CN114470155A - 新冠病毒重组蛋白复合物药物及其制备方法与应用 - Google Patents
新冠病毒重组蛋白复合物药物及其制备方法与应用 Download PDFInfo
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Abstract
本发明涉及医药技术领域,尤其涉及新冠病毒重组蛋白复合物药物及其制备方法与应用。本发明提供了由新冠病毒蛋白类药物和含有VPGKG特征的五肽重复序列的融合蛋白,并提供了该融合蛋白与聚乙二醇复合而成的蛋白复合物。该蛋白复合物能够用于低成本,长半衰期新冠病毒蛋白类药物的制备,可用于新型冠状肺炎的辅助治疗,疗效明显。
Description
技术领域
本发明涉及医药技术领域,尤其涉及新冠病毒重组蛋白复合物药物及其制备方法与应用。
背景技术
新型冠状病毒肺炎(Corona Virus Disease 2019,COVID-19),简称新冠肺炎,自2019年12月爆发后迅速进展为全球性大流行病,成为全球最关注的突发公共卫生事件,重创全球各国。
新冠肺炎由严重急性呼吸道综合征冠状病毒2(SARS-CoV-2,简称新冠病毒)引起,临床表现复杂多样,严重者会出现呼吸窘迫,感染性休克,合并其他器官功能衰竭,甚至死亡。新冠病毒属于β属的冠状病毒,具体结构包括核蛋白(N)与RNA基因组包裹形成的核衣壳,围绕在外侧的病毒包膜(E),以及其中包膜的基质蛋白(M)与刺突蛋白(S)等。其中S蛋白负责与细胞表面血管紧张素转化酶2(ACE-2)结合并介导病毒进入细胞,在新冠病毒感染细胞的过程中起到至关重要的作用。
在目前的新冠肺炎治疗指南中,除了一般支持治疗和对症治疗以外,针对新冠病毒的推荐药物主要包括以下几类:第一类为传统抗病毒药物瑞德西韦(Remdesivir)、巴瑞替尼(Baricitinib)等,第二类为免疫调节类药物包括激素类药物地塞米松,以及白细胞介素6(Interleukin-6)拮抗剂等,第三类为以针对新冠病毒的单克隆抗体和多肽类拮抗剂为代表的蛋白类药物。前两类药物都属于“老药新用”,以瑞德西韦为代表的的广谱抗病毒药物目前只适用于病毒感染早期,对于新冠肺炎中晚期的患者不仅获益不大,还可能带来严重的肝肾不良反应,进一步加重病情,另外过短的药物半衰期也进一步限制了其临床应用;免疫调节药物通过控制新冠病毒引起的“炎症风暴”来减轻机体的损伤,并不是针对新冠病毒的特效药物,不能从根本上解决新冠病毒感染的问题,故疗效有限。
而蛋白类药物中的单克隆抗体又被称为“生物导弹”,靶向性强,针对新冠病毒研发的单克隆抗体,包括casirivimab、imdevimab(分别称为REGN10933和REGN10987)、bamlanivimab(LY-CoV555),etesevimab(JS016或LY-CoV016)以及sotrovimab(VIR-7831)等,选择与新冠病毒感染细胞最为相关的S蛋白作为攻击靶点,从而阻止其与细胞表面受体结合,防止细胞的感染,同时结合了抗体还能促进病毒被机体的清除,因此单克隆抗体类药物在新冠肺炎的治疗中被寄予厚望。但是单克隆抗体制备工艺复杂,稳定性差等缺点严重限制了其广泛应用。完整的单克隆抗体通常包括两条重链(heavy chain,H)和两条轻链(light chain,L),并分为可变区(variable region,V)和恒定区(constant region,C)。抗体与抗原的特异性结合主要由可变区中的抗原互补决定区(complementaritydeterminingregion,CDR)负责,因此利用部分抗体功能片段来实现完整抗体的治疗作用便成为了目前突破单克隆抗体应用瓶颈的重要方式,其中就包括了单链抗体技术。单链抗体(single-chain variable fragment,scFv)由重链与轻链的可变区及连接肽(linker)连接而成,是拥有抗体活性的最小功能结构单位。单链抗体保留了与抗原的结合能力,还具备分子量小,制备工艺简单,成本低廉等优点,展现出了替代单克隆抗体应用于疾病治疗的潜力。但目前还存在血液循环半衰期短,疗效减弱的问题,需进一步优化。
纳米抗体(Nanobody,Nb),也称为重链单域抗体(VHH singledomainantibodies),最早来源于从骆驼血清中分离发现的重链抗体,是一类有别于传统抗体的天然小体积抗体。与传统抗体相比,纳米抗体拥有理化性质稳定,组织穿透性强的特征,也是一类新兴抗体类药物。主要缺陷与单链抗体类似,由于分子量小,血液中的纳米抗体可被快速清除,影响其作用的发挥。
另一类蛋白类药物,多肽类拮抗剂与传统抗病毒化学药物具有相似的抗病毒机制。目前针对新冠病毒的多肽类拮抗剂主要通过阻断新冠病毒与细胞表面受体接触或融合的过程发挥抗病毒作用,与传统抗病毒化药相比具有更高的特异性,更小的毒副作用。但是同时也存在生物利用度低及半衰期短的缺陷。
发明内容
有鉴于此,本发明要解决的技术问题在于提供新冠病毒重组蛋白复合物药物及其制备方法与应用。
本发明提供了一种融合蛋白,其包括新冠病毒蛋白类药物和五肽重复单元;
所述新冠病毒蛋白类药物包括新冠病毒的单链抗体、新冠病毒的纳米抗体或新冠病毒的多肽拮抗剂。
其中,所述五肽重复单元为[(VPGKG)n(VPGVG)]m,其中n为5~10的整数;m为2~16的整数。
本发明所述的融合蛋白中:所述新冠病毒的单链抗体包括轻链可变区、linker和重链可变区:
一些实施例中,所述新冠病毒的单链抗体中,所述轻链可变区的氨基酸序列如SEQID NO:1~9中任一项所示。
一些实施例中,所述新冠病毒的单链抗体中,所述重链可变区的氨基酸序列如SEQID NO:10~18中任一项所示。
一些实施例中,所述新冠病毒的单链抗体中,轻链可变区和重链可变区之间以linker连接。所述linker为(G4S)x,x为2~10之间的整数。一些具体实施例中,所述linker的氨基酸序列为(G4S)3。
一些具体实施例中,所述新冠病毒的单链抗体中轻链可变区的氨基酸序列如SEQID NO:1所示,所述新冠病毒的单链抗体中重链可变区的氨基酸序列如SEQ ID NO:10所示。
一些具体实施例中,所述新冠病毒的单链抗体中轻链可变区的氨基酸序列如SEQID NO:2所示,所述新冠病毒的单链抗体中重链可变区的氨基酸序列如SEQ ID NO:11所示。
一些具体实施例中,所述新冠病毒的单链抗体中轻链可变区的氨基酸序列如SEQID NO:3所示,所述新冠病毒的单链抗体中重链可变区的氨基酸序列如SEQ ID NO:12所示。
一些具体实施例中,所述新冠病毒的单链抗体中轻链可变区的氨基酸序列如SEQID NO:4所示,所述新冠病毒的单链抗体中重链可变区的氨基酸序列如SEQ ID NO:13所示。
一些具体实施例中,所述新冠病毒的单链抗体中轻链可变区的氨基酸序列如SEQID NO:5所示,所述新冠病毒的单链抗体中重链可变区的氨基酸序列如SEQ ID NO:14所示。
一些具体实施例中,所述新冠病毒的单链抗体中轻链可变区的氨基酸序列如SEQID NO:6所示,所述新冠病毒的单链抗体中重链可变区的氨基酸序列如SEQ ID NO:15所示。
一些具体实施例中,所述新冠病毒的单链抗体中轻链可变区的氨基酸序列如SEQID NO:7所示,所述新冠病毒的单链抗体中重链可变区的氨基酸序列如SEQ ID NO:16所示。
一些具体实施例中,所述新冠病毒的单链抗体中轻链可变区的氨基酸序列如SEQID NO:8所示,所述新冠病毒的单链抗体中重链可变区的氨基酸序列如SEQ ID NO:17所示。
一些具体实施例中,所述新冠病毒的单链抗体中轻链可变区的氨基酸序列如SEQID NO:9所示,所述新冠病毒的单链抗体中重链可变区的氨基酸序列如SEQ ID NO:18所示。
一些具体实施例中,所述单链抗体与五肽重复单元之间以二肽HM连接。
本发明中,所述新冠病毒的纳米抗体的氨基酸序列如SEQ ID NO:19所示。
一些实施例中,所述新冠病毒的纳米抗体与五肽重复单元之间以短肽连接。连接的短肽的氨基酸序列为HHHHHHLEGGGGSGGGGS。
所述新冠病毒多肽拮抗剂包括新冠病毒受体结合结构域(RBD)拮抗肽、新冠病毒保守重复氨基酸序列HR1拮抗肽。本发明中,所述新冠病毒的多肽拮抗剂的氨基酸序列如SEQ ID NO:20~24中任一项所示。
一些实施例中,所述新冠病毒的多肽拮抗剂与五肽重复单元之间以短肽连接。连接的短肽为(G4S)x,x为2~10之间的整数。一些具体实施例中,所述连接的短肽为(G4S)3。
本发明实施例中,所述五肽重复单元为[(VPGKG)9(VPGVG)]8。
本发明还提供了编码所述的融合蛋白的核酸。
本发明还提供了一种重组载体,其包括本发明所述的核酸和骨架载体。
本发明实施例中,所述骨架载体为大肠杆菌表达载体。一些实施例中,所述骨架载体为pET系列载体。一些具体实施例中,所述骨架载体为pET-25b。
本发明还提供了转化或转染重组载体的宿主。所述宿主为大肠杆菌。一些实施例中,所述宿主为E.coli BLR(DE3)。
本发明还提供了所述融合蛋白的制备方法,其包括:培养本发明所述的宿主,诱导所述融合蛋白的表达。
本发明还提供了一种蛋白复合物,其由本发明所述的融合蛋白与PEG制得。本发明实施例中,所述PEG的平均分子量为5000~10000。
本发明所述的蛋白复合物中融合蛋白与聚乙二醇通过静电作用复合。所述蛋白复合物的制备方法包括:将本发明所述融合蛋白与PEG混合,搅拌反应后经脱盐层析后,制得所述蛋白复合物。
本发明实施例中,所述融合蛋白与PEG的摩尔比为1:70~75。一些实施例中,所述融合蛋白与PEG的摩尔比为1:72。
一些实施例中,所述PEG的平均分子量为5000~10000,作为优选,所述PEG为羧基化的PEG。
本发明所述搅拌反应的条件包括,温和搅拌,反应30~60min,反应的温度为室温。优选的,所述室温为18~30℃。
本发明所述制备方法中,所述脱盐层析的洗脱采用超纯水。
本发明所述的融合蛋白、核酸、重组载体、宿主或蛋白复合物在制备防治新型冠状病毒肺炎的药物中的应用。
本发明还提供了一种治疗新型冠状病毒肺炎的药物,其包括融合蛋白、核酸、重组载体、宿主或蛋白复合物。所述药物的剂型为注射剂。
本发明还提供了一种治疗新型冠状病毒肺炎的方法,其包括给予本发明所述的药物。所述给予的方法包括注射。
本发明提供了由新冠病毒蛋白类药物和含有VPGKG特征的五肽重复序列的融合蛋白,并提供了该融合蛋白与聚乙二醇复合而成的蛋白复合物。该蛋白复合物能够用于低成本,长半衰期新冠病毒蛋白类药物的制备,可用于新型冠状肺炎的辅助治疗,疗效明显。
附图说明
图1示目标蛋白的SDS-PAGE凝胶电泳鉴定;
图2示蛋白复合物的电镜检测图;
图3示蛋白复合物的粒径统计分析;
图4示假病毒感染水平及假病毒中和水平;
图5示血药浓度半衰期。
具体实施方式
本发明提供了新冠病毒重组蛋白复合物药物及其制备方法与应用,本领域技术人员可以借鉴本文内容,适当改进工艺参数实现。特别需要指出的是,所有类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述,相关人员明显能在不脱离本发明内容、精神和范围内对本文的方法和应用进行改动或适当变更与组合,来实现和应用本发明技术。
本发明采用的试材皆为普通市售品,皆可于市场购得。
本发明涉及蛋白片段序列及其编码核酸序列如下:
其中,编码[(VPGKG)9VPGVG]8的核酸序列为:
ggcgcggggccgggcgtgggtgttccgggtaaaggtgttccgggcaaaggtgtgccaggcaaaggtgttccgggtaaaggtgtgccgggtaaaggcgtaccgggtaaaggcgtaccaggcaaaggtgttccgggtaaaggcgtaccaggtaaaggtgtgccgggcgtgggtgttccgggtaaaggtgttccgggcaaaggtgtgccaggcaaaggtgttccgggtaaaggtgtgccgggtaaaggcgtaccgggtaaaggcgtaccaggcaaaggtgttccgggtaaaggcgtaccaggtaaaggtgtgccgggcgtgggtgttccgggtaaaggtgttccgggcaaaggtgtgccaggcaaaggtgttccgggtaaaggtgtgccgggtaaaggcgtaccgggtaaaggcgtaccaggcaaaggtgttccgggtaaaggcgtaccaggtaaaggtgtgccgggcgtgggtgttccgggtaaaggtgttccgggcaaaggtgtgccaggcaaaggtgttccgggtaaaggtgtgccgggtaaaggcgtaccgggtaaaggcgtaccaggcaaaggtgttccgggtaaaggcgtaccaggtaaaggtgtgccgggcgtgggtgttccgggtaaaggtgttccgggcaaaggtgtgccaggcaaaggtgttccgggtaaaggtgtgccgggtaaaggcgtaccgggtaaaggcgtaccaggcaaaggtgttccgggtaaaggcgtaccaggtaaaggtgtgccgggcgtgggtgttccgggtaaaggtgttccgggcaaaggtgtgccaggcaaaggtgttccgggtaaaggtgtgccgggtaaaggcgtaccgggtaaaggcgtaccaggcaaaggtgttccgggtaaaggcgtaccaggtaaaggtgtgccgggcgtgggtgttccgggtaaaggtgttccgggcaaaggtgtgccaggcaaaggtgttccgggtaaaggtgtgccgggtaaaggcgtaccgggtaaaggcgtaccaggcaaaggtgttccgggtaaaggcgtaccaggtaaaggtgtgccgggcgtgggtgttccgggtaaaggtgttccgggcaaaggtgtgccaggcaaaggtgttccgggtaaaggtgtgccgggtaaaggcgtaccgggtaaaggcgtaccaggcaaaggtgttccgggtaaaggcgtaccaggtaaaggtgtgccgggctggccg
编码SEQ ID NO.1所示氨基酸序列的核酸序列为:
atggacatccaaatgactcagtctccatcttctttgtcagccagtgtgggtgatcgcgtaacgatcacatgccaggccagccaagatattacaaattatctcaattggtatcaacaaaaaccaggtaaggccccaaaattattgatttacgccgcgagtaatctggaaactggggtaccttctcgtttctcggggagtgggtcgggcacagacttcacattcacgatttccggtttacaacctgaggatatcgctacttactactgtcaacaatacgacaaccttccgcttacttttggcggtggcaccaaagtagaaattaaa
编码SEQ ID NO.2所示氨基酸序列的核酸序列为:
atgcagtcagctttgacacagccagcctcagtgagcggttcgccgggtcaaagtatcaccatttcatgtacgggtacatcatctgacgtcggcgggtacaactatgtttcttggtatcaacaacatccagggaaagctccgaaacttatgatttatgacgtttccaaacgcccatctggcgtaagtaaccggttcagcggttcaaaatctggcaataccgcgagtttgacgatcagcggtcttcaatccgaggatgaggcggattactattgcaattctctgacttcgatttccacatgggtgtttgggggcggcacaaaattaacagttctc
编码SEQ ID NO.3所示氨基酸序列的核酸序列为:
atggaaattgtgttgacgcagtctccaggcaccctgtctttgtctccaggggagagagccaccctctcctgcagggccagtcagagtgttagcagcagctacttagcctggtaccagcagaaacctggccaggctcccaggctcctcatctatggtgcatccagcagggccactggcatcccagacaggttcagtggcagtgggtctgggacagacttcactctcaccatcagcagactggagcctgaagattttgcagtgtattactgtcagcactatggtagctcacggggttggacgttcggccaagggaccaaggtggaaatcaaa
编码SEQ ID NO.4所示氨基酸序列的核酸序列为:
atggacatcgtgatgacccagtctccagactccctggctgtgtctctgggcgagagggccaccatcaactgcaagtccagccagagtgttttatacagctccaacaataagaactacttagcttggtaccagcagaaaccaggacagcctcctaagctgctcatgtactgggcatctacccgggaatccggggtccctgaccgattcagtggcagcgggtctggggcagagttcactctcaccatcagcagcctgcaggctgaagatgtggcaatttattactgtcagcaatattatagtaccctcactttcggcggagggaccaaggtggagatcaaa
编码SEQ ID NO.5所示氨基酸序列的核酸序列为:
atggatattgtgatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccgggcaagtcagagcattagcaggtatttaaattggtatcagcagaaaccagggaaagcccctaagctcctgatctatgctgcatccagtttgcaaagtggggtcccatcaaggttcagtggcagtggatctgggacagatttcactctcaccatcagcagtctgcaacctgaagattttgcaacttactactgtcaacagagttacagtacccctccggagtacacttttggccaggggaccaagctggag
编码SEQ ID NO.6所示氨基酸序列的核酸序列为:
atggatattcagatgacacagtcgccatcaagcctcagcgcaagcgttggggatcgcgtaaccattacatgtcgcgcgtcacaaagtatctcgagttatttgtcttggtatcaacagaaaccggggaaagcaccaaagttacttatctatgctgcgtctagcttacagagtggtgtaccaagccggttctctggttctggctccggcacggatttcacacttactattacatcgttgcagccagaagactttgcgacctactattgtcaacagtcttactcaacgccacgcacatttgggcaagggactaaagtagag
编码SEQ ID NO.7所示氨基酸序列的核酸序列为:
atggagattgtgctcacccagtctccagggacgttgagcttatctcctggggagcgtgcgactttgtcatgtcgtgctagtcagactgtaagttccactagcctggcgtggtatcaacaaaagccgggtcaggcaccacgcttgcttatttatggtgcgagttcacgggctacaggtatcccagatcggttctcggggtccgggtcgggtactgactttactttaacgatctcacgcttggagccggaagacttcgctgtctattattgccagcaacacgacacgtctttgacattcgggggtggcaccaaagtcgag
编码SEQ ID NO.8所示氨基酸序列的核酸序列为:
atggaacttgtgctcactcagccaccaagcgtttcggctgcgccgggccagaaagttactatttcttgctcagggtcctcctcgaatatcgggaacaattacgtgagctggtatcaacaactgccaggcactgcgcctaaactcttaatttatgataacaataagcgtcctagcggtatccctgaccgcttctcggggtcaaagtcaggcacgtccgccactctcgggatcactgggctgcagaccggggacgaggcagactattattgtggcacatgggattcctcgctgagtgccggcgtatttgggggtggcacggagttg
编码SEQ ID NO.9所示氨基酸序列的核酸序列为:
atgcaaagtgttctgacgcagccggcaagtgttagtggttcgccgggtcagtcgattaccatcagctgtacgggcatcagttcggatgttggcggctataatagtgttagttggtaccaacaacacccaggcaaagcgccgaaactgatgatttatgatgtgaccaaccgtccgtcgggcgtgagcaaccgctttagtggctcgaaatctggcaataccgcctcgctgaccatcagcgggttgcaggcagaggatgaggcggactactattgctcgtcgtacacctcgagtagtacgccgccgtatgtgtttggtaccggtaccaaagtgtcggtgttggggcaa
编码SEQ ID NO.10所示氨基酸序列的核酸序列为:
caggtacagcttgtcgaatcaggcggtgggctcgtgaaaccaggcgggtcacttcggctctcgtgcgcggcgagcggcttcacgttttccgactattatatgagctggattcgtcaagctccaggcaagggccttgaatgggtttcttatattacctacagcggcagcacaatttactacgccgattcagtcaaaggtcgtttcacgatctctcgtgacaatgcgaagtctagcctgtacttacagatgaattctttacgtgccgaagatacagcggtctattattgcgcccgcgaccgtgggacaaccatggtcccttttgactattggggtcaaggcaccctggttactgtaagctcc
编码SEQ ID NO.11所示氨基酸序列的核酸序列为:
caagtacagctggtagagtcagggggtggggtagtccagccaggtcgtagtttacgtctgtcttgcgctgcatctggttttaccttttccaattacgctatgtactgggtgcggcaggcgccgggtaagggtctggaatgggtggcggttattagttacgatggtagtaataagtactatgccgactccgtcaaggggcggtttacgattagtcgggataattcaaaaaacacgttataccttcagatgaactccctccgcacagaggacaccgccgtgtattactgcgcaagcgggagcgattatggtgactacttgttggtttattggggtcaaggcacattagtgaccgtgtcatca
编码SEQ ID NO.12所示氨基酸序列的核酸序列为:
caaatgcagctggtgcagtctgggcctgaggtgaagaagcctgggacctcagtgaaggtctcctgcaaggcttctggattcacctttatgagctctgctgtgcagtgggtgcgacaggctcgtggacaacgccttgagtggataggatggatcgtcattggcagtggtaacacaaactacgcacagaagttccaggaaagagtcaccattaccagggacatgtccacaagcacagcctacatggagctgagcagcctgagatccgaggacacggccgtgtattactgtgcggccccatattgtagtagtatcagctgcaatgatggttttgatatctggggccaagggacaatggtcaccgtctcttca
编码SEQ ID NO.13所示氨基酸序列的核酸序列为:
gaggtgcagctggtggagtctgggggaggcttggtaaagcctggggggtcccttagactctcctgtgcagcctctggattcactttcagagacgtctggatgagctgggtccgccaggctccagggaaggggctggagtgggttggccgtattaaaagcaaaattgatggtgggacaacagactacgctgcacccgtgaaaggcagattcaccatctcaagagatgattcaaaaaacacgctgtatctgcaaatgaacagcctgaaaaccgaggacacagccgtgtattactgtaccacagcgggaagctattactatgatactgttggtccaggcctcccagagggaaaatttgactactggggccagggaaccctggtcaccgtctcctca
编码SEQ ID NO.14所示氨基酸序列的核酸序列为:
gaggtgcagctggtggagtctgggggaggcttggtccagcctggggggtccctgagactctcctgtgcagcctctggattcaccgtcagtagcaactacatgagctgggtccgccaggctccagggaaggggctggagtgggtctcagttatttatagcggtggtagcacattctacgcagactccgtgaagggcagattcaccatctccagagacaattccatgaacacgctgtttcttcaaatgaacagcctgagagccgaggacacggctgtgtattactgtgcgagagtgctacctatgtacggtgactaccttgactactggggccagggaaccctggtcacc
编码SEQ ID NO.15所示氨基酸序列的核酸序列为:
caagttcagcttgtgcaatcaggcgccgaggttaaaaaaccgggctctagcgtgaaggtgtcgtgcaaggccagtgggggcacgttctcaaattatgcgatttcgtgggtgcgccaggccccagggcaagggttagaatggatggggcgcatcattccaatcctcggtatcgctaattatgcacaaaagtttcagggccgggtgacaatcacggcggacaaatctacttcgactgcttatatggaattaagttcgctccggtctgaagacactgcggtctattactgtgcgcgtggttattatgaggcccgccactactactattattatgccatggatgtgtggggtcagggcacggcagtgacg
编码SEQ ID NO.16所示氨基酸序列的核酸序列为:
caggtacagcttgtacaaagcggtgccgaagtcaaaaaaccgggggcgtctgtaaaagtctcctgcaaagcctcagggtacccattcactagctacggtattagttgggtccgccaggctccaggtcaggggttggagtggatgggttggatttcgacatacaatggcaacactaactacgctcagaagttccaagggcgtgtaactatgactactgacacgagcacgacgacggggtacatggaactgcgccgtcttcgtagcgacgatactgctgtgtattactgcgctcgtgattatacgcgcggggcttggtttggggagagtctgatcggcgggttcgataactggggtcaaggcacgttagtgacg
编码SEQ ID NO.17所示氨基酸序列的核酸序列为:
cagattactctgaaagaaagcggtcctacattagtgaagccaacccagacgctgacacttacttgcagcttttcagggttttcccttagtacttcaggggtaggggtgggctggatccgtcaaccgccaggcaaggcccttgaatggttagctctcatcgattgggacgataataaataccatacgacttcgttgaagacccggctcacaattagcaaagatacctctaagaaccaggttgtacttacgatgactaacatggatccagtagacacagcgacctattattgtgcccggattccggggtttttgcgctaccgtaatcgctactattactacgggatggatgtatgggggcagggcacaacggtaacc
编码SEQ ID NO.18所示氨基酸序列的核酸序列为:
caggtgcgtctggtccagagtggcgccgaggtgaagaagagtggtgagagcctgaaaattagttgcaaaggcagcggctatagttttacttcgtactggattggctgggtgcgtcagatgccgggtaaaggcttagaatggatgggtattatctacccaggggacagtgacacgcgttattcgccgtcgttccagggccaagtgacgattagcgccgataaaagcatcagcactgtttatttgcaatggagtagcttaaaggcgagtgataccgccatgtattactgcgcgcgccaatggtctcattatacgtatgattattactattggggtcagggtaccctggttaccattagtagcgcgagc
编码SEQ ID NO.19所示氨基酸序列的核酸序列为:
caggtacagctggtagaaagtggtggtggtcttgtccaggccggtggtagcttgcgtctctcttgcgcagtctctgggttaggtgcgcaccgtgttggttggttccgtcgggctccaggcaaagaacgtgaatttgtggcggcaattggtgcaaatggtgggaatactaattacttagattccgtaaaagggcggttcacgatcagtcgggacaatgcaaaaaatacgatttatttgcaaatgaacagtttaaaaccacaagacacggcggtttattactgcgcagcacgggacattgagacagccgaatatacatactggggtcaaggcactcaggtcacagtttcctct
编码SEQ ID NO.20所示氨基酸序列的核酸序列为:
atgtcagcgctggaagaacaacttaaaacattcctggataaatttatgcacgagcttgaagatttgttatatcagcttgcgctt
编码SEQ ID NO.21所示氨基酸序列的核酸序列为:
atggaacttgaggagcaagtgatgcacgtattggatcaagtttccgaactggcgcatgagctgctgcataaattgacaggcgaggagttggaacgtgcggcgtatttcaactggtgggccaccgagatgatgttggaactcatcaagagcgacgatgagcgtgagatccgcgaaatcgaggaggaagcacgccgtatcctggaacacctggaagaacttgctcgtaaa
编码SEQ ID NO.22所示氨基酸序列的核酸序列为:
atggataaagaatggattcttcaaaagatttatgaaattatgcgtctcctcgacgaattaggtcacgcagaagcaagtatgcgggtgagcgacttgatttatgagtttatgaaaaagggggatgagcggctcctggaggaggcagagcgtctcctggaggaagtagag
编码SEQ ID NO.23所示氨基酸序列的核酸序列为:
atgaacgacgacgagctgcacatgctgatgacggacctggtttacgaagctcttcactttgcaaaggacgaagagatcaagaaacgggtttttcagctttttgaattagccgataaagcatacaagaataacgaccggcaaaaattggagaaagtggttgaagaattgaaagagcttctggaacgtttactctcg
编码SEQ ID NO.24所示氨基酸序列的核酸序列为:
atggacatctctggcatcaatgcaagtgtagtcaacatccaaaaggaaatcgaccggctgaacgaagtcgcaaagaatttgaatgaaagcttaatcgatttacaggaactt
下面结合实施例,进一步阐述本发明:
实施例1:重组蛋白表达与纯化
本实施例中,发明人选择VPGKG五肽重复序列K72与新冠病毒单链抗体10933scFv、纳米抗体Nb21融合蛋白进行表达及纯化。
表1重组蛋白序列及特征
重组蛋白编号 | 对应(VPGKG)特征序列 |
10933scFv-K72 | [(VPGKG)<sub>9</sub>VPGVG]<sub>8</sub> |
K72-Nb21 | [(VPGKG)<sub>9</sub>VPGVG]<sub>8</sub> |
编码本发明所使用重组蛋白的核苷酸序列由苏州金唯智生物科技有限公司合成,并连接到表达载体pET-25b上,得到pET-25b-10933scFv-K72、pET-25b-K72-Nb21质粒。
将表达载体转化到大肠杆菌原核表达感受态细胞E.coli BLR(DE3)中。具体的实施方案如下:将1ng的pET-25b-10933scFv-K72(或pET-25b-K72-Nb21)质粒在冰浴环境中加入10μL的BLR大肠杆菌感受态中(购自Novagen公司),并在冰浴环境中维持20min;然后将上述混合物放入42℃水浴中热激60s,随后再次冰浴5min。向混合物中加入LB培养基500μL,于37℃、180rpm震荡环境中处理1h。将混合物均匀涂布在含有氨苄青霉素钠(100μg/mL)抗生素的LB固体培养基上,37℃培养12h,即可获得可以稳定表达重组蛋白的菌株。挑取转化成功的单克隆菌株于100mL LB培养基中(含100μg/mL氨苄西林)培养种子液,培养时间约9小时,培养条件为37℃,220rpm震荡。当种子液OD600达到2-3时,取10mL加入到1L LB培养基中(含100μg/mL氨苄西林)培养发酵液,培养时间约3小时,培养条件为37℃,220rpm震荡。当发酵液OD600达到0.4-0.6时添加诱导剂IPTG(isopropylβ-D-1-thiogalactopyranoside,异丙基硫代半乳糖苷),终浓度为1mM,诱导大肠杆菌发酵表达蛋白,诱导发酵4小时后将发酵液离心,离心条件为4℃,6000rpm,10分钟,弃去上清液保留含有目的蛋白的菌体沉淀。
随后利用蛋白质盐析原理对目标蛋白进行第一步纯化。利用pH为6的含有200mM氯化钠的50mM磷酸盐缓冲溶液(PB)将收集的菌体沉淀重悬,利用超声波细胞粉碎机将菌体裂解的同时,将所表达的目标蛋白盐析沉淀,随后离心,离心条件为4℃,12000rpm,30分钟,弃去上清液,用pH为6的含有50mM氯化钠的50mM磷酸钠缓冲溶液将沉淀中的目标蛋白溶解,再次离心,离心条件为4℃,12000rpm,30分钟,收集上清目标蛋白溶液。
之后利用SP阳离子交换层析对目标蛋白溶液进一步纯化。将目标蛋白溶液上样到SP阳离子交换层析柱中,随后依次用100mL含有0mM、50mM、100mM氯化钠的磷酸盐缓冲洗脱液进行洗脱,并收集含有100mM氯化钠的磷酸盐缓冲洗脱液的洗脱产物。将上述洗脱产物上样到Superdex100(购自GE公司)中进行分子筛层析,随后用超纯水进行洗脱,收集得到高纯度目标蛋白水溶液,冻干后保存于-80℃条件,并取样进行SDS-PAGE凝胶电泳鉴定,如(图1)所示。
实施例2:重组蛋白复合物的制备
重组蛋白复合物1:
将实施例1中得到的纯化后目标重组蛋白10933scFv-K72与羧基化的PEG分别用超纯水溶解,按照摩尔比1:72的比例混合,温和搅拌30分钟。将混合物利用脱盐层析柱(购自GE公司)进行纯化,用超纯水进行洗脱,收集产物得到直径100nm左右的重组蛋白PEG纳米颗粒复合物1(图2)。
重组蛋白复合物2:
将实施例1中得到的纯化后目标重组蛋白K72-Nb21与羧基化的PEG分别用超纯水溶解,按照摩尔比1:72的比例混合,温和搅拌30分钟。将混合物利用脱盐层析柱(购自GE公司)进行纯化,用超纯水进行洗脱,收集产物得到直径80nm左右的重组蛋白PEG纳米颗粒复合物2(图2)。
实施例3:重组蛋白复合物粒径测定
将实施例2中新鲜制备的重组蛋白纳米颗粒复合物1、2水溶液进行透射电镜检测(图2),并进行粒径统计分析(图3),结果显示依照实施例2制备方案所得重组蛋白纳米颗粒复合物1、2形态规则,大小均匀,直径均分布在40-160nm。
实施例4:重组蛋白复合物假病毒中和实验
首先将高表达hACE2的293T细胞接种在96孔板中,接种密度约40%,在37℃,5%(vol/vol)CO2的培养箱中培养过夜后,更换培养基。将实施例2所得重组蛋白纳米复合物1水溶液经0.22μm的滤膜进行过滤后,梯度稀释为100μg/mL、80μg/mL、60μg/mL、40μg/mL、20μg/mL、及1μg/mL;将实施例2所得重组蛋白纳米复合物2水溶液经0.22μm的滤膜进行过滤后,梯度稀释为25μg/mL、5μg/mL、1μg/mL、0.2μg/mL、0.04μg/mL后,分别加入50μL预先准备好的1.3×104TCID50/mL的SARS-CoV-2假病毒并混合均匀,于4℃条件下静置作用0.5h。随后将上述混合物加入细胞培养基中并混匀,继续在37℃,5%(vol/vol)CO2的培养箱中培养使假病毒感染细胞48h后,再次更换培养基。上述假病毒携带荧光素酶报告基因,在成功感染进入细胞后可表达荧光素酶,添加底物后测定荧光强度可代表荧光素酶达水平,并根据荧光素酶报告基因表达水平计算假病毒感染水平及假病毒中和水平,如图4所示,实施例2所制备的重组蛋白纳米颗粒复合物1可在微克(微摩尔)的浓度水平实现对假病毒的有效中和;重组蛋白纳米颗粒复合物2可在纳克(纳摩尔)的浓度水平实现对假病毒的有效中和。
实施例5:重组蛋白复合物在大鼠体内药物代谢变化检测
取体重为200±20g的雄性SD大鼠30只,随机分为3组,每组10只大鼠。分别于尾静脉注射1μmol纳米抗体Nb21蛋白、1μmol实施例1所得重组蛋白K72-Nb21、1μmol实施例2所得重组蛋白纳米复合物2、以及同等体积的PBS。给药后在0h、0.5h、2h、4h、6h、8h、12h、24h、30h、36h、48h、60h、72h、96h、120h、144h、168h时间点从各组取三只大鼠经异氟烷麻醉后,通过眶下静脉采血约0.5mL。将采集的血样4℃过夜静置凝血后,于1000g、4℃条件下离心20min,收集上层血清样品于-80℃条件下保存。
利用新冠抗体定量ELISA检测试剂盒检测血清样品中重组蛋白抗体含量,并计算其半衰期,图5展示了Nb21蛋白、重组蛋白K72-Nb21及重组蛋白纳米颗粒复合物2在大鼠体内血药浓度-时间曲线以及对应的血药浓度半衰期计算结果,可见与纳米抗体、重组蛋白相比,重组蛋白纳米颗粒复合物经单次尾静脉给药后,在大鼠体内的血药浓度降低速度减缓,具有更长的血液循环周期,长达18.7h。目前常见单链抗体、纳米抗体、多肽拮抗剂类蛋白药物的血液半衰期多不超过1h,相比之下本发明重组蛋白纳米颗粒复合物对血药半衰期延长作用显著。
以上仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
序列表
<110> 清华大学
<120> 新冠病毒重组蛋白复合物药物及其制备方法与应用
<130> MP21035817
<160> 24
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Met Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly
1 5 10 15
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp
20 25 30
Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Ser Tyr Ile Thr Tyr Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser
50 55 60
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Ser Ser Leu
65 70 75 80
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
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Cys Ala Arg Asp Arg Gly Thr Thr Met Val Pro Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 2
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<212> PRT
<213> 人工序列(Artificial Sequence)
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Met Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly
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Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly
20 25 30
Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys
35 40 45
Leu Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg
50 55 60
Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly
65 70 75 80
Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Leu Thr Ser
85 90 95
Ile Ser Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 3
<211> 110
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Met Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro
1 5 10 15
Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser
20 25 30
Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu
35 40 45
Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe
50 55 60
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu
65 70 75 80
Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Gly Ser Ser
85 90 95
Arg Gly Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 4
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
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Met Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu
1 5 10 15
Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr
20 25 30
Ser Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly
35 40 45
Gln Pro Pro Lys Leu Leu Met Tyr Trp Ala Ser Thr Arg Glu Ser Gly
50 55 60
Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Ala Glu Phe Thr Leu
65 70 75 80
Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Ile Tyr Tyr Cys Gln
85 90 95
Gln Tyr Tyr Ser Thr Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys
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<212> PRT
<213> 人工序列(Artificial Sequence)
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Met Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
1 5 10 15
Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Arg
20 25 30
Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro
85 90 95
Pro Glu Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu
100 105
<210> 6
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
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Met Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
1 5 10 15
Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser
20 25 30
Tyr Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro
85 90 95
Arg Thr Phe Gly Gln Gly Thr Lys Val Glu
100 105
<210> 7
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Met Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro
1 5 10 15
Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Val Ser Ser
20 25 30
Thr Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu
35 40 45
Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe
50 55 60
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu
65 70 75 80
Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln His Asp Thr Ser
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu
100 105
<210> 8
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Met Glu Leu Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly
1 5 10 15
Gln Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn
20 25 30
Asn Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu
65 70 75 80
Gln Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser
85 90 95
Leu Ser Ala Gly Val Phe Gly Gly Gly Thr Glu Leu
100 105
<210> 9
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Met Gln Val Arg Leu Val Gln Ser Gly Ala Glu Val Lys Lys Ser Gly
1 5 10 15
Glu Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser
20 25 30
Tyr Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp
35 40 45
Met Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser
50 55 60
Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Val
65 70 75 80
Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr
85 90 95
Cys Ala Arg Gln Trp Ser His Tyr Thr Tyr Asp Tyr Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Ile Ser Ser Ala Ser
115 120
<210> 10
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Thr Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Gly Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 11
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Ala Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Gly Ser Asp Tyr Gly Asp Tyr Leu Leu Val Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 12
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Gln Met Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Thr
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Met Ser Ser
20 25 30
Ala Val Gln Trp Val Arg Gln Ala Arg Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Trp Ile Val Ile Gly Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Glu Arg Val Thr Ile Thr Arg Asp Met Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Pro Tyr Cys Ser Ser Ile Ser Cys Asn Asp Gly Phe Asp Ile
100 105 110
Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 13
<211> 131
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asp Val
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Ser Lys Ile Asp Gly Gly Thr Thr Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Thr Ala Gly Ser Tyr Tyr Tyr Asp Thr Val Gly Pro Gly
100 105 110
Leu Pro Glu Gly Lys Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
115 120 125
Val Ser Ser
130
<210> 14
<211> 116
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Met Asn Thr Leu Phe Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Val Leu Pro Met Tyr Gly Asp Tyr Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr
115
<210> 15
<211> 122
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Asn Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Tyr Tyr Glu Ala Arg His Tyr Tyr Tyr Tyr Tyr Ala Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Ala Val Thr
115 120
<210> 16
<211> 124
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Pro Phe Thr Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Thr Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Thr Thr Gly Tyr
65 70 75 80
Met Glu Leu Arg Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Tyr Thr Arg Gly Ala Trp Phe Gly Glu Ser Leu Ile Gly
100 105 110
Gly Phe Asp Asn Trp Gly Gln Gly Thr Leu Val Thr
115 120
<210> 17
<211> 125
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser
20 25 30
Gly Val Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu
35 40 45
Trp Leu Ala Leu Ile Asp Trp Asp Asp Asn Lys Tyr His Thr Thr Ser
50 55 60
Leu Lys Thr Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Ile Pro Gly Phe Leu Arg Tyr Arg Asn Arg Tyr Tyr Tyr
100 105 110
Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr
115 120 125
<210> 18
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Gln Ser Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Ile Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Ser Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Thr Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser
85 90 95
Ser Thr Pro Pro Tyr Val Phe Gly Thr Gly Thr Lys Val Ser Val Leu
100 105 110
Gly Gln
<210> 19
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Leu Gly Ala His Arg Val
20 25 30
Gly Trp Phe Arg Arg Ala Pro Gly Lys Glu Arg Glu Phe Val Ala Ala
35 40 45
Ile Gly Ala Asn Gly Gly Asn Thr Asn Tyr Leu Asp Ser Val Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Ile Tyr Leu Gln
65 70 75 80
Met Asn Ser Leu Lys Pro Gln Asp Thr Ala Val Tyr Tyr Cys Ala Ala
85 90 95
Arg Asp Ile Glu Thr Ala Glu Tyr Thr Tyr Trp Gly Gln Gly Thr Gln
100 105 110
Val Thr Val Ser Ser
115
<210> 20
<211> 28
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 20
Met Ser Ala Leu Glu Glu Gln Leu Lys Thr Phe Leu Asp Lys Phe Met
1 5 10 15
His Glu Leu Glu Asp Leu Leu Tyr Gln Leu Ala Leu
20 25
<210> 21
<211> 76
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 21
Met Glu Leu Glu Glu Gln Val Met His Val Leu Asp Gln Val Ser Glu
1 5 10 15
Leu Ala His Glu Leu Leu His Lys Leu Thr Gly Glu Glu Leu Glu Arg
20 25 30
Ala Ala Tyr Phe Asn Trp Trp Ala Thr Glu Met Met Leu Glu Leu Ile
35 40 45
Lys Ser Asp Asp Glu Arg Glu Ile Arg Glu Ile Glu Glu Glu Ala Arg
50 55 60
Arg Ile Leu Glu His Leu Glu Glu Leu Ala Arg Lys
65 70 75
<210> 22
<211> 56
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 22
Met Asp Lys Glu Trp Ile Leu Gln Lys Ile Tyr Glu Ile Met Arg Leu
1 5 10 15
Leu Asp Glu Leu Gly His Ala Glu Ala Ser Met Arg Val Ser Asp Leu
20 25 30
Ile Tyr Glu Phe Met Lys Lys Gly Asp Glu Arg Leu Leu Glu Glu Ala
35 40 45
Glu Arg Leu Leu Glu Glu Val Glu
50 55
<210> 23
<211> 65
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 23
Met Asn Asp Asp Glu Leu His Met Leu Met Thr Asp Leu Val Tyr Glu
1 5 10 15
Ala Leu His Phe Ala Lys Asp Glu Glu Ile Lys Lys Arg Val Phe Gln
20 25 30
Leu Phe Glu Leu Ala Asp Lys Ala Tyr Lys Asn Asn Asp Arg Gln Lys
35 40 45
Leu Glu Lys Val Val Glu Glu Leu Lys Glu Leu Leu Glu Arg Leu Leu
50 55 60
Ser
65
<210> 24
<211> 37
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 24
Met Asp Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu
1 5 10 15
Ile Asp Arg Leu Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile
20 25 30
Asp Leu Gln Glu Leu
35
Claims (12)
1.融合蛋白,包括新冠病毒蛋白类药物和五肽重复单元;
所述新冠病毒蛋白类药物包括新冠病毒的多肽拮抗剂、新冠病毒的纳米抗体或新冠病毒的单链抗体;
所述五肽重复单元为[(VPGKG)n(VPGVG)]m,其中n为5~10的整数;m为2~16的整数。
2.根据权利要求1所述的融合蛋白,其特征在于,
所述新冠病毒的多肽拮抗剂的氨基酸序列如SEQ ID NO:20~24中任一项所示;
所述新冠病毒的纳米抗体的氨基酸序列如SEQ ID NO:19所示;
所述新冠病毒的单链抗体包括如SEQ ID NO:1~9中任一项所示的轻链可变区、linker和如SEQ ID NO:10~18中任一项所示的重链可变区。
3.根据权利要求1所述的融合蛋白,其特征在于,所述五肽重复单元为[(VPGKG)9(VPGVG)]8。
4.编码权利要求1~3任一项所述的融合蛋白的核酸。
5.重组载体,其包括权利要求4所述的核酸和骨架载体。
6.转化或转染权利要求5所述重组载体的宿主。
7.权利要求1~3任一项所述的融合蛋白的制备方法,其特征在于,包括:培养权利要求6所述的宿主,诱导所述融合蛋白的表达。
8.一种蛋白复合物,其特征在于,由权利要求1~3任一项所述的融合蛋白与PEG制得。
9.根据权利要求8所述的蛋白复合物,其特征在于,所述PEG的平均分子量为5000~10000。
10.权利要求8或9所述的蛋白复合物的制备方法,其特征在于,包括:
将权利要求1~3任一项所述的融合蛋白与PEG混合,搅拌反应后经脱盐层析后,制得所述蛋白复合物。
11.权利要求1~3任一项所述的融合蛋白、权利要求4所述的核酸、权利要求5所述重组载体、权利要求6所述的宿主、权利要求8或9所述的蛋白复合物在制备防治新型冠状病毒肺炎的药物中的应用。
12.一种治疗新型冠状病毒肺炎的药物,其特征在于,包括权利要求1~3任一项所述的融合蛋白、权利要求4所述的核酸、权利要求5所述重组载体、权利要求6所述的宿主或权利要求8或9所述的蛋白复合物。
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CN112521514A (zh) * | 2020-12-21 | 2021-03-19 | 清华大学 | 一种蛋白复合物及其制备方法和应用 |
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