CN116751305A - β属冠状病毒融合重组蛋白及其制备方法和应用 - Google Patents
β属冠状病毒融合重组蛋白及其制备方法和应用 Download PDFInfo
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- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
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- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
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Abstract
本发明公开一种β属冠状病毒融合重组蛋白,包括新冠病毒COVID‑19的S蛋白的RBD区域和COVID19‑SF5片段,所述COVID19‑SF5片段的氨基酸序列为新冠病毒COVID‑19的S蛋白的第880位氨基酸至第1084位氨基酸。本发明通过将恒定保守片段(COVID19‑SF5)与受体结合域(RBD)片段进行融合表达,提供更强效的、针对该类冠状病毒的恒定通sF用疫苗候选重组融合蛋白,从抑制受体识别和通用保护两个维度提供更广泛、更有利的保护措施。
Description
技术领域
本发明属于生物学领域,更具体地,本发明涉及β属冠状病毒融合重组蛋白及其应用。
背景技术
新冠病毒与非典型性肺炎病毒(SARS-CoV)和中东呼吸综合征病毒(MERS-CoV)同属β属-冠状病毒,能够引起极为严重的呼吸系统综合征。虽然目前已有多款疫苗上市,但由于新冠病毒的高突变率,不同疫苗在预防感染方面的效力均出现不同程度的降低,特别是最近出现的Omicron毒株具有强烈的免疫逃逸能力,不仅可躲避大多数治疗性单克隆抗体,且在很大程度上避开了已上市疫苗产生的抗体免疫。最新的研究报道也有表明,Omicron毒株有新的侵入细胞途径。此外,未来仍存在爆发其他新型冠状病毒的风险,因此研发针对此类冠状病毒(包括正流行的新冠病毒、Delta毒株、Omicron毒株及未来可能发生的冠状病毒)的通用性预防性高效疫苗迫在眉睫。
目前在研的新冠病毒疫苗主要包括灭活疫苗、腺病毒载体疫苗、核酸疫苗(mRNA疫苗)、减毒活疫苗等,这些疫苗普遍存在特异免疫原性不足,保护效果在人群间差别较大,存在抗体依赖感染增强作用,安全性有待考量等缺点。此外,面对新冠病毒的快速变异,如目前广泛出现的Delta和Omicron等变体导致疫苗的特异性作用时间和作用效果大大受限。目前新冠确诊已超3亿,鉴于新冠病毒的高传染性、突变性,寻找应对多种冠状病毒及其变体的通用疫苗防治药物迫在眉睫。
S蛋白(Spike)在冠状病毒的结合和入侵中发挥着重要作用。S蛋白位于冠状病毒表面,组成了病毒表面上独特的穗状结构,S蛋白由S1和S2两个亚基组成,其中S1形成了刺突蛋白的球状头,包含S蛋白的大受体结合结构域(N端结构域NTD和受体结合结构域RBD),负责识别宿主细胞受体,而S2形成了刺突蛋白的茎,参与膜融合过程。S2亚基包含三个功能域,融合肽(FP)和肽重复序列(HR1和HR2),在S1尖端的RBD与受体结合后,S2中的FP插入宿主细胞膜而改变构象,刺激HR1和HR2形成六螺旋束(6HB),导致病毒膜与细胞膜融合。
S蛋白具有与人上呼吸道细胞受体结合和膜融合活性,是介导这类病毒识别、感染人细胞的关键蛋白。CN113943375A公开了一类来源于新型冠状病毒S2蛋白HR区域的重组融合蛋白及其应用。该类新型冠状病毒重组融合蛋白是由新型冠状病毒膜蛋白S2蛋白的两个膜融合相关的保守氨基酸序列HR1和HR2通过连接肽连接得到的重组融合蛋白。该重组融合蛋白可在大肠杆菌中诱导表达,表达量高,同时易于纯化。本发明提供的新型冠状病毒重组融合蛋白,可以形成并维持稳定的三聚体结构,模拟新型冠状病毒膜融合中间态的构象,可作为检测新型冠状病毒膜融合过程的检测原料;具有很好的抗新型冠状病毒活性和很好的免疫原性,在预防或治疗新型冠状病毒蛋白药物开发以及新型冠状病毒疫苗和抗新型冠状病毒抗体开发领域具有广阔的应用前景。
CN112409469B公开了一种跨膜表达新型冠状病毒抗原S2的融合蛋白、重组载体、重组树突状细胞及其应用,属于全细胞疫苗技术领域,所述融合蛋白,包括顺次链接的CD4信号肽、新型冠状病毒抗原S2蛋白、Flag标签序列和CD4跨膜结构域;该发明将S2单独进行跨膜的细胞表达,避免了其他S蛋白表位可能导致的ADE风险,本发明提供的融合蛋白构建的细胞疫苗在小鼠体内可以诱发出更高的中和抗体滴度。
然而,更强效的通用性预防性高效疫苗仍迫在眉睫。
发明内容
我们前期已通过该属S蛋白同源性结构与其生物学功能分析,对S蛋白进行分段重组表达,制备了综合血清IgG抗体库,进而筛选出与多种冠状病毒S蛋白能够交叉反应的抗体及对应的恒定保守区域蛋白片段,该片段为COVID19-SF5,序列为新冠病毒COVID-19的S蛋白的第880位氨基酸至第1084位氨基酸,具体地,该片段的氨基酸序列为(SEQ ID NO.SEQID NO.13):GTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAP AICHD。
本发明将该恒定保守片段(COVID19-SF5)与受体结合域(RBD)片段进行融合表达,得到β属冠状病毒融合重组蛋白,其氨基酸序列如SEQ ID NO.1,从而提供更强效的、针对该类冠状病毒的恒定通用疫苗候选重组融合蛋白,从抑制受体识别和通用保护两个维度提供更广泛、更有利的保护措施。
其中,所述新冠病毒COVID-19的S蛋白的RBD区域为COVID19-SF2片段(SEQ IDNO.10),其氨基酸序列为新冠病毒COVID-19的S蛋白的第305位氨基酸至第525位氨基酸。本发明的RBD区域主要是根据参考文献Wrapp D,Wang N,Corbett KS,Goldsmith JA,HsiehC-L,Abiona O,et al.Cryo-EM structure of the 2019-nCoV spike in the prefusionconformation.Science.2020;367(6483):1260-3中公开的RBD是第335位-第522位,本申请的COVID19-SF2包含了该RBD区域,同时与前后区域有一定交叉重叠的部分。
所述融合重组蛋白的氨基酸序列如SEQ ID NO.1所示。具体地,COVID19-SF2+5的氨基酸序列如下:
SFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGGGGSGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHD。
本发明进一步提出了编码上述融合重组蛋白的基因。优选地,所述基因的核苷酸序列为SEQ ID NO.2。
本发明还提出了一种重组载体,其包含编码上述融合重组蛋白的基因和载体。其中,所示载体可以为pET系列载体,哺乳动物表达载体pcDNA3系列等。在具体的实施方式中,本申请采用表达载体pQE-3。
进一步地,本发明还提出了一种重组菌,其包含上述重组载体。宿主菌可以选用包含大肠杆菌BL21、M15,昆虫细胞sf9,哺乳动物细胞CHO,293等。
本发明还提出了上述融合重组蛋白、编码融合重组蛋白的基因、重组载体、重组菌在制备β属冠状病毒通用疫苗、通用抗体上的应用。
在一个具体的实施方式中,通过如下方法实现SARS-CoV-2的COVID19-SF2蛋白片段和COVID19-SF5蛋白片段融合蛋白的表达菌株构建及蛋白表达纯化:
1)以SARS-CoV-2全长DNA作为模板,设计针对COVID19-SF2蛋白片段和COVID19-SF5蛋白片段的不同的PCR引物,在COVID19-SF2蛋白片段的5’端引入BamH I酶切位点,3’端引入柔性连接肽的反向互补序列,在COVID19-SF5蛋白片段的5’端引入柔性连接肽序列,3’端引入HindⅢ酶切位点,C端引入6×His编码基因。首先分别进行COVID19-SF2蛋白片段和COVID19-SF5蛋白片段PCR,完成扩增后,2%琼脂糖凝胶电泳验证PCR产物。用PCR产物纯化试剂盒对PCR产物进行纯化。
2)将第一步中分别扩增得到的COVID19-SF2蛋白片段和COVID19-SF5蛋白片段的PCR产物进行重叠延伸PCR,通过连接得到融合蛋白表达基因,完成扩增后,1%琼脂糖凝胶电泳验证PCR产物。用PCR产物纯化试剂盒对PCR产物进行纯化。
3)将目的基因通过序列5’-端和3’-端的BamH I和HindⅢ两个酶切位点与表达载体pQE-3连接。1%琼脂糖电泳验证酶切产物。载体和目的基因分别使用胶回收纯化试剂盒对酶切产物进行回收纯化。纯化后,用One drop分光光度仪检测核酸浓度。
4)按目的基因片段与pQE-3质粒载体摩尔比4:1计算酶连体系中目的基因片段和质粒的量。酶连条件:4℃,过夜。得到的酶连产物即含有融合蛋白基因的表达载体。
5)转化:将含有融合蛋白基因的表达载体用感受态法转化入大肠杆菌M15菌株中。
6)挑选阳性克隆:挑选在选择性平板上生长的菌株并进行菌落PCR,对PCR呈阳性的菌株进行蛋白表达诱导。
7)诱导表达:取菌落PCR呈阳性的克隆进行扩大培养,具体方法为:挑取平板上的阳性克隆过夜培养,取过夜菌,加新鲜培养基扩大培养,培养4h左右,添加终浓度为100mM的IPTG,诱导表达4h。离心收获菌体沉淀,SDS-PAGE验证蛋白表达情况。
8)收获包涵体并进行纯化复性:收获表达菌体并裂解收获重组融合蛋白包涵体,溶解于6M盐酸胍溶液(0.05mol/L tris,5mmol/L EDTA,6mol/L盐酸胍,1%β-巯基乙醇,pH8.0)中,1g包涵体溶解于100ml 6M盐酸胍中。
Ni-NTA亲和柱纯化:按照Ni-NTA亲和柱制造商建议的步骤进行装柱,随后用8M的尿素(5个柱体积,溶于磷酸盐缓冲液,PH8.0)平衡亲和柱,以5ml/min的速度上样溶解在盐酸胍中的包涵体溶液,上样结束后以PH6.0的磷酸钠(5个柱体积)洗脱杂蛋白,随后以PH4.5的醋酸钠收集目的蛋白。
采用尿素梯度溶液透析的复性步骤:以3M尿素(包含于醋酸钠缓冲液中,15PH4.5)稀释上述经纯化的蛋白液至0.3mg/ml,在4℃下依次用不同浓度的尿素透析液各透析1次,每次24h,其中透析袋内外液的比例为1:5,内液为3.5M尿素-醋酸钠缓冲液,外液依次为3M、2.5M、1.5M、1M、0.5M、0M和0M尿素的透析缓冲液。
9)收获重组融合蛋白:透析后将目的融合蛋白液利用低温离心机15000rpm离心20min,通过Braford法测定蛋白浓度,并经0.22μm滤膜过滤灭菌,添加甘露醇后,存放于-80℃冰箱。
通过以上方法,获得高效通用性冠状病毒融合蛋白,命名为“COVID19-SF2+5”,其抗体与每个S蛋白片段均存在一定的交叉反应性,特别是与COVID19-SF2和COVID19-SF5的结合能力较高。提示该融合蛋白既保留了RBD区域,能够诱导产生特异性阻断病毒与受体结合的IgG抗体,又同时包括了恒定保守片段COVID19-SF5,能够诱导产生更广泛的,与多个S蛋白片段发生交叉反应性的广谱IgG抗体。
进一步,利用小鼠免疫获得“COVID19-SF2+5”融合蛋白的抗血清,纯化获得血清综合抗体IgG,制备新冠病毒SARS-CoV-2S蛋白COVID19-SF2+COVID19-SF5融合蛋白血清综合抗体IgG。
本发明进一步提出了工业化发酵制备重组融合蛋白的方法,包括如下步骤:
(1)以重组菌作为种子菌,种子菌经过夜摇菌放大作为种子液;
(2)将种子液在2×YT培养基中进行发酵培养,发酵后菌体通过工业化自动连续离心机收集,收集的菌体先用提取液A制成悬液,再用水性裂解酶裂解,然后用提取液B处理,离心后收取沉淀包涵体,用缓冲液稀释后,离心,沉淀物为不溶性包涵体;
(3)进一步将包涵体溶于缓冲液后,离心去上清超滤浓缩,浓缩样品经Ni-NTA亲和柱,在AKTA蛋白纯化系统上进行纯化,收集样品;
(4)收集样品在4℃层析柜中透析,透析后的样品经离心取上清,上清液经超滤浓缩器浓缩,后再经AKTA蛋白纯化系统Sephadex G-75层析纯化;根据AKTA蛋白纯化系统的蛋白峰收集样品,即为精纯后的融合蛋白。
在一个具体的实施例中,包括如下步骤:
1)发酵接种前进行清洁,注意无菌操作,在同一发酵时间内不得进行其他菌种发酵;
2)发酵罐及管道灭菌,每次发酵前需进行空罐灭菌121℃30min,配制培养基装入罐内再次灭菌121℃30min,待冷却至所需温度37℃时接种种子液(之前冻存的优势表达菌株,种子菌经过夜摇菌放大);40L发酵罐加种子液500mL,培养基35000mL(过夜菌作为种子液,培养基为2×YT培养基),其中,2×YT培养基:1L培养液中含胰蛋白胨16g,酵母提取物10g,氯化钠5g,搅拌均匀后高温高压灭菌。
3)发酵条件,如温度、pH、氧流量及发酵时间等参数均由发酵罐配套电脑操作系统控制。设定温度37℃,pH7.0,发酵时间约7小时。(溶氧值或溶氧浓度:DO值60%,温度37℃,pH7.0.在细菌浓度量达峰值时加入诱导剂IPTG,总培养时间为7小时。)
4)发酵后菌体通过工业化自动连续离心机收集,离心速度10000g,温度4℃,离心1小时。
5)收获的菌体每40g加入提取液A(50mM Tris,pH8.0,含1.5mM EDTA)1000mL制成悬液,再用水性裂解酶(Lysozyme)250mg裂解。
6)用提取液B(1.5M NaCl,100mM CaCl2,100mM MgCl2,0.002%DNase I)处理。每1000mL上述裂解液加100mL提取液B。
7)经4℃,10000g离心10min后,收取沉淀包涵体,均匀地悬浮于50mM的磷酸缓冲液(含0.15M的氯化钠和4M尿素,pH7.0)。1g沉淀加10mL缓冲液,10000g 4℃离心10min,沉淀物为不溶性包涵体,可收集贮存于-80℃,保存半年。
蛋白的复性与精纯化:
1)每10g粗纯化的包涵体溶于2000mL缓冲液中(0.1M Tris-HCl,pH7.5含6M盐酸胍,20mM DTT,20mM EDTA),20℃搅拌1h。
2)10000g 4℃离心30min后取上清超滤浓缩。每2000mL浓缩至约200mL。
3)浓缩样品经Ni-NTA亲和柱,在AKTA蛋白纯化系统上进行纯化。具体操作步骤与前述相同。
4)收集的样品按照前述方法在4℃层析柜中透析。
5)透析后的样品经10000g,4℃离心30min,取上清。
6)上清液经超滤浓缩器浓缩,每2000mL浓缩到300mL。
7)样品再经AKTA蛋白纯化系统Sephadex G-75层析纯化。柱长1.2米,直径4cm,流速1mL/min。
8)根据AKTA蛋白纯化系统的蛋白峰收集样品,即为精纯后的融合蛋白。
蛋白的除菌和去内毒素
1)纯化的蛋白通过Polymyxin(Bio-rad)层析柱去除内毒素。
2)去内毒素的样品经0.22μm的无菌滤器过滤除菌,分装保存于4℃。
有益效果:不同于以往的研究手段,本发明结合本实验室前期研究,从β属冠状病毒S蛋白的结构和功能分析作为切入点,进行了多种冠状病毒蛋白的氨基酸序列区域化、线性同源性匹配分析,通过S蛋白同源性结构进行分段表达,建立覆盖S蛋白全区域的重组蛋白片段库,并通过免疫小鼠获得的血清抗体库与多种S蛋白片段的交叉反应等研究找到了与SARS-CoV S蛋白各片段及SARS-CoV-2 S蛋白各片段有通用性交叉反应的SARS-CoV-2的S蛋白片段COVID19-SF5。本发明将有通用交叉反应性的COVID19-SF5蛋白片段和包含病毒受体结合域(RBD)的COVID19-SF2蛋白片段通过柔性连接肽Gly4Ser进行连接,形成了具有多功能效应的融合蛋白,并通过将该融合蛋白免疫小鼠,获得血清IgG抗体。经测试,该融合蛋白与细胞结合的能力较单独COVID19-SF2或COVID19-SF5蛋白片段显著提高,其血清IgG抗体能与多种S蛋白片段的发生交叉反应,并能显著抑制假病毒感染细胞。综上,通用融合蛋白疫苗优势明显:
(1)利用基因重组技术,本发明的产品是病毒S蛋白的两个靶向特异片段连接后的融合蛋白,不涉及基因、其它病毒载体、失活病毒进入人体,产品质量控制和质量保证体系明确,保证产品的安全性;
(2)从研究S蛋白的结构和功能切入,将β冠状病毒属的恒定保守、通用蛋白区域和受体结合域连接,能强烈激发人体免疫系统的应答,从而产生既可以高效预防病毒感染的IgG中和抗体又可以识别β冠状病毒属通用表位的特异性抗体;
(3)任何病毒的自然进化、变异,都会帮助病毒更易侵染寄主,并和寄主长期共生,而其各种功能都是在病毒自身蛋白或通过寄主的蛋白调控表现出来,新冠病毒S蛋白的融合蛋白功能很多方面仍待研究、明确,本项目的融合蛋白片段在小鼠体内产生的有效抗体,具有在功能上的特异性。
附图说明
图1为双酶切验证质粒构建示意图;
图2为SDS-PAGE鉴定重组融合蛋白的表达;
图3为三种蛋白片段与Vero-E6细胞的结合能力。
具体实施方式
下面结合具体实施例对本发明做进一步详细说明,实施例将有助于理解本发明,但是本发明的保护范围不限于下述的实施例。
实施例1:SARS-CoV-2的COVID19-SF2蛋白片段与COVID19-SF5蛋白片段融合蛋白“COVID19SF-2+5”的表达菌株构建及蛋白表达纯化。
1)以SARS-CoV-2全长DNA作为模板,设计针对COVID19-SF2蛋白片段和COVID19-SF5蛋白片段的不同的PCR引物,在COVID19-SF2蛋白片段的5’端引入BamH I酶切位点,3’端引入柔性连接肽的反向互补序列,在COVID19-SF5蛋白片段的5’端引入柔性连接肽序列,柔性连接肽为Gly4Ser,3’端引入HindⅢ酶切位点,C端引入6×His编码基因。首先分别进行COVID19-SF2蛋白片段和COVID19-SF5蛋白片段的PCR,其中PCR体系和扩增条件如下:
表1-1 PCR引物序列
表1-2 PCR体系
扩增条件为:94℃,30s;56℃,1min;72℃,1min30s;35个循环。
完成扩增后,2%琼脂糖凝胶电泳验证PCR产物。用PCR产物纯化试剂盒对PCR产物进行纯化。其中,COVID19-SF2基因序列如SEQ ID NO.7所示,COVID19-SF5基因序列如SEQID NO.8所示。
2)将第一步中分别扩增得到的COVID19-SF2蛋白片段和COVID19-SF5蛋白片段的PCR产物进行重叠延伸PCR,通过连接得到融合蛋白表达基因,其中PCR体系和扩增条件如下:
表2 PCR体系
扩增条件为:94℃,30s;56℃,1min;72℃,2min40s;30个循环。
完成扩增后,1%琼脂糖凝胶电泳验证PCR产物。用PCR产物纯化试剂盒对PCR产物进行纯化。
3)酶切:将目的基因(SEQ ID NO.2)通过序列5’端和3’端的BamH I和HindⅢ两个酶切位点与表达载体pQE-3连接。酶切体系如下:
表3载体
表4目的基因
酶切条件为:37℃水浴中酶切0.5小时。1%agarose gel验证酶切产物。载体和目的基因分别使用胶回收纯化试剂盒对酶切产物进行回收纯化。纯化后,用One drop检测核酸浓度。
4)酶连
按目的基因片段与pQE-3质粒载体摩尔比4:1计算酶连体系中目的基因片段和质粒的量。酶连体系如下:
表5
酶连条件:4℃,过夜。
得到的酶连产物即含有融合蛋白基因的表达载体。
5)转化
将含有融合蛋白基因的表达载体用感受态法转化入大肠杆菌M15菌株中。
6)挑选阳性克隆
挑选在选择性平板上生长的菌株并进行菌落PCR,对PCR呈阳性的菌株进行蛋白表达诱导。
7)诱导表达
取菌落PCR呈阳性的克隆进行扩大培养,具体方法为:挑取平板上的阳性克隆过夜培养,取过夜菌,加新鲜培养基扩大培养,培养4h左右,添加终浓度为100mM的IPTG,诱导表达4h。离心收获菌体沉淀,SDS-PAGE验证蛋白表达情况。
8)收获包涵体并进行纯化复性
收获表达菌体并裂解收获重组融合蛋白包涵体,溶解于6M盐酸胍溶液(0.05mol/Ltris,5mmol/L EDTA,6mol/L盐酸胍,1%β-巯基乙醇,pH 8.0)中,1g包涵体溶解于100ml 6M盐酸胍中。
Ni-NTA亲和柱纯化:按照Ni-NTA亲和柱制造商建议的步骤进行装柱,随后用8M的尿素(5个柱体积,溶于磷酸盐缓冲液,PH8.0)平衡亲和柱,以5ml/min的速度上样溶解在盐酸胍中的包涵体溶液,上样结束后以PH6.0的磷酸钠(5个柱体积)洗脱杂蛋白,随后以PH4.5的醋酸钠收集目的蛋白。
采用尿素梯度溶液透析的复性步骤:以3M尿素(包含于醋酸钠缓冲液中,PH4.5)稀释上述经纯化的蛋白液至0.3mg/ml,在4℃下依次用不同浓度的尿素透析液各透析1次,每次24h,其中透析袋内外液的比例为1:5,内液为3.5M尿素-醋酸钠缓冲液,外液依次为3M,2.5M,1.5M,1M,0.5M,0M和0M尿素的透析缓冲液。
9)收获融合蛋白
透析后将目的蛋白液利用低温离心机15000rpm离心20min,通过Braford法测定蛋白浓度,并经0.22μm滤膜过滤灭菌,添加甘露醇后,存放于-80℃冰箱。
通过双酶切验证质粒构建见图1。使用BamHⅠ限制性内切酶和距离HindⅢ酶切位点673bp的Ncol限制性内切酶进行双酶切,酶切结果见下图,其中全长质粒4689bp,在琼脂糖凝胶电泳中显示有双酶切后的两条带:目的基因加上HindⅢ酶与Ncol酶之间的673bp为1966bp,剩余载体2723bp,与理论相符。
通过SDS-PAGE验证蛋白表达见下图2。图中可见融合蛋白的条带位置与理论条带位置48.2kD一致,且经Ni柱纯化后蛋白条带单一,表达和复性效果良好。
实施例2:β属冠状病毒通用融合蛋白的鉴定。
通过ELISA方法检测融合蛋白抗体的特异性和通用交叉反应性。
1)测定抗体效价:使用进行免疫的重组融合蛋白作为抗原,将纯化后的血清IgG抗体进行倍比稀释并设置复孔,之后进行ELISA测定,于450nm处检测OD值,分析结果。
通过ELISA检测融合蛋白首次免疫6个月后的综合抗体IgG(50μg/mL)滴度(见表2),小鼠对融合蛋白片段产生良好免疫效果,首次免疫6个月后的抗体滴度达仍可达1:1600。
表6.ELISA检测融合蛋白血清综合抗体IgG滴度
重组蛋白 | 抗体滴度 |
COVID-SF2+5融合蛋白 | 1:1600 |
2)测定通用交叉反应性:使用12个重组蛋白片段作为抗原,将融合蛋白抗体与其进行反应,每组设置3个复孔,进行ELISA测定,于450nm处检测OD值,分析结果。其中,12个重组蛋白片段的起始-终止氨基酸位置以及对应的氨基酸序列如表7-1所示:
表7-1 12个包含重叠结构域的S蛋白片段
通过ELISA检测融合蛋白综合抗体IgG与各S蛋白片段的结合能力,发现其抗体与每个S蛋白片段均存在一定的交叉反应性,且结合能力较高,甚至在首次免疫6个月后,虽然反应效力减弱,但其抗体仍与大部分蛋白片段具有明显的交叉反应,提示该融合蛋白免疫小鼠后不仅可产生高特异性的中和抗体,而且包含多种β-属冠状病毒恒定保守、特异性的蛋白片段,ELISA检测结果见表7-2和7-3。
表7-2 COVID19-SF2+5融合蛋白抗体与蛋白片段的交叉反应检测
表7-3 COVID19-SF2+5融合蛋白抗体与蛋白片段的交叉反应检测
实施例3:通用特异性冠状病毒融合蛋白疫苗的小鼠安全性和抗体应答检测。
将0.20mg/ml的COVID19-SF2+5融合蛋白给20只BALB/c小鼠进行免疫,观察小鼠在注射期间的安全性,于28天及45天检测IgG应答水平。
观察注射COVID19-SF2+5融合蛋白后45天,小鼠的安全性和IgG应答检测。
接种COVID19-SF2+5融合蛋白的20只小鼠健康状况良好,且均能产生有效的IgG抗体。安全性检测及IgG应答检测结果如下表8:
表8.COVID19-SF2+5在小鼠体内安全性及IgG应答检测
实施例4:通用特异性冠状病毒融合蛋白COVID19-SF2+5与细胞的结合能力检测。
将非洲绿猴肾细胞(Vero-E6)细胞处理计数后,用100μL细胞洗液(含1%BSA的PBS)重悬1.5×105个细胞;加入终浓度2μg/mL的通用特异性冠状病毒融合蛋白,同时对照管中加入相同摩尔量的COVID19-SF2和COVID19-SF5做对照研究,充分混匀,至37℃孵育1h,孵育期间每隔10min晃动一下反应管,使细胞和蛋白充分反应;加入适量细胞洗液,5000rpm离心2min,弃上清,洗涤2次;加入适量的荧光标记二抗(anti-His Tag PE,Abcam,以1:50稀释),充分混匀,至4℃避光孵育1h,孵育期间每隔10min晃动一下反应管;加入适量细胞洗液,5000rpm离心2min,弃上清,洗涤2次;使用200μL细胞洗液重悬细胞,以流式细胞仪检测细胞表面的荧光信号。
通用特异性冠状病毒蛋白融合蛋白COVID19-SF2+5与Vero-E6细胞结合后存在很强的荧光偏移,如图3所示。融合蛋白COVID19-SF2+5与Vero-E6细胞的结合能力高于单纯的COVID19-SF2或者COVID19-SF5片段。具体的细胞与蛋白结合的比例见表9。
表9.Vero-E6细胞与COVID19-SF2蛋白、COVID19-SF5蛋白或COVID19-SF2+COVID19-SF5融合蛋白的结合
蛋白片段 | COVID19--SF2 | COVID19-SF5 | COVID19-SF2+5 |
结合能力(%) | 11.7 | 67.5 | 77.5 |
实施例5:β属冠状病毒通用融合蛋白对应的综合抗体IgG对假病毒抑制能力检测。
通过多功能酶标仪检测SARS-CoV-2假病毒感染细胞后细胞中荧光素酶表达情况,从而判断通用融合蛋白对应的综合抗体对假病毒抑制能力。
以hACE2-293T细胞为感染细胞,前一晚将hACE2-293T细胞以2×104/孔接种在96孔板中。18小时后将10μg/mL的融合蛋白抗血清IgG与650TCID50/孔的假病毒混合。然后将混合物加入细胞中并孵育48小时。根据制造商的方案,利用荧光素酶检测试剂盒通过多功能酶标仪测量荧光素酶的表达,以获得血清抗体的抗病毒能力。在每个板中设置仅含有细胞的细胞对照和只含有病毒和细胞的病毒对照。每组设三个平行实验。将仅含有细胞的细胞对照抑制率视为100%,将具有病毒和细胞的病毒对照的抑制率视为0%,计算血清抗体的抑制率。
通过假病毒中和实验检测融合蛋白抗血清对假病毒感染细胞的抑制率(见表10),为三次平行实验的结果值,表中可见,融合蛋白COVID19-SF2+5免疫小鼠产生的血清IgG抗体能够在一定程度上抑制假病毒对细胞的侵染,其抑制率在40%左右。
表10 COVID19-SF2+5融合蛋白抗体对SARS-CoV-2假病毒的抑制作用
实施例6工业化发酵制备重组融合蛋白。
1)发酵接种前进行清洁,注意无菌操作,在同一发酵时间内不得进行其他菌种发酵;
2)发酵罐及管道灭菌,每次发酵前需进行空罐灭菌121℃30min,配制培养基装入罐内再次灭菌121℃30min,待冷却至所需温度37℃时接种种子液(之前冻存的优势表达菌株,种子菌经过夜摇菌放大);40L发酵罐加种子液500mL,培养基35000mL(过夜菌作为种子液,培养基为2×YT培养基),其中,2×YT培养基:1L培养液中含胰蛋白胨16g,酵母提取物10g,氯化钠5g,搅拌均匀后高温高压灭菌。
3)发酵条件,如温度、pH、氧流量及发酵时间等参数均由发酵罐配套电脑操作系统控制。设定温度37℃,pH7.0,发酵时间约7小时。(件溶氧值或溶氧浓度:DO值60%,温度37℃,pH7.0.在细菌浓度量达峰值时加入诱导剂IPTG,总培养时间为7小时。)
4)发酵后菌体通过工业化自动连续离心机收集,离心速度10000g,温度4℃,离心1小时。
5)收获的菌体每40g加入提取液A(50mM Tris,pH8.0,含1.5mM EDTA)1000mL制成悬液,再用水性裂解酶(Lysozyme)250mg裂解。
6)用提取液B(1.5M NaCl,100mM CaCl2,100mM MgCl2,0.002%DNase I)处理。每1000mL上述裂解液加100mL提取液B。
7)经4℃,10000g离心10min后,收取沉淀包涵体,均匀地悬浮于50mM的磷酸缓冲液(含0.15M的氯化钠和4M尿素,pH7.0)。1g沉淀加10mL缓冲液,10000g 4℃离心10min,沉淀物为不溶性包涵体,可收集贮存于-80℃,保存半年。
蛋白的复性与精纯化:
1)每10g粗纯化的包涵体溶于2000mL缓冲液中(0.1M Tris-HCl,pH7.5含6M盐酸胍,20mM DTT,20mM EDTA),20℃搅拌1h。
2)10000g 4℃离心30min后取上清超滤浓缩。每2000mL浓缩至约200mL。
3)浓缩样品经Ni-NTA亲和柱,在AKTA蛋白纯化系统上进行纯化。具体操作步骤与前述相同。
4)收集的样品按照前述方法在4℃层析柜中透析。
5)透析后的样品经10000g,4℃离心30min,取上清。
6)上清液经超滤浓缩器浓缩,每2000mL浓缩到300mL。
7)样品再经AKTA蛋白纯化系统Sephadex G-75层析纯化。柱长1.2米,直径4cm,流速1mL/min。
8)根据AKTA蛋白纯化系统的蛋白峰收集样品,即为精纯后的融合蛋白。
蛋白的除菌和去内毒素
1)纯化的蛋白通过Polymyxin(Bio-rad)层析柱去除内毒素。
2)去内毒素的样品经0.22μm的无菌滤器过滤除菌,分装保存于4℃。
本发明提出了一种β属冠状病毒融合蛋白及其制备方法的思路,具体实现本发明技术方案的方法和途径很多,以上所述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。本实施例中未明确的各组成部分均可用现有技术加以实现。
序列表
<110> 苏州方舟生物科技有限公司
<120> β属冠状病毒融合重组蛋白及其制备方法和应用
<160> 20
<170> SIPOSequenceListing 1.0
<210> 1
<211> 431
<212> PRT
<213> COVID19-SF2+5氨基酸序列(Artificial Sequence)
<400> 1
Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
1 5 10 15
Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
20 25 30
Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
35 40 45
Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
50 55 60
Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
65 70 75 80
Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
85 90 95
Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
100 105 110
Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
115 120 125
Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
130 135 140
Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
145 150 155 160
Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
165 170 175
Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
180 185 190
Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
195 200 205
Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Gly Gly
210 215 220
Gly Ser Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala
225 230 235 240
Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile
245 250 255
Gly Val Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn
260 265 270
Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr
275 280 285
Ala Ser Ala Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln
290 295 300
Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile
305 310 315 320
Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala
325 330 335
Glu Val Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln
340 345 350
Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser
355 360 365
Ala Asn Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser
370 375 380
Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro
385 390 395 400
Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro
405 410 415
Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp
420 425 430
<210> 2
<211> 1293
<212> DNA
<213> COVID19-SF2+5核苷酸序列(Artificial Sequence)
<400> 2
tccttcactg tagaaaaagg aatctatcaa acttctaact ttagagtcca accaacagaa 60
tctattgtta gatttcctaa tattacaaac ttgtgccctt ttggtgaagt ttttaacgcc 120
accagatttg catctgttta tgcttggaac aggaagagaa tcagcaactg tgttgctgat 180
tattctgtcc tatataattc cgcatcattt tccactttta agtgttatgg agtgtctcct 240
actaaattaa atgatctctg ctttactaat gtctatgcag attcatttgt aattagaggt 300
gatgaagtca gacaaatcgc tccagggcaa actggaaaga ttgctgatta taattataaa 360
ttaccagatg attttacagg ctgcgttata gcttggaatt ctaacaatct tgattctaag 420
gttggtggta attataatta cctgtataga ttgtttagga agtctaatct caaacctttt 480
gagagagata tttcaactga aatctatcag gccggtagca caccttgtaa tggtgttgaa 540
ggttttaatt gttactttcc tttacaatca tatggtttcc aacccactaa tggtgttggt 600
taccaaccat acagagtagt agtactttct tttgaacttc tacatgcacc agcaactgtt 660
tgtggcggag gcggaagcgg tacaatcact tctggttgga cctttggtgc aggtgctgca 720
ttacaaatac catttgctat gcaaatggct tataggttta atggtattgg agttacacag 780
aatgttctct atgagaacca aaaattgatt gccaaccaat ttaatagtgc tattggcaaa 840
attcaagact cactttcttc cacagcaagt gcacttggaa aacttcaaga tgtggtcaac 900
caaaatgcac aagctttaaa cacgcttgtt aaacaactta gctccaattt tggtgcaatt 960
tcaagtgttt taaatgatat cctttcacgt cttgacaaag ttgaggctga agtgcaaatt 1020
gataggttga tcacaggcag acttcaaagt ttgcagacat atgtgactca acaattaatt 1080
agagctgcag aaatcagagc ttctgctaat cttgctgcta ctaaaatgtc agagtgtgta 1140
cttggacaat caaaaagagt tgatttttgt ggaaagggct atcatcttat gtccttccct 1200
cagtcagcac ctcatggtgt agtcttcttg catgtgactt atgtccctgc acaagaaaag 1260
aacttcacaa ctgctcctgc catttgtcat gat 1293
<210> 3
<211> 24
<212> DNA
<213> COVID19-SF2上游引物(Artificial Sequence)
<400> 3
cttggatcct ccttcactgt agaa 24
<210> 4
<211> 27
<212> DNA
<213> COVID19-SF2下游引物(Artificial Sequence)
<400> 4
gcttccgcct ccgccacaaa cagttgc 27
<210> 5
<211> 27
<212> DNA
<213> COVID19-SF5上游引物(Artificial Sequence)
<400> 5
ggcggaggcg gaagcggtac aatcact 27
<210> 6
<211> 43
<212> DNA
<213> COVID19-SF5下游引物(Artificial Sequence)
<400> 6
gtctcaagct tatggtgatg gtgatgatga tcatgacaaa tgg 43
<210> 7
<211> 663
<212> DNA
<213> COVID19-SF2 的基因序列(Artificial Sequence)
<400> 7
tccttcactg tagaaaaagg aatctatcaa acttctaact ttagagtcca accaacagaa 60
tctattgtta gatttcctaa tattacaaac ttgtgccctt ttggtgaagt ttttaacgcc 120
accagatttg catctgttta tgcttggaac aggaagagaa tcagcaactg tgttgctgat 180
tattctgtcc tatataattc cgcatcattt tccactttta agtgttatgg agtgtctcct 240
actaaattaa atgatctctg ctttactaat gtctatgcag attcatttgt aattagaggt 300
gatgaagtca gacaaatcgc tccagggcaa actggaaaga ttgctgatta taattataaa 360
ttaccagatg attttacagg ctgcgttata gcttggaatt ctaacaatct tgattctaag 420
gttggtggta attataatta cctgtataga ttgtttagga agtctaatct caaacctttt 480
gagagagata tttcaactga aatctatcag gccggtagca caccttgtaa tggtgttgaa 540
ggttttaatt gttactttcc tttacaatca tatggtttcc aacccactaa tggtgttggt 600
taccaaccat acagagtagt agtactttct tttgaacttc tacatgcacc agcaactgtt 660
tgt 663
<210> 8
<211> 615
<212> DNA
<213> COVID19-SF5的基因序列(Artificial Sequence)
<400> 8
ggtacaatca cttctggttg gacctttggt gcaggtgctg cattacaaat accatttgct 60
atgcaaatgg cttataggtt taatggtatt ggagttacac agaatgttct ctatgagaac 120
caaaaattga ttgccaacca atttaatagt gctattggca aaattcaaga ctcactttct 180
tccacagcaa gtgcacttgg aaaacttcaa gatgtggtca accaaaatgc acaagcttta 240
aacacgcttg ttaaacaact tagctccaat tttggtgcaa tttcaagtgt tttaaatgat 300
atcctttcac gtcttgacaa agttgaggct gaagtgcaaa ttgataggtt gatcacaggc 360
agacttcaaa gtttgcagac atatgtgact caacaattaa ttagagctgc agaaatcaga 420
gcttctgcta atcttgctgc tactaaaatg tcagagtgtg tacttggaca atcaaaaaga 480
gttgattttt gtggaaaggg ctatcatctt atgtccttcc ctcagtcagc acctcatggt 540
gtagtcttct tgcatgtgac ttatgtccct gcacaagaaa agaacttcac aactgctcct 600
gccatttgtc atgat 615
<210> 9
<211> 292
<212> PRT
<213> COVID19-SF1的氨基酸序列(Artificial Sequence)
<400> 9
Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn
1 5 10 15
Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser
20 25 30
Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val
35 40 45
Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg
50 55 60
Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser
65 70 75 80
Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu
85 90 95
Asp Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val
100 105 110
Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly
115 120 125
Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg
130 135 140
Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro
145 150 155 160
Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg
165 170 175
Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys
180 185 190
His Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala
195 200 205
Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe
210 215 220
Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser
225 230 235 240
Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu
245 250 255
Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr
260 265 270
Asp Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr
275 280 285
Leu Lys Ser Phe
290
<210> 10
<211> 221
<212> PRT
<213> CCOVID19-SF2的氨基酸序列(Artificial Sequence)
<400> 10
Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val
1 5 10 15
Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys
20 25 30
Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala
35 40 45
Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu
50 55 60
Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
65 70 75 80
Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe
85 90 95
Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly
100 105 110
Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys
115 120 125
Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn
130 135 140
Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe
145 150 155 160
Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys
165 170 175
Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
180 185 190
Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val
195 200 205
Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys
210 215 220
<210> 11
<211> 171
<212> PRT
<213> CCOVID19-SF3的氨基酸序列(Artificial Sequence)
<400> 11
Ala Pro Ala Thr Val Cys Gly Pro Lys Lys Ser Thr Asn Leu Val Lys
1 5 10 15
Asn Lys Cys Val Asn Phe Asn Phe Asn Gly Leu Thr Gly Thr Gly Val
20 25 30
Leu Thr Glu Ser Asn Lys Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg
35 40 45
Asp Ile Ala Asp Thr Thr Asp Ala Val Arg Asp Pro Gln Thr Leu Glu
50 55 60
Ile Leu Asp Ile Thr Pro Cys Ser Phe Gly Gly Val Ser Val Ile Thr
65 70 75 80
Pro Gly Thr Asn Thr Ser Asn Gln Val Ala Val Leu Tyr Gln Asp Val
85 90 95
Asn Cys Thr Glu Val Pro Val Ala Ile His Ala Asp Gln Leu Thr Pro
100 105 110
Thr Trp Arg Val Tyr Ser Thr Gly Ser Asn Val Phe Gln Thr Arg Ala
115 120 125
Gly Cys Leu Ile Gly Ala Glu His Val Asn Asn Ser Tyr Glu Cys Asp
130 135 140
Ile Pro Ile Gly Ala Gly Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn
145 150 155 160
Ser Pro Arg Arg Ala Arg Ser Val Ala Ser Gln
165 170
<210> 12
<211> 199
<212> PRT
<213> CCOVID19-SF4的氨基酸序列(Artificial Sequence)
<400> 12
Ala Arg Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu
1 5 10 15
Gly Ala Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro
20 25 30
Thr Asn Phe Thr Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met
35 40 45
Thr Lys Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr
50 55 60
Glu Cys Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu
65 70 75 80
Asn Arg Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln
85 90 95
Glu Val Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys
100 105 110
Asp Phe Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys
115 120 125
Pro Ser Lys Arg Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr
130 135 140
Leu Ala Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp
145 150 155 160
Ile Ala Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr
165 170 175
Val Leu Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser
180 185 190
Ala Leu Leu Ala Gly Thr Ile
195
<210> 13
<211> 205
<212> PRT
<213> CCOVID19-SF5的氨基酸序列(Artificial Sequence)
<400> 13
Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln
1 5 10 15
Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val
20 25 30
Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe
35 40 45
Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser
50 55 60
Ala Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu
65 70 75 80
Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser
85 90 95
Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val
100 105 110
Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr
115 120 125
Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn
130 135 140
Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg
145 150 155 160
Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser
165 170 175
Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro Ala Gln
180 185 190
Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp
195 200 205
<210> 14
<211> 172
<212> PRT
<213> CCOVID19-SF6的氨基酸序列(Artificial Sequence)
<400> 14
Thr Tyr Val Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile
1 5 10 15
Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser
20 25 30
Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln
35 40 45
Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val Val
50 55 60
Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro Glu Leu
65 70 75 80
Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn His Thr Ser
85 90 95
Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala Ser Val Val
100 105 110
Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu Val Ala Lys Asn Leu
115 120 125
Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu Gly Lys Tyr Glu Gln Tyr
130 135 140
Ile Lys Trp Pro Trp Tyr Ile Trp Leu Gly Phe Ile Ala Gly Leu Ile
145 150 155 160
Ala Ile Val Met Val Thr Ile Met Leu Cys Cys Met
165 170
<210> 15
<211> 278
<212> PRT
<213> SARS-SF1的氨基酸序列(Artificial Sequence)
<400> 15
Gly Ser Asp Leu Asp Arg Cys Thr Thr Phe Asp Asp Val Gln Ala Pro
1 5 10 15
Asn Tyr Thr Gln His Thr Ser Ser Met Arg Gly Val Tyr Tyr Pro Asp
20 25 30
Glu Ile Phe Arg Ser Asp Thr Leu Tyr Leu Thr Gln Asp Leu Phe Leu
35 40 45
Pro Phe Tyr Ser Asn Val Thr Gly Phe His Thr Ile Asn His Thr Phe
50 55 60
Asp Asn Pro Val Ile Pro Phe Lys Asp Gly Ile Tyr Phe Ala Ala Thr
65 70 75 80
Glu Lys Ser Asn Val Val Arg Gly Trp Val Phe Gly Ser Thr Met Asn
85 90 95
Asn Lys Ser Gln Ser Val Ile Ile Ile Asn Asn Ser Thr Asn Val Val
100 105 110
Ile Arg Ala Cys Asn Phe Glu Leu Cys Asp Asn Pro Phe Phe Ala Val
115 120 125
Ser Lys Pro Met Gly Thr Gln Thr His Thr Met Ile Phe Asp Asn Ala
130 135 140
Phe Asn Cys Thr Phe Glu Tyr Ile Ser Asp Ala Phe Ser Leu Asp Val
145 150 155 160
Ser Glu Lys Ser Gly Asn Phe Lys His Leu Arg Glu Phe Val Phe Lys
165 170 175
Asn Lys Asp Gly Phe Leu Tyr Val Tyr Lys Gly Tyr Gln Pro Ile Asp
180 185 190
Val Val Arg Asp Leu Pro Ser Gly Phe Asn Thr Leu Lys Pro Ile Phe
195 200 205
Lys Leu Pro Leu Gly Ile Asn Ile Thr Asn Phe Arg Ala Ile Leu Thr
210 215 220
Ala Phe Ser Pro Ala Gln Asp Thr Trp Gly Thr Ser Ala Ala Ala Tyr
225 230 235 240
Phe Val Gly Tyr Leu Lys Pro Thr Thr Phe Met Leu Lys Tyr Asp Glu
245 250 255
Asn Gly Thr Ile Thr Asp Ala Val Asp Cys Ser Gln Asn Pro Leu Ala
260 265 270
Glu Leu Lys Cys Ser Val
275
<210> 16
<211> 196
<212> PRT
<213> SARS-SF2的氨基酸序列(Artificial Sequence)
<400> 16
Val Val Arg Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val
1 5 10 15
Phe Asn Ala Thr Lys Phe Pro Ser Val Tyr Ala Trp Glu Arg Lys Lys
20 25 30
Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Thr Phe
35 40 45
Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Ala Thr Lys Leu Asn Asp
50 55 60
Leu Cys Phe Ser Asn Val Tyr Ala Asp Ser Phe Val Val Lys Gly Asp
65 70 75 80
Asp Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Val Ile Ala Asp Tyr
85 90 95
Asn Tyr Lys Leu Pro Asp Asp Phe Met Gly Cys Val Leu Ala Trp Asn
100 105 110
Thr Arg Asn Ile Asp Ala Thr Ser Thr Gly Asn Tyr Asn Tyr Lys Tyr
115 120 125
Arg Tyr Leu Arg His Gly Lys Leu Arg Pro Phe Glu Arg Asp Ile Ser
130 135 140
Asn Val Pro Phe Ser Pro Asp Gly Lys Pro Cys Thr Pro Pro Ala Leu
145 150 155 160
Asn Cys Tyr Trp Pro Leu Asn Asp Tyr Gly Phe Tyr Thr Thr Thr Gly
165 170 175
Ile Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu
180 185 190
Asn Ala Pro Ala
195
<210> 17
<211> 161
<212> PRT
<213> SARS-SF3的氨基酸序列(Artificial Sequence)
<400> 17
Asn Ala Pro Ala Thr Val Cys Gly Pro Lys Leu Ser Thr Asp Leu Ile
1 5 10 15
Lys Asn Gln Cys Val Asn Phe Asn Phe Asn Gly Leu Thr Gly Thr Gly
20 25 30
Val Leu Thr Pro Ser Ser Lys Arg Phe Gln Pro Phe Gln Gln Phe Gly
35 40 45
Arg Asp Val Ser Asp Phe Thr Asp Ser Val Arg Asp Pro Lys Thr Ser
50 55 60
Glu Ile Leu Asp Ile Ser Pro Cys Ser Phe Gly Gly Val Ser Val Ile
65 70 75 80
Thr Pro Gly Thr Asn Ala Ser Ser Glu Val Ala Val Leu Tyr Gln Asp
85 90 95
Val Asn Cys Thr Asp Val Ser Thr Ala Ile His Ala Asp Gln Leu Thr
100 105 110
Pro Ala Trp Arg Ile Tyr Ser Thr Gly Asn Asn Val Phe Gln Thr Gln
115 120 125
Ala Gly Cys Leu Ile Gly Ala Glu His Val Asp Thr Ser Tyr Glu Cys
130 135 140
Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala Ser Tyr His Thr Val Ser
145 150 155 160
Leu
<210> 18
<211> 200
<212> PRT
<213> SARS-SF4的氨基酸序列(Artificial Sequence)
<400> 18
Leu Arg Ser Thr Ser Gln Lys Ser Ile Val Ala Tyr Thr Met Ser Leu
1 5 10 15
Gly Ala Asp Ser Ser Ile Ala Tyr Ser Asn Asn Thr Ile Ala Ile Pro
20 25 30
Thr Asn Phe Ser Ile Ser Ile Thr Thr Glu Val Met Pro Val Ser Met
35 40 45
Ala Lys Thr Ser Val Asp Cys Asn Met Tyr Ile Cys Gly Asp Ser Thr
50 55 60
Glu Cys Ala Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu
65 70 75 80
Asn Arg Ala Leu Ser Gly Ile Ala Ala Glu Gln Asp Arg Asn Thr Arg
85 90 95
Glu Val Phe Ala Gln Val Lys Gln Met Tyr Lys Thr Pro Thr Leu Lys
100 105 110
Tyr Phe Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Leu Lys
115 120 125
Pro Thr Lys Arg Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr
130 135 140
Leu Ala Asp Ala Gly Phe Met Lys Gln Tyr Gly Glu Cys Leu Gly Asp
145 150 155 160
Ile Asn Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr
165 170 175
Val Leu Pro Pro Leu Leu Thr Asp Asp Met Ile Ala Ala Tyr Thr Ala
180 185 190
Ala Leu Val Ser Gly Thr Ala Thr
195 200
<210> 19
<211> 205
<212> PRT
<213> SARS-SF5的氨基酸序列(Artificial Sequence)
<400> 19
Gly Thr Ala Thr Ala Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln
1 5 10 15
Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val
20 25 30
Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Gln Ile Ala Asn Gln Phe
35 40 45
Asn Lys Ala Ile Ser Gln Ile Gln Glu Ser Leu Thr Thr Thr Ser Thr
50 55 60
Ala Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu
65 70 75 80
Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser
85 90 95
Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val
100 105 110
Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr
115 120 125
Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn
130 135 140
Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg
145 150 155 160
Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ala
165 170 175
Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro Ser Gln
180 185 190
Glu Arg Asn Phe Thr Thr Ala Pro Ala Ile Cys His Glu
195 200 205
<210> 20
<211> 253
<212> PRT
<213> SARS-SF6的氨基酸序列(Artificial Sequence)
<400> 20
Arg Leu Asp Lys Val Glu Ala Glu Val Gln Ile Asp Arg Leu Ile Thr
1 5 10 15
Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val Thr Gln Gln Leu Ile Arg
20 25 30
Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu Ala Ala Thr Lys Met Ser
35 40 45
Glu Cys Val Leu Gly Gln Ser Lys Arg Val Asp Phe Cys Gly Lys Gly
50 55 60
Tyr His Leu Met Ser Phe Pro Gln Ala Ala Pro His Gly Val Val Phe
65 70 75 80
Leu His Val Thr Tyr Val Pro Ser Gln Glu Arg Asn Phe Thr Thr Ala
85 90 95
Pro Ala Ile Cys His Glu Gly Lys Ala Tyr Phe Pro Arg Glu Gly Val
100 105 110
Phe Val Phe Asn Gly Thr Ser Trp Phe Ile Thr Gln Arg Asn Phe Phe
115 120 125
Ser Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys
130 135 140
Asp Val Val Ile Gly Ile Ile Asn Asn Thr Val Tyr Asp Pro Leu Gln
145 150 155 160
Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn
165 170 175
His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala
180 185 190
Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu Val Ala
195 200 205
Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu Gly Lys Tyr
210 215 220
Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Val Trp Leu Gly Phe Ile Ala
225 230 235 240
Gly Leu Ile Ala Ile Val Met Val Thr Ile Leu Leu Cys
245 250
Claims (9)
1.一种β属冠状病毒融合重组蛋白,其特征在于,所述融合重组蛋白的氨基酸序列如SEQ ID NO.1所示。
2.编码权利要求1所述的融合重组蛋白的基因。
3.一种重组表达载体,其特征在于,包含权利要求2所述的基因和表达载体。
4.一种重组菌,其特征在于,包含权利要求3所述的重组表达载体。
5.权利要求1所述的β属冠状病毒融合重组蛋白的制备方法,包括如下步骤:
(1)以SARS-CoV-2全长DNA作为模板,设计针对COVID19-SF2蛋白片段和COVID19-SF5蛋白片段的不同的PCR引物,在COVID19-SF2蛋白片段的5’ 端引入BamH I酶切位点,3’端引入柔性连接肽的反向互补序列,在COVID19-SF5蛋白片段的5’ 端引入柔性连接肽序列,3’端引入Hind Ⅲ 酶切位点,C端引入6×His编码基因,得到COVID19-SF2蛋白片段和COVID19-SF5蛋白片段的PCR产物;其中,COVID19-SF2片段氨基酸序列为新冠病毒COVID-19 的S蛋白的第305位氨基酸至第525位氨基酸,COVID19-SF5片段的氨基酸序列为新冠病毒COVID-19的S蛋白的第880位氨基酸至第1084位氨基酸;
(2)将第一步中分别扩增得到的COVID19-SF2蛋白片段和COVID19-SF5蛋白片段的PCR产物进行重叠延伸PCR,通过连接得到融合蛋白表达基因;
(3)将融合蛋白表达基因通过序列5’-端和3’-端的BamH I和 Hind Ⅲ两个酶切位点与表达载体pQE-3连接,得到含有融合蛋白基因的表达载体;
(4)将含有融合蛋白基因的表达载体用感受态法转化入大肠杆菌M15菌株中;
(5)挑选在选择性平板上生长的菌株并进行菌落PCR,对PCR呈阳性的菌株进行蛋白表达诱导;
(6)取菌落PCR呈阳性的克隆进行扩大培养,使用IPTG进行诱导表达;
(7)收获包涵体并进行纯化复性收获重组融合蛋白。
6.权利要求1所述的融合重组蛋白的工业化制备方法,其特征在于,包括如下步骤:
(1)以权利要求4所述的重组菌作为种子菌,种子菌经过夜摇菌放大作为种子液;
(2)将种子液在2×YT培养基中进行发酵培养,发酵后菌体通过工业化自动连续离心机收集,收集的菌体先用提取液A制成悬液,再用水性裂解酶裂解,然后用提取液B处理,离心后收取沉淀包涵体,用缓冲液稀释后,离心,沉淀物为不溶性包涵体;
(3)进一步将包涵体溶于缓冲液后,离心去上清超滤浓缩,浓缩样品经Ni-NTA亲和柱,在AKTA蛋白纯化系统上进行纯化,收集样品;
(4)收集样品在4℃层析柜中透析,透析后的样品经离心取上清,上清液经超滤浓缩器浓缩,后再经AKTA蛋白纯化系统Sephadex G-75层析纯化;根据AKTA蛋白纯化系统的蛋白峰收集样品,即为精纯后的融合蛋白。
7.根据权利要求6所述的方法,其特征在于,发酵条件为: 溶氧值或溶氧浓度DO值60%,温度37℃,pH7.0,在细菌浓度量达峰值时加入诱导剂IPTG,总培养时间为7小时。
8.一种融合蛋白血清综合抗体IgG,其特征在于,利用权利要求1所述的重组融合蛋白免疫小鼠,获得抗血清,纯化获得血清综合抗体IgG。
9.权利要求1所述的融合重组蛋白、权利要求所述的基因、权利要求3所述的重组表达载体、权利要求4所述的重组菌在制备β属冠状病毒通用疫苗、通用抗体上的应用。
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