基团,并按照给定的氨基酸序列由C端逐个向N端延伸。合成完成后,用含4%对甲基苯酚的三氟乙酸将合成的胰岛素原相关肽从树脂上切割下来并除去保护基,可过滤除树脂后乙醚沉淀分离得到粗肽。将所得产物的溶液冻干后,用凝胶过滤和反相高压液相层析法纯化所需的肽。当使用Boc系统进行固相合成时,优选树脂为连接有肽中C端氨基酸的PAM树脂,PAM树脂结构为聚苯乙烯,与氨基酸间的手臂是4-羟甲基苯乙酰胺;在Boc合成系统中,在去保护、中和、偶联的循环中,用TFA/二氯甲烷(DCM)除去保护基团Boc并用二异丙基乙胺(DIEA/二氯甲烷中和。肽链缩合完成后,用含对甲苯酚(5-10%) 的氟化氢(HF),在0℃下处理1小时,将肽链从树脂上切下,同时除去保护基团。以50-80%乙酸(含少量巯基乙醇)抽提肽,溶液冻干后进一步用分子筛Sephadex G10或Tsk-40f分离纯化,然后再经高压液相纯化得到所需的肽。可以使用肽化学领域内已知的各种偶联剂和偶联方法偶联各氨基酸残基,例如可使用二环己基碳二亚胺(DCC),羟基苯骈三氮唑(HOBt)或1,1,3,3-四脲六氟磷酸酯(HBTU) 进行直接偶联。对于合成得到的短肽,其纯度与结构可用反相高效液相和质谱分析进行确证。
在一实施方式中,本发明的抗原肽,按其序列,采用固相合成的方法制备,行高效液相色谱纯化,获得高纯度目的肽冻干粉,-20℃贮存。
另一种方法是用重组技术产生本发明多肽。通过常规的重组DNA技术,可利用本发明的多核苷酸来表达或生产本发明的抗原肽。一般来说有以下步骤:
(1).用本发明的抗原肽的多核苷酸(或变异体),或用含有该多核苷酸的重组表达载体转化或转导合适的宿主细胞;
(2).在合适的培养基中培养的宿主细胞;
(3).从培养基或细胞中分离、纯化蛋白质。
重组多肽可在细胞内、或在细胞膜上表达、或分泌到细胞外。如果需要,可利用其物理的、化学的和其它特性通过各种分离方法分离和纯化重组的蛋白。这些方法是本领域技术人员所熟知的。这些方法的例子包括但并不限于:常规的复性处理、用蛋白沉淀剂处理(盐析方法)、离心、渗透破菌、超处理、超离心、分子筛层析(凝胶过滤)、吸附层析、离子交换层析、高效液相层析(HPLC) 和其它各种液相层析技术及这些方法的结合。
由于本发明多肽较短,因此可以考虑将多个多肽串联在一起,重组表达后获得多聚体形式的表达产物,然后通过酶切等方法形成所需的小肽。
制备疫苗组合物
本发明还提供了一种制备疫苗组合物的方法,具体地,包括步骤:
将本发明制备的抗原肽与药学上可接受的疫苗佐剂混合,从而形成疫苗组合物。
在另一优选例中,所述的佐剂为铝佐剂、GLA佐剂,较佳的GLA佐剂。
组合物和施用方法
本发明还提供了一种组合物,所述组合物含有:(i)用本发明方法制备的重组抗原肽或疫苗多肽,以及(ii)药学上或免疫学上可接受的赋形剂或佐剂。本发明中,术语“含有”表示各种成分可一起应用于或存在于本发明的组合物中。因此,术语“主要由...组成”和“由...组成”包含在术语“含有”中。
本发明的组合物包括药物组合物和疫苗组合物。本发明的组合物可以是单价的,也可以是多价的。
本发明的药物组合物或疫苗组合物可制备成各种常规剂型,其中包括(但并不限于):注射剂、粒剂、片剂、丸剂、栓剂、胶囊、悬浮液、喷雾剂等。
(i)药物组合物
本发明的药物组合物包括有效量的用本发明方法制备的抗原肽或疫苗多肽,所述抗原肽或疫苗多肽可以是单价的,也可以是多价的。
本文所用的术语“有效量”指治疗剂治疗、缓解或预防目标疾病或状况的量,或是表现出可检测的治疗或预防效果的量。该效果可通过例如抗原水平来检测。治疗效果也包括生理性症状的减少。对于某一对象的精确有效量取决于该对象的体型和健康状况、病症的性质和程度、以及选择给予的治疗剂和/或治疗剂的组合。因此,预先指定准确的有效量是没用的。然而,对于某给定的状况而言,可以用常规实验来确定该有效量。
为了本发明的目的,有效的剂量为给予个体约0.2微克/千克至2微克/千克。
药物组合物还可含有药学上可接受的载体。术语“药学上可接受的载体”指用于治疗剂(例如抗原肽或其它治疗剂)给药的载体。该术语指这样一些药剂载体:它们本身不诱导产生对接受该组合物的个体有害的抗体,且给药后没有过分的毒性。合适的载体可以是大的、代谢缓慢的大分子,如蛋白质、多糖、聚乳酸(polylactic acid)、聚乙醇酸等。这些载体是本领域普通技术人员所熟知的。在Remington’s Pharmaceutical Sciences(MackPub.Co.,N.J.1991) 中可找到关于药学上可接受的载体或赋形剂的充分讨论。
组合物中药学上可接受的载体可包括液体,如水、盐水、甘油和乙醇。另外,这些载体中还可能存在辅助性的物质,如润湿剂或乳化剂、pH缓冲物质等。通常,可将组合物制成可注射剂,例如液体溶液或悬液;还可制成在注射前适合配入溶液或悬液、液体赋形剂的的固体形式。脂质体也包括在药学上可接受的载体的定义中。
(ii)疫苗组合物
本发明的疫苗组合物可以是预防性的(即预防感染),也可以是治疗性的。所述的疫苗组合物包含免疫性抗原(包括本发明蛋白或自组装的病毒样颗粒),并且通常与“药学上可接受的载体”组合,这些载体包括本身不诱导产生对接受该组合物的个体有害的抗体的任何载体。合适的载体通常是大的、代谢缓慢的大分子,如蛋白质、多糖、聚乳酸、聚乙醇酸、氨基酸聚合物、氨基酸共聚物、脂质凝集物(如油滴或脂质体)等。这些载体是本领域普通技术人员所熟知的。另外,这些载体可起免疫刺激剂(“佐剂”)作用。另外,抗原也可以和细菌类毒素(如白喉、破伤风、霍乱、幽门螺杆菌等病原体的类毒素)偶联。
增强免疫组合物效果的优选佐剂包括但不限于:(1)铝盐(alum),如氢氧化铝、磷酸铝、硫酸铝等;(2)水包油型乳剂配方,例如,(a)MF59(参见WO 90/14837),(b)SAF,和(c)RibiTM佐剂系统(RAS)(Ribi Immunochem,Hamilton, MT),(3)皂素佐剂;(4)Freund完全佐剂(CFA)和Freund不完全佐剂(IFA);(5) 细胞因子,如白介素(如IL-1、IL-2、IL-4、IL-5、IL-6、IL-7、IL-12等)、干扰素(如γ干扰素)、巨噬细胞集落刺激因子(M-CFS)、肿瘤坏死因子(TNF)等; (6)细菌ADP-核糖基化毒素(如霍乱毒素CT,百日咳毒素PT或大肠杆菌热不稳定毒素LT)的脱毒变异体,参见例如WO93/13302和WO92/19265;以及(7)作为免疫刺激剂来增强组合物效果的其它物质。
包括免疫原性组合物在内的疫苗组合物(例如,可包括抗原、药学上可接受的载体以及佐剂),通常含有稀释剂,如水,盐水,甘油,乙醇等。另外,辅助性物质,如润湿剂或乳化剂、pH缓冲物质等可存在于这类运载体中。
更具体地,包括免疫原性组合物在内的疫苗,包含免疫学有效量的免疫原性多肽,以及上述其它所需的组分。“免疫学有效量”指以单剂或连续剂一部分给予个体的量对治疗或预防是有效的。该用量可根据所治疗个体的健康状况和生理状况、所治疗个体的类别(如人)、个体免疫系统合成抗体的能力、所需的保护程度、疫苗的配制、治疗医师对医疗状况的评估、及其它的相关因素而定。预计该用量将在相对较宽的范围内,可通过常规实验来确定。
通常,可将疫苗组合物或免疫原性组合物制成可注射剂,例如液体溶液或悬液;还可制成在注射前适合配入溶液或悬液、液体赋形剂的固体形式。该制剂还可乳化或包封在脂质体中,以增强佐剂效果。
(iii)给药途径和剂量
所述组合物可以直接给予对象。对象可以是人或非人哺乳动物,较佳地为人。当用作疫苗时,可用已知的方法将本发明的病毒样颗粒直接施用于个体。通常采用与常规疫苗相同的施用途径和/或模拟病原体感染路径施用这些疫苗。
给予本发明药物组合物或疫苗组合物的途径包括(但并不限于):肌内、皮下、皮内、肺内、静脉内、经鼻、阴道内、经口服或其它肠胃外给药途径。如果需要,可以组合给药途径,或根据疾病情况进行调节。疫苗组合物可以单剂量或多剂量给予,且可以包括给予加强剂量以引发和/或维持免疫力。
应以“有效量”给予病毒样颗粒疫苗,即病毒样颗粒的量在所选用的给药路径中足以引发免疫应答,能有效促使保护宿主抵抗新型冠状病毒感染。
在各疫苗剂份中所选用的病毒样颗粒的量,是按可引发免疫保护性应答而无明显的副作用的量而定。通常,在感染宿主细胞后,各剂的疫苗足以含有约 1μg-1000μg,较佳地为1μg-100μg,更佳地10μg-50μg蛋白质或VLP。可用包括观察对象中的抗体滴定度和其它反应的标准研究方法来确定具体疫苗的最佳用量。可通过监控疫苗提供的免疫力水平来确定是否需要增强剂量。在评估了血清中的抗体滴定度后,可能需要选用增强剂量免疫接种。施用佐剂和/或免疫刺激剂就可提高对本发明的蛋白质的免疫应答。优选方法是从肠胃外(皮下或肌内) 途径通过注射给予免疫原性组合物。
本发明的主要优点在于:
(1)本发明首次发现,新型冠状病毒S蛋白氨基酸序列的SEQ ID NO.:1 的第815位的精氨酸突变后,可有效防止S蛋白产生细胞融合效应,并且R815 的位点突变还可有效阻止各种S蛋白突变株发挥融合效应,从而有效防止新型冠状病毒的感染。
(2)本发明首次发现,含有R815的位点突变的蛋白还可有效治疗冠状病毒 SARS-CoV-2感染或其相关疾病。
(3)本发明首次发现,Spike蛋白氨基酸位点突变,能有效抑制新型冠状病毒所诱导的细胞融合效果,从而防止病毒感染。
(4)本发明首次发现,通过基因修改后的Spike蛋白对细胞具有低毒性,从而有助于安全疫苗的开发。
(5)本发明首次发现,本发明的该突刺蛋白位点(即,R815位点)还能成为广谱性小分子药物靶点,从而筛选出后期针对冠状病毒的特效药。因此,所发现的特效药物可为将来类似冠状病毒感染的防控提供前瞻性知识储备和临床应用价值。
(6)本发明首次发现,单R815位点氨基酸的替换可以完全导致病毒融合功能丧失,从而有效阻断今后因新冠病毒突变株导致的感染。
(7)本发明首次发现,通过突变产生的S蛋白可以最大化地保留原有病毒的结构与形态,激活宿主免疫反应;同时避免S蛋白融合效应产生的组织副作用或机体损伤。
(8)本发明首次发现,本发明的突变S蛋白(即抗原肽)能制备无副作用的,更安全的病毒载体及mRNA疫苗。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,例如Sambrook等人,分子克隆实验指南(New York:Cold Spring Harbor LaboratoryPress,1989);或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
通用方法
突变型S制备
通过SARS-CoV-2(Wuhan-Hu-1,GenBank:QHD43419.1)毒株克隆出的人类优化S基因序列,并加入可通过CMV启动子在人类细胞内表达的S蛋白载体质粒。通过自定义引物、KOD plus酶高保真性聚合酶和DpnI内切酶对S蛋白位点进行定点突变。突变S基因通过Lipofectamine 2000转入HEK293T细胞表达24小时,然后使用冰磷酸缓冲盐溶液冲脱HEK293T细胞,然后进行细胞融合实验。
细胞融合
人类HEK293T细胞通过转染SARS-CoV-2表达野生型或突变型S蛋白24小时后,在细胞培养盘中与稳定表达或不表达ACE2受体的HEK293T细胞进行混合培养16小时。融合细胞状态通过20X光学显微镜捕捉,融合后细胞通过1x Laemmli蛋白上样液裂解煮样,并进行SDS-PAGE跑胶,并且使用针对新冠S2 兔多抗、HA-和Myc-标签蛋白的鼠单抗进行蛋白印迹。免疫共沉淀
人类HEK293T细胞通过Lipofectamine 2000,同时转染表达HA-野生型或突变型S蛋白和Myc-标签型野生型S蛋白24小时后,用含有0.5%的NP-40细胞裂解缓冲液,收细胞裂解液样本。细胞溶液通过加入HA-标签鼠单抗过夜,并使用磁珠沉淀S蛋白。免疫共沉淀样本通过裂解液冲洗三次后,进行进行蛋白印迹法。
实施例1新冠S蛋白与宿主ACE2细胞的细胞融合效应
SARS-CoV-2表面的突刺蛋白(Spike glycoprotein,简称S)是病毒外膜唯一暴露的、能识别宿主受体和发挥结合作用的蛋白。S蛋白具有识别宿主受体,直到经历结构变化将病毒融合进入宿主细胞的功能。结合受体后的S引发三聚体发生不稳定性,然后在S中间685氨基酸位点酶切割后产生S1和S2亚基,从而造成S1亚基脱落,同时辅助S2亚基形成融合后的稳定结构,并促进与细胞结合后的新冠病毒与宿主发生膜融合反应。值得一提的是,SARS-CoV-2 的S基因与蝙蝠RaTG13冠状病毒S基因具有93.1%的相似度,与往年的 SARS-CoV只有不到80%的吻合度;因此,如何通过S基因位点,探索冠状病毒产生细胞融合的机制,对探索及研发广谱小分子抑制剂具有重要意义。
因为SARS-CoV-2S蛋白识别的是人类血管紧张素转化酶2(ACE2)受体,首先本发明通过一种细胞细胞融合实验研究了Spike突刺蛋白的融合功能。单独表达S蛋白的HEK293T细胞,显微镜下能清楚地观察到细胞形态不发生任何变化(图1A);加入表达人类ACE2受体的HEK293T细胞后,两种细胞呈现多细胞聚合融合状态(图1B)。通过收集这些融合后的细胞,我们使用蛋白质印迹法,发现了只有通过细胞融合产生出来的一种大约在68kDa分子量的蛋白条带,命名为S2’(图1C)。S2’的产生只在加入ACE2细胞后产生,并且与ACE2加入的量及其相关。因此我们推测S2’的产生对细胞融合是必要的。
实施例2 R815位点突变S蛋白的融合效应缺失
通过上述片段长度和多种冠状病毒S蛋白的排列对比,我们初步分析出 S2’片段为S蛋白的816-1273aa(图1D);并且定位这个条带由宿主细胞膜蛋白酶切割,为一个氨基酸的P0切割位点,且保守与其它冠状病毒相同S2’的位置。通过设计自定义引物和制作定点突变,我们将处于S2’蛋白的精氨酸 815(R815)分别突变成了天冬酰胺(R815N)和丙氨酸(R815A)。突变后的全长S蛋白表达与野生型S蛋白并无差距(图2A);更重要的是,在加入表达 ACE2的HEK293T细胞后,两种R815位点的突变都未像野生型S蛋白产生S2’蛋白条带(图2A)。这说明S蛋白的定点突变,成功防止了S2’精氨酸位置受宿主蛋白酶识别,并且避免了蛋白切割反应。我们继续通过显微镜观察了R815N和R815A突变型S细胞与宿主ACE2细胞的融合效应,发现只有野生型能继续与ACE2细胞发生融合反应,而不是上述两种突变型S蛋白(图2B)。因此R815的位点突变能造成S蛋白细胞融合效应缺失。
实施例3 R815位点有效防止其它突变株S蛋白的融合效应
因R815N和R815A位点突变能造成野生型S蛋白的功能缺失,本发明继续分析了R815位点突变能否防止新型突变株新冠病毒的融合效应。D614G是一种新型变种新冠S蛋白突变(S-D614G),发生在S1结构域上,且造成S蛋白感染能力增强。我们首先制作了D614G型S蛋白,并在其基础上分别插入了R815N 和R815A。与野生型相同,R815N和R815A点突变都能有效防止S蛋白产生细胞融合效应(图3A)。除此之外,本发明也测试了S蛋白的C端19氨基酸(S-CT Δ19)截短的功能增强突变,并也测试了R815N和R815A。S-CTΔ19细胞与ACE2 细胞发生了极其强烈的细胞融合效应,但与上图一致的是,R815N和R815A位点突变都阻止了S-CTΔ19细胞发生融合(图3B)。因此,R815的位点突变能够有效阻止多种S蛋白突变株发挥融合效应。
实施了4 R815位点突变有效防止假病毒感染ACE2细胞
为了更加强调S蛋白位点突变对病毒颗粒的作用,本发明制作了含有野生型、及带有R815N和R815A单氨基酸位点突变的逆转录病毒载体颗粒 (Pseudotype particles,PPs)。不包装S蛋白的病毒载体颗粒无法感染稳定表达ACE2的HEK293T细胞;而组装了野生型S蛋白的病毒载体颗粒有效感染细胞,并且表达可通过荧光显微镜拍摄到的绿色荧光体GFP蛋白标签(图4A、图4B)。与细胞融合结果一致,组装R815N与R815A突变S蛋白的病毒载体颗粒均未能成功感染ACE2细胞(图4A、图4B)。这些数据说明R815位点突变对SARS-CoV-2S蛋白的融合感染效应尤其重要。
实施例5 R815位点突变S蛋白直接干预野生型S蛋白的融合效应
新冠野生型S蛋白需要形成同源三聚体,从而发挥其在病毒或细胞表面的感染与融合效应。使用HEK293T细胞,我们分别将带有HA-标签的野生型或 R815A突变型的S蛋白、与野生型Myc-标签的S蛋白表达在HEK293T细胞内。 24小时内,收样裂解液并且查看细胞中的突变型S蛋白是否能与野生型S蛋白组装。通过使用针对HA-标签的免疫共沉淀,我们用HA鼠单克隆抗体拉出了同样多带有Myc-标签的S蛋白(图5A)。这说明野生型和突变型S蛋白均能组装在其它的野生型S蛋白上,并形成同源三聚体。我们接下来给这些共表达S 蛋白的细胞加入了表达ACE2细胞的HEK293T细胞,并且共培养16小时。通过蛋白印迹我们发现,共同表达突变型与野生型S蛋白的细胞产生了明显减少的 S2’(图5B)。因此这些实验数据证明,R815A突变型S蛋白能干扰野生型S 蛋白发生融合功能,从而在已经表达S蛋白的细胞中具有治疗作用。如上所述, SARS-CoV-2的S蛋白R815位点是目前是本发明发现的,对细胞融合及感染抑制最显著的氨基酸位点。因不具有细胞融合效应,突变S蛋白能制备无副作用的,更安全的病毒载体及mRNA疫苗。这些基础现象和特征均为目前临床上使用的疫苗提供了新型理论基础和参考。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
序列表
<110> 中国科学院上海巴斯德研究所
<120> 基于S蛋白R815位点的冠状病毒干预的方法和产品
<130> P2021-0281
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770 775 780
Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe
785 790 795 800
Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser
805 810 815
Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly
820 825 830
Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp
835 840 845
Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu
850 855 860
Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly
865 870 875 880
Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile
885 890 895
Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr
900 905 910
Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn
915 920 925
Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala
930 935 940
Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn
945 950 955 960
Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val
965 970 975
Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln
980 985 990
Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val
995 1000 1005
Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu
1010 1015 1020
Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg Val
1025 1030 1035 1040
Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser Ala
1045 1050 1055
Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro Ala Gln Glu
1060 1065 1070
Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly Lys Ala His
1075 1080 1085
Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr His Trp Phe Val
1090 1095 1100
Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr Thr Asp Asn Thr
1105 1110 1115 1120
Phe Val Ser Gly Asn Cys Asp Val Val Ile Gly Ile Val Asn Asn Thr
1125 1130 1135
Val Tyr Asp Pro Leu Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu
1140 1145 1150
Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp Leu Gly Asp
1155 1160 1165
Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp
1170 1175 1180
Arg Leu Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu
1185 1190 1195 1200
Gln Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile
1205 1210 1215
Trp Leu Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile
1220 1225 1230
Met Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys
1235 1240 1245
Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro Val
1250 1255 1260
Leu Lys Gly Val Lys Leu His Tyr Thr
1265 1270
<210> 2
<211> 3822
<212> DNA
<213> 人工序列(artificial sequence)
<400> 2
atgttcgtgt ttctggtgct gctgcctctg gtgagctccc agtgcgtgaa tctgaccaca 60
aggacccagc tgccccctgc ctataccaac tccttcacac ggggcgtgta ctatcccgac 120
aaggtgttcc ggagcagcgt gctgcactcc acacaggatc tgtttctgcc tttcttttct 180
aacgtgacct ggttccacgc catccacgtg agcggcacca atggcacaaa gaggttcgac 240
aacccagtgc tgcccttcaa tgatggcgtg tacttcgcct ccaccgagaa gtctaatatc 300
atccgcggct ggatctttgg caccacactg gacagcaaga cacagtccct gctgatcgtg 360
aacaatgcca ccaacgtggt catcaaggtg tgcgagttcc agttttgtaa cgatccattc 420
ctgggcgtgt actatcacaa gaacaataag tcttggatgg agagcgagtt tcgcgtgtat 480
tcctctgcca acaattgcac atttgagtac gtgtcccagc ccttcctgat ggacctggag 540
ggcaagcagg gcaatttcaa gaacctgcgg gagttcgtgt ttaagaacat cgatggctac 600
ttcaaaatct actccaagca caccccaatc aatctggtga gagacctgcc acagggcttc 660
tctgccctgg agccactggt ggatctgccc atcggcatca acatcacccg gtttcagaca 720
ctgctggccc tgcacagaag ctacctgaca ccaggcgaca gctcctctgg atggaccgca 780
ggagcagcag cctactatgt gggctatctg cagcccagga ccttcctgct gaagtacaac 840
gagaatggca ccatcacaga cgcagtggat tgcgcactgg accccctgtc tgagaccaag 900
tgtacactga agagctttac cgtggagaag ggcatctatc agacaagcaa cttcagggtg 960
cagcctaccg agtccatcgt gcgctttccc aatatcacaa acctgtgccc ttttggcgag 1020
gtgttcaatg caaccaggtt cgcaagcgtg tacgcatgga ataggaagcg catctccaac 1080
tgcgtggccg actattctgt gctgtacaat agcgcctcct tctctacctt taagtgctac 1140
ggcgtgagcc ccacaaagct gaatgacctg tgctttacca acgtgtacgc cgattccttc 1200
gtgatcaggg gcgacgaggt gcgccagatc gcaccaggac agacaggcaa gatcgcagac 1260
tacaactata agctgcctga cgatttcacc ggctgcgtga tcgcctggaa cagcaacaat 1320
ctggatagca aagtgggcgg caactacaat tatctgtacc ggctgtttag aaagtctaac 1380
ctgaagccat tcgagaggga catctccaca gaaatctacc aggccggctc taccccctgc 1440
aatggcgtgg agggctttaa ctgttatttc cctctgcaga gctacggctt ccagccaaca 1500
aatggcgtgg gctatcagcc ctaccgcgtg gtggtgctgt cttttgagct gctgcacgcc 1560
cctgcaacag tgtgcggacc aaagaagagc accaatctgg tgaagaacaa gtgcgtgaac 1620
ttcaacttca acggactgac cggcacaggc gtgctgaccg agtccaacaa gaagttcctg 1680
ccttttcagc agttcggcag ggacatcgca gataccacag acgccgtgcg cgaccctcag 1740
accctggaga tcctggatat cacaccatgc tccttcggcg gcgtgtctgt gatcacacca 1800
ggcaccaata caagcaacca ggtggccgtg ctgtatcagg acgtgaactg taccgaggtg 1860
cccgtggcaa tccacgcaga tcagctgacc cctacatggc gggtgtactc taccggcagc 1920
aacgtgttcc agacaagagc cggatgcctg atcggagcag agcacgtgaa caatagctat 1980
gagtgcgaca tccctatcgg cgccggcatc tgtgcctcct accagaccca gacaaactcc 2040
ccaaggagag cacggtctgt ggcaagccag tccatcatcg cctataccat gagcctgggc 2100
gccgagaact ccgtggccta ctccaacaat tctatcgcca tccctaccaa tttcacaatc 2160
tccgtgacca cagagatcct gccagtgagc atgaccaaga catccgtgga ctgcacaatg 2220
tatatctgtg gcgattccac cgagtgctct aatctgctgc tgcagtacgg ctctttttgt 2280
acccagctga acagagccct gacaggcatc gccgtggagc aggacaagaa tacacaggag 2340
gtgttcgccc aggtgaagca aatctacaag accccaccca tcaaggactt tggcggcttc 2400
aactttagcc agatcctgcc cgatcctagc aagccatcca agcggtcttt tatcgaggac 2460
ctgctgttca ataaggtgac cctggccgat gccggcttca tcaagcagta tggcgattgc 2520
ctgggcgaca tcgccgccag agacctgatc tgtgcccaga agtttaacgg cctgaccgtg 2580
ctgcctccac tgctgacaga tgagatgatc gcccagtaca catctgccct gctggcaggc 2640
accatcacaa gcggatggac cttcggcgca ggagccgccc tgcagatccc ctttgccatg 2700
cagatggcct atcggttcaa tggcatcggc gtgacccaga atgtgctgta cgagaaccag 2760
aagctgatcg ccaatcagtt taactccgcc atcggcaaga tccaggactc tctgagctcc 2820
acagcaagcg ccctgggcaa gctgcaggat gtggtgaatc agaacgccca ggccctgaac 2880
accctggtga agcagctgtc tagcaatttc ggcgccatct cctctgtgct gaacgatatc 2940
ctgagccggc tggacaaggt ggaggcagag gtgcagatcg accggctgat cacaggcaga 3000
ctgcagtccc tgcagaccta cgtgacacag cagctgatca gggcagcaga gatcagggca 3060
tctgccaacc tggcagcaac caagatgagc gagtgcgtgc tgggccagtc caagagagtg 3120
gacttttgtg gcaagggcta tcacctgatg agcttcccac agtccgcccc tcacggagtg 3180
gtgtttctgc acgtgaccta cgtgccagcc caggagaaga acttcaccac agcaccagca 3240
atctgccacg atggcaaggc acactttcct agggagggcg tgttcgtgag caatggcacc 3300
cactggtttg tgacacagcg caacttctac gagccacaga tcatcaccac agacaataca 3360
ttcgtgtccg gcaactgtga cgtggtcatc ggcatcgtga acaataccgt gtatgatcct 3420
ctgcagccag agctggactc ttttaaggag gagctggata agtacttcaa gaaccacacc 3480
agccccgacg tggatctggg cgacatctct ggcatcaatg ccagcgtggt gaacatccag 3540
aaggagatcg acaggctgaa tgaggtggcc aagaatctga acgagtccct gatcgatctg 3600
caggagctgg gcaagtatga gcagtacatc aagtggccct ggtatatctg gctgggcttc 3660
atcgccggcc tgatcgccat cgtgatggtg accatcatgc tgtgctgtat gacaagctgc 3720
tgttcctgcc tgaagggctg ctgttcttgt ggcagctgct gtaagtttga tgaggacgat 3780
agcgagcctg tgctgaaggg cgtgaagctg cactacacct ga 3822
<210> 3
<211> 1273
<212> PRT
<213> 人工序列(artificial sequence)
<400> 3
Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
1 5 10 15
Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
20 25 30
Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
35 40 45
His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
50 55 60
Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
65 70 75 80
Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
85 90 95
Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
100 105 110
Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
115 120 125
Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
130 135 140
Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
145 150 155 160
Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
165 170 175
Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
180 185 190
Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
195 200 205
Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
210 215 220
Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
225 230 235 240
Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
245 250 255
Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
260 265 270
Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
275 280 285
Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
290 295 300
Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
305 310 315 320
Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
325 330 335
Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
340 345 350
Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
355 360 365
Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
370 375 380
Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
385 390 395 400
Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
405 410 415
Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
420 425 430
Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
435 440 445
Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
450 455 460
Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
465 470 475 480
Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
485 490 495
Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
500 505 510
Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
515 520 525
Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
530 535 540
Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
545 550 555 560
Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
565 570 575
Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
580 585 590
Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
595 600 605
Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
610 615 620
His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
625 630 635 640
Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
645 650 655
Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
660 665 670
Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val Ala
675 680 685
Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser
690 695 700
Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile
705 710 715 720
Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val
725 730 735
Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu
740 745 750
Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr
755 760 765
Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln
770 775 780
Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe
785 790 795 800
Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Ala Ser
805 810 815
Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly
820 825 830
Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp
835 840 845
Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu
850 855 860
Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly
865 870 875 880
Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile
885 890 895
Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr
900 905 910
Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn
915 920 925
Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala
930 935 940
Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn
945 950 955 960
Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val
965 970 975
Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln
980 985 990
Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val
995 1000 1005
Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu
1010 1015 1020
Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg Val
1025 1030 1035 1040
Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser Ala
1045 1050 1055
Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro Ala Gln Glu
1060 1065 1070
Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly Lys Ala His
1075 1080 1085
Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr His Trp Phe Val
1090 1095 1100
Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr Thr Asp Asn Thr
1105 1110 1115 1120
Phe Val Ser Gly Asn Cys Asp Val Val Ile Gly Ile Val Asn Asn Thr
1125 1130 1135
Val Tyr Asp Pro Leu Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu
1140 1145 1150
Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp Leu Gly Asp
1155 1160 1165
Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp
1170 1175 1180
Arg Leu Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu
1185 1190 1195 1200
Gln Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile
1205 1210 1215
Trp Leu Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile
1220 1225 1230
Met Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys
1235 1240 1245
Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro Val
1250 1255 1260
Leu Lys Gly Val Lys Leu His Tyr Thr
1265 1270
<210> 4
<211> 1273
<212> PRT
<213> 人工序列(artificial sequence)
<400> 4
Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
1 5 10 15
Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
20 25 30
Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
35 40 45
His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
50 55 60
Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
65 70 75 80
Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
85 90 95
Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
100 105 110
Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
115 120 125
Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
130 135 140
Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
145 150 155 160
Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
165 170 175
Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
180 185 190
Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
195 200 205
Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
210 215 220
Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
225 230 235 240
Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
245 250 255
Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
260 265 270
Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
275 280 285
Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
290 295 300
Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
305 310 315 320
Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
325 330 335
Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
340 345 350
Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
355 360 365
Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
370 375 380
Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
385 390 395 400
Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
405 410 415
Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
420 425 430
Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
435 440 445
Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
450 455 460
Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
465 470 475 480
Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
485 490 495
Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
500 505 510
Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
515 520 525
Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
530 535 540
Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
545 550 555 560
Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
565 570 575
Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
580 585 590
Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
595 600 605
Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
610 615 620
His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
625 630 635 640
Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
645 650 655
Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
660 665 670
Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val Ala
675 680 685
Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser
690 695 700
Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile
705 710 715 720
Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val
725 730 735
Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu
740 745 750
Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr
755 760 765
Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln
770 775 780
Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe
785 790 795 800
Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Asn Ser
805 810 815
Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly
820 825 830
Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp
835 840 845
Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu
850 855 860
Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly
865 870 875 880
Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile
885 890 895
Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr
900 905 910
Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn
915 920 925
Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala
930 935 940
Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn
945 950 955 960
Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val
965 970 975
Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln
980 985 990
Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val
995 1000 1005
Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu
1010 1015 1020
Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg Val
1025 1030 1035 1040
Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser Ala
1045 1050 1055
Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro Ala Gln Glu
1060 1065 1070
Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly Lys Ala His
1075 1080 1085
Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr His Trp Phe Val
1090 1095 1100
Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr Thr Asp Asn Thr
1105 1110 1115 1120
Phe Val Ser Gly Asn Cys Asp Val Val Ile Gly Ile Val Asn Asn Thr
1125 1130 1135
Val Tyr Asp Pro Leu Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu
1140 1145 1150
Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp Leu Gly Asp
1155 1160 1165
Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp
1170 1175 1180
Arg Leu Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu
1185 1190 1195 1200
Gln Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile
1205 1210 1215
Trp Leu Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile
1220 1225 1230
Met Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys
1235 1240 1245
Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro Val
1250 1255 1260
Leu Lys Gly Val Lys Leu His Tyr Thr
1265 1270
<210> 5
<211> 1273
<212> PRT
<213> 人工序列(artificial sequence)
<400> 5
Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val
1 5 10 15
Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe
20 25 30
Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu
35 40 45
His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp
50 55 60
Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp
65 70 75 80
Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu
85 90 95
Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser
100 105 110
Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile
115 120 125
Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
130 135 140
Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr
145 150 155 160
Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu
165 170 175
Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe
180 185 190
Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr
195 200 205
Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu
210 215 220
Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr
225 230 235 240
Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
245 250 255
Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro
260 265 270
Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala
275 280 285
Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys
290 295 300
Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
305 310 315 320
Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
325 330 335
Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
340 345 350
Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
355 360 365
Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
370 375 380
Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
385 390 395 400
Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
405 410 415
Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
420 425 430
Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
435 440 445
Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
450 455 460
Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
465 470 475 480
Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
485 490 495
Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
500 505 510
Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys
515 520 525
Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn
530 535 540
Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu
545 550 555 560
Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val
565 570 575
Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe
580 585 590
Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val
595 600 605
Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
610 615 620
His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser
625 630 635 640
Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val
645 650 655
Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala
660 665 670
Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val Ala
675 680 685
Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser
690 695 700
Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile
705 710 715 720
Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val
725 730 735
Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu
740 745 750
Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr
755 760 765
Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln
770 775 780
Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe
785 790 795 800
Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Lys Ser
805 810 815
Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly
820 825 830
Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp
835 840 845
Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu
850 855 860
Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly
865 870 875 880
Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile
885 890 895
Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr
900 905 910
Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn
915 920 925
Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala
930 935 940
Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn
945 950 955 960
Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val
965 970 975
Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln
980 985 990
Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val
995 1000 1005
Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu
1010 1015 1020
Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg Val
1025 1030 1035 1040
Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser Ala
1045 1050 1055
Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro Ala Gln Glu
1060 1065 1070
Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly Lys Ala His
1075 1080 1085
Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr His Trp Phe Val
1090 1095 1100
Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr Thr Asp Asn Thr
1105 1110 1115 1120
Phe Val Ser Gly Asn Cys Asp Val Val Ile Gly Ile Val Asn Asn Thr
1125 1130 1135
Val Tyr Asp Pro Leu Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu
1140 1145 1150
Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp Leu Gly Asp
1155 1160 1165
Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp
1170 1175 1180
Arg Leu Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu
1185 1190 1195 1200
Gln Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile
1205 1210 1215
Trp Leu Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile
1220 1225 1230
Met Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys
1235 1240 1245
Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro Val
1250 1255 1260
Leu Lys Gly Val Lys Leu His Tyr Thr
1265 1270
Claims (10)
1.一种抗原肽,其特征在于,所述抗原肽衍生自新型冠状病毒S蛋白,并且所述抗原肽在对应于新型冠状病毒S蛋白氨基酸序列的SEQ ID NO.:1的第815位的精氨酸发生突变。
2.一种疫苗多肽,其特征在于,所述疫苗多肽包括权利要求1所述的抗原肽。
3.一种mRNA疫苗,其特征在于,所述的疫苗含有用于表达权利要求1所述抗原肽的编码mRNA、以及DNA表达载体。
4.一种分离的多核苷酸,其特征在于,所述的多核苷酸编码权利要求1所述的抗原肽或权利要求2所述的疫苗多肽。
5.一种表达载体,其特征在于,所述表达载体含有权利要求4所述的多核苷酸。
6.一种宿主细胞,其特征在于,所述的宿主细胞含有权利要求5所述的表达载体,或者在基因组中整合有权利要求4所述的多核苷酸。
7.一种丧失新型冠状病毒S蛋白细胞融合效应的抗原病毒株,其特征在于,所述病毒株的基因组中的对应于新型冠状病毒S蛋白氨基酸序列的SEQ ID NO.:1的第815位的精氨酸发生突变。
8.一种药物组合物,其特征在于,所述的组合物含有权利要求1所述的抗原肽、权利要求2所述的疫苗多肽或权利要求3所述的mRNA疫苗或权利要求4所述的多核苷酸或者权利要求5所述的表达载体或者权利要求6所述的宿主细胞或权利要求7所述的病毒株,以及药学上可接受的载体和/或辅料。
9.一种疫苗组合物,其特征在于,所述的组合物含有权利要求1所述的抗原肽、权利要求2所述的疫苗多肽或权利要求3所述的mRNA疫苗或权利要求4所述的多核苷酸或者权利要求5所述的表达载体或者权利要求6所述的宿主细胞或权利要求7所述的病毒株,以及免疫学上可接受的载体和/或辅料。
10.如权利要求1所述的抗原肽或权利要求2所述的疫苗多肽或权利要求3所述的mRNA疫苗或权利要求7所述的病毒株或权利要求8所述的药物组合物或权利要求9所述的疫苗组合物的用途,其特征在于,(a)用于制备针对新型冠状病毒的抗体;和/或(b)用于制备预防和/或治疗冠状病毒感染或其相关疾病的药物。
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PCT/CN2022/070763 WO2022179318A1 (zh) | 2021-02-26 | 2022-01-07 | 基于s蛋白r815位点的冠状病毒干预的方法和产品 |
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