CN115704012A - 一种含有降解决定子的重组病毒及其制备方法和应用 - Google Patents
一种含有降解决定子的重组病毒及其制备方法和应用 Download PDFInfo
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- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 1
- 108010000761 leucylarginine Proteins 0.000 description 1
- 108700021021 mRNA Vaccine Proteins 0.000 description 1
- 229940126582 mRNA vaccine Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 108010063431 methionyl-aspartyl-glycine Proteins 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 238000012536 packaging technology Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
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- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 1
- 108010018625 phenylalanylarginine Proteins 0.000 description 1
- 108010051242 phenylalanylserine Proteins 0.000 description 1
- 108010020755 prolyl-glycyl-glycine Proteins 0.000 description 1
- 108010029020 prolylglycine Proteins 0.000 description 1
- 108010090894 prolylleucine Proteins 0.000 description 1
- 108010053725 prolylvaline Proteins 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 238000000455 protein structure prediction Methods 0.000 description 1
- 230000007111 proteostasis Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 108010048818 seryl-histidine Proteins 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940031626 subunit vaccine Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
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- 238000013519 translation Methods 0.000 description 1
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- IBIDRSSEHFLGSD-UHFFFAOYSA-N valinyl-arginine Natural products CC(C)C(N)C(=O)NC(C(O)=O)CCCN=C(N)N IBIDRSSEHFLGSD-UHFFFAOYSA-N 0.000 description 1
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- 229960004854 viral vaccine Drugs 0.000 description 1
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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Abstract
本发明提供了一种含有降解决定子的重组病毒及其制备方法和应用,所述含有降解决定子的重组病毒的至少一种病毒蛋白中含有至少一个能被宿主细胞的蛋白质降解系统识别的降解决定子;所述降解决定子包括氨基酸序列、多肽或结构基序中的任意一种或至少两种的组合。本发明还提供了一种核酸分子、一种重组载体、所述含有降解决定子的重组病毒的制备方法、一种含有降解决定子的重组病毒的制备系统、一种疫苗、一种溶瘤病毒以及一种药物。本发明所述含有降解决定子的重组病毒可以被宿主细胞内的蛋白质降解系统识别并降解,复制能力减弱甚至去除,制成相应的疫苗、溶瘤病毒或药物后,效果良好,具有实际应用的价值。
Description
技术领域
本发明属于生物技术领域,尤其涉及一种含有降解决定子的重组病毒及其制备方法和应用。
背景技术
病毒感染严重危害人类健康和社会经济发展。疫苗是预防病毒感染最有效的手段之一。当前主要的病毒疫苗种类包括灭活疫苗、减毒疫苗、亚单位疫苗、病毒载体疫苗、DNA疫苗、mRNA疫苗和病毒样颗粒等。
过去几十年间,病毒疫苗技术已得到了长足发展,然而仍存在一定的局限,例如由于病毒灭活处理,导致抗原天然结构被破坏从而使得病毒疫苗的免疫原性降低,或由于病毒减毒不充分,导致病毒疫苗的复制活性残留从而使得疫苗携带安全隐患,或因病毒疫苗的制备技术复杂而不能推广至其他病毒疫苗等。因此,突破传统的病毒疫苗设计理念,开发一种兼具安全、高效、简单和通用的新型疫苗技术,是未来理想病毒疫苗的重要发展方向,具有重要的科学价值和临床价值。
如何提供一种更加安全、适用性广、免疫原性强的病毒疫苗的制备方法,已成为亟待解决的问题。
发明内容
针对现有技术的不足和实际需求,本发明提供一种含有降解决定子的重组病毒及其制备方法和应用,通过在病毒的至少一个蛋白编码基因中插入至少一个降解决定子,制备得到的重组病毒可以被宿主细胞内的蛋白质降解系统识别,并降解病毒蛋白,病毒的复制能力被减弱,甚至完全失去复制能力,制备得到的疫苗或溶瘤病毒更加安全,应用前景广阔。
为达此目的,本发明采用如下技术方案:
第一方面,本发明提供了一种含有降解决定子的重组病毒,所述含有降解决定子的重组病毒的至少一种病毒蛋白中含有至少一个能被宿主细胞的蛋白质降解系统识别的降解决定子;
所述降解决定子包括氨基酸序列、多肽或结构基序中的任意一种或至少两种的组合。
本发明中,通过在病毒的至少一个蛋白中插入至少一个降解决定子,该降解决定子可以随着病毒基因组的复制而复制,并且可以随着病毒蛋白的翻译而融合表达于病毒蛋白中,从而得到被降解决定子定点修饰的重组病毒。同时,利用宿主细胞内的蛋白质降解系统,实现了病毒蛋白在宿主细胞内的稳定降解,人为控制病毒在宿主内的复制等生命活动,可用于制备复制可控的病毒疫苗或者溶瘤病毒,具有极高的应用价值。
本发明中,降解决定子(Degrons)是指可以被蛋白质降解系统特异性地识别,进而介导底物蛋白降解的各种分子,例如特异性的氨基酸序列、多肽、结构基序或者其他分子。降解决定子通常是一种短的线性基序(motif),具有特异性的序列模式,其对于相互作用非常关键的氨基酸残基表现出强烈的进化保守性。
优选地,所述蛋白质降解系统包括泛素-蛋白酶体系统、溶酶体系统、细胞器水解系统、细胞膜表面水解系统或Caspase蛋白酶系统中的任意一种或至少两种的组合。
本发明中,病毒蛋白质功能的正常执行是病毒在宿主细胞内复制等所有生命活动的先决条件。宿主细胞中存在多种天然的蛋白质降解系统,其对维持细胞内蛋白质稳态进而维持正常的细胞功能至关重要。蛋白质降解系统可以特异性地识别底物蛋白中的降解决定子。降解决定子的一个重要特征是其可以转移,通过基因工程连接上这些降解决定子之后,生命周期长的蛋白变得不稳定。这些蛋白质降解系统及其对应的降解决定子为设计可调控病毒蛋白质在宿主细胞内稳定与降解的“生命开关”提供了生物学基础。
优选地,所述降解决定子的位置位于病毒蛋白的C端、N端或中间编码区域中的任意一种或至少两种的组合。
本发明中,动物和人体等的蛋白质降解系统可以识别多种降解决定子,因此可以在病毒蛋白的N端、C端或者其他任意位点引入不同种类、不同数量的降解决定子;这些不同种类和数量的降解决定子可以进行任意组合,为制备不同复制效率、不同减毒程度的病毒疫苗提供了保证,这对于病毒疫苗的生产效率和免疫原性至关重要。
优选地,所述降解决定子包括SEQ ID No.1~110所示的氨基酸序列中的任意一种。
SEQ ID No.1:ALAPYIP;
SEQ ID No.2:DRHDSGLDSM;
SEQ ID No.3:SHGFPPEVEEQDDGTLPMSCAQESGMDRHPAACASARINV;
SEQ ID No.4:FVNQHLCGSHLVEALYLVCGERGFFYTPKA;
SEQ ID No.5:DSGXXS(其中,X表示任意氨基酸);
SEQ ID No.6:DRHDSGXXSM(其中,X表示任意氨基酸);
SEQ ID No.7:LGSWRHWRGQEG;
SEQ ID No.8:SLYKKVVGTMAAG;
SEQ ID No.9:MLSESRNFPAQA;
SEQ ID No.10:ERAPTGRWGRRG;
SEQ ID No.11:KKVGRARPCQRG;
SEQ ID No.12:APRAPRQRSRDG;
SEQ ID No.13:SWRLTGSGMKG;
SEQ ID No.14:WRPGRRGPSSGG;
SEQ ID No.15:LRGPSPPPMAGG;
SEQ ID No.16:WRPGRRGPSSGG;
SEQ ID No.17:MALAVRVVYCGA;
SEQ ID No.18:KKNVEAIGLLGG;
SEQ ID No.19:PPGPPLSSPRPR;
SEQ ID No.20:TMNNEEDLLRSL;
SEQ ID No.21:TMEPPGGRQKKR;
SEQ ID No.22:QERGPTWDKNLR;
SEQ ID No.23:GTMAVLRQRPGR;
SEQ ID No.24:LCTRSWDVTPNR;
SEQ ID No.25:ANQPAQCRKTRI;
SEQ ID No.26:EEARLKYDKSRI;
SEQ ID No.27:LNDGPKPGQSRF;
SEQ ID No.28:TSLYKKVGMGRK;
SEQ ID No.29:YKKVGTMRGRGL;
SEQ ID No.30:VGTMAAGRAPGK;
SEQ ID No.31:KKVGTMRGVGYP;
SEQ ID No.32:EGPLWHPRICGS;
SEQ ID No.33:EMALSPPRSWGQ;
SEQ ID No.34:RSGLRRRRHRGE;
SEQ ID No.35:VSGIMRRPWGMN;
SEQ ID No.36:KRVLIRVTYCGL;
SEQ ID No.37:MALAVRVVYCGA;
SEQ ID No.38:PSSPVQTTPLSQAVATPSRSSAAAAAALDLSGRRG;
SEQ ID No.39:HHGKGFFGSGHYTAYCYNTEGGACALLCGVGDTERG;
SEQ ID No.40:VAEITKQLPPVVPVSKPGALRRSLSRSMSQEAQRG;
SEQ ID No.41:KKRPPPGLDR;
SEQ ID No.42:SVNSLLKELR;
SEQ ID No.43:HEWVLREGEE;
SEQ ID No.44:EYLLKMATEE;
SEQ ID No.45:ELCKSYRRLQ;
SEQ ID No.46:VALKFKPRKH;
SEQ ID No.47:GLGCKVLRRH;
SEQ ID No.48:RHCGRT;
SEQ ID No.49:RSHGTL;
SEQ ID No.50:RFRGLR;
SEQ ID No.51:RNLGIR;
SEQ ID No.52:RGRLTRNKGP;
SEQ ID No.53:SLFRKRNKGK;
SEQ ID No.54:RTAASGRRWG;
SEQ ID No.55:GLLKRPCLRG;
SEQ ID No.56:QRKLQRTSRG;
SEQ ID No.57:PKSKVCQQRG;
SEQ ID No.58:KRLLKGSQYG;
SEQ ID No.59:PHKRLLKGSQYG;
SEQ ID No.60:KESNDCSCGG;
SEQ ID No.61:DCVCRGSTGG;
SEQ ID No.62;VAPRSRDERG;
SEQ ID No.63:AHQLQALRRG;
SEQ ID No.64:LTGKG;
SEQ ID No.65:YYCFFG;
SEQ ID No.66:LEKGG;
SEQ ID No.67:AAHKG;
SEQ ID No.68:ALRRG;
SEQ ID No.69:GGSGG;
SEQ ID No.70:RDERG;
SEQ ID No.71:SRVKG;
SEQ ID No.72:PASGG;
SEQ ID No.73:AIHGG;
SEQ ID No.74:GAEAG;
SEQ ID No.75:GSTGG;
SEQ ID No.76:RGMGG;
SEQ ID No.77:LVHAG;
SEQ ID No.78:SLQTG;
SEQ ID No.79:PVPGG;
SEQ ID No.80:NYKSG;
SEQ ID No.81:PRKQG;
SEQ ID No.82:TPRGG;
SEQ ID No.83:GCSGG;
SEQ ID No.84:EAQRG;
SEQ ID No.85:GKAWG;
SEQ ID No.86:PAGGG;
SEQ ID No.87:VVLYG;
SEQ ID No.88:LTLKG;
SEQ ID No.89:GFQSG;
SEQ ID No.90:RVQWG;
SEQ ID No.91:SRTEGQFGTTQSNGTFFNGASPGTPPAPSQHQQSLTSL;
SEQ ID No.92:
YRPIPFQPEGAGEGTDEDKSNRIGNNGLRLNDGNGNGQLAPSPTPQGTEAVRA;
SEQ ID No.93:RKFSNNPQPNAISNGTSTSERPGEGATQGIVEEEVLQ;
SEQ ID No.94:IRTESAEEAEMASVPNGSPSWHPGASHVVNGAAGHSN;
SEQ ID No.95:WHEIEMESGEEAMEPANETGNTLNGSPSWHPSPSHVI;
SEQ ID No.96:NRTDFAGEEDEMDGVLNGSPSWHAATSHIVNGATVHQ;
SEQ ID No.97:NRTDTAAEAEMDSVLNGSPSWHPPAGHVVNGATVHRS;
SEQ ID No.98:NRTDTAAEAEMDSVLNGSPSWHPPAGHVVNGAAVHRS;
SEQ ID No.99:NRTEVLEGAEIPSTVNGSPSWHPADSRAVSGATGHSS;
SEQ ID No.100:NRTEAPEGTELPSTVNGSPSWHPADSRAGSGATGHSS;
SEQ ID No.101:NRTEAPEGTESERETPSAINGNPSWHLADSPAVNGAT;
SEQ ID No.102:
NRTEAPEGTESEVETPSAINGNPSWQLADSPAINGATGHSSSLDAREVIPMAAVKQQAL;
SEQ ID No.103:NRTEAPEGTESDMETPSAINGNASWHLADSPAVNGAT;
SEQ ID No.104:NRTEAPEGTGPEMETPSAINGNPAWHPADSPAVNGAT;
SEQ ID No.105:NRTEAPEGTESDMETPSAINGNPSWHLADSPAVNGAT;
SEQ ID No.106:NRTEAPEGTESEAETPSAINGNPSWHLADSPAVNGAT;
SEQ ID No.107:NRTEAPEGTESEMETPSAINGNPSWHLADSPPANGAT;
SEQ ID No.108:NRTEAPEGTDSEMETPSAINGNPAWHLADSPAVNGAT;
SEQ ID No.109:NRTEAPEGTDSEMETPSAINGNPSWHLADSPVVNGAT;
SEQ ID No.110:NRTEAPEGTESEMETPSAINGNPSWHLADSPAVNGAT。
优选地,所述病毒包括流感病毒、艾滋病毒、新冠病毒(SARS-CoV-2)、手足口病毒、柯萨奇病毒、丙肝病毒(HCV)、乙肝病毒(HBV)、甲肝病毒、丁型肝炎病毒、戊型肝炎病毒、人类疱疹病毒(EB病毒)、人乳头瘤病毒(HPV)、单纯疱疹病毒(HSV)、巨细胞病毒、水痘-带状疱疹病毒、水泡性口炎病毒、呼吸道合胞病毒(RSV)、登革病毒、埃博拉病毒、马尔堡病毒、寨卡病毒(Zika)、严重急性呼吸综合征病毒(SARS)、中东呼吸综合征病毒、轮状病毒、狂犬病毒、麻疹病毒、腺病毒、脊髓灰质炎病毒、埃可病毒、乙型脑炎病毒、森林脑炎病毒、汉坦病毒、新型肠道病毒、风疹病毒、腮腺炎病毒、副流感病毒、蓝耳病毒、猪瘟病毒、口蹄疫病毒、细小病毒、朊病毒、天花病毒、烟草花叶病毒、噬菌体、疱疹病毒、西尼罗河病毒、诺如病毒(Norovirus)、人博卡病毒或冠状病毒中的任意一种,优选为流感病毒、艾滋病毒或新冠病毒中的任意一种。
优选地,在流感病毒的PA蛋白、PB1蛋白、PB2蛋白、NP蛋白、HA蛋白、NA蛋白、M1蛋白、M2蛋白、NS1蛋白或NEP蛋白中的任意一种或至少两种的组合中包含至少一个降解决定子,例如可以是在流感病毒的PA和PB2中均包含至少一个降解决定子;在流感病毒的PA蛋白和PB1蛋白中均包含至少一个降解决定子;在流感病毒的PB2蛋白和PB1蛋白中均包含至少一个降解决定子;在流感病毒的PA蛋白、PB2蛋白和PB1蛋白中均包含至少一个降解决定子;在流感病毒的PA蛋白、PB2蛋白、PB1蛋白和M1蛋白中均包含至少一个降解决定子;在流感病毒的PA蛋白、PB2蛋白、PB1蛋白、M1蛋白和NP蛋白中均包含至少一个降解决定子;在流感病毒的PB2蛋白、PB1蛋白和M1蛋白中均包含至少一个降解决定子;在流感病毒的PA蛋白和M1蛋白中均包含至少一个降解决定子;在流感病毒的PB1蛋白和M1蛋白中均包含至少一个降解决定子;在流感病毒的PB2蛋白和M1蛋白中均包含至少一个降解决定子;在流感病毒的PB2蛋白、PB1蛋白、M1蛋白和NS1蛋白中均包含至少一个降解决定子;在流感病毒的PB2蛋白、PB1蛋白、M1蛋白和NEP蛋白中均包含至少一个降解决定子;在流感病毒的NS1蛋白和NEP蛋白中均包含至少一个降解决定子。
优选地,在艾滋病毒的Gag多聚蛋白(Gag polyprotein)、pol多聚蛋白(polpolyprotein)、gp160、HIV转录反式激活子(HIV trans-activator of transcription,Tat)、病毒体蛋白表达调节蛋白(regulator of expression of virion proteins,Rev)、病毒负因子(negative factor,Nef)、慢病毒蛋白R(lentivirus protein R,Vpr)、病毒感染性因子(viral infectivity factor,Vif)、病毒蛋白U(virus protein U,Vpu)、基质蛋白(matrix protein,MA,p17)、衣壳蛋白(capsid protein,CA,p24)、间隔肽1(spacerpeptide 1,SP1,p2)、核衣壳蛋白(nucleocapsid protein,NC,p7)、间隔肽2(spacerpeptide 2,SP2,p1)、P6、逆转录酶(reverse transcriptase,RT)、核糖核酸酶H(Rnase H)、整合酶(integrase,IN)、HIV蛋白酶(HIV protease,PR)、gp120或gp41蛋白中的任意一种或至少两种的组合中包含至少一个降解决定子。
优选地,在新冠病毒的刺突蛋白(spike protein,S protein)、包膜糖蛋白(envelope glycoprotein,E glycoprotein)、膜糖蛋白(membrane glycoprotein,Mglycoprotein)、核衣壳蛋白(nucleocapsid protein,N protein)、非结构蛋白1(nonstructural protein 1,nsp1)、非结构蛋白2、非结构蛋白3、非结构蛋白4、非结构蛋白5、非结构蛋白6、非结构蛋白7、非结构蛋白8、非结构蛋白9、非结构蛋白10、非结构蛋白11、非结构蛋白12、非结构蛋白13、非结构蛋白14、非结构蛋白15、非结构蛋白16、3a蛋白、3b蛋白、6蛋白、7a蛋白、7b蛋白、8a蛋白、8b蛋白、9b蛋白、3C样蛋白酶(3C-like proteinase)、前导蛋白(leader protein)、2’-O-核糖甲基转移酶(2’-O-ribose methyltransferase)、核酸内切酶(endoRNAse)、3’-至-5’核酸外切酶(3’-to-5’exonuclease)、解旋酶(helicase)、RNA依赖的RNA聚合酶(RNA-dependent RNA polymerase)、orf1a多聚蛋白(orf1apolyprotein)、ORF10蛋白(ORF10protein)、ORF8蛋白(ORF8 protein)、ORF7a蛋白(ORF7aprotein)、ORF6蛋白(ORF6protein)或ORF3a蛋白(ORF3a protein)中的任意一种或至少两种的组合中包含至少一个降解决定子。
本发明中,所述重组病毒还可以进一步被修饰,例如引入一些免疫增强剂到病毒蛋白的特定区域或者特定氨基酸,从而得到性能改善、免疫原性增强的重组病毒。
第二方面,本发明提供了一种核酸分子,所述核酸分子编码第一方面所述的含有降解决定子的重组病毒。
第三方面,本发明提供了一种重组载体,所述重组载体含有第二方面所述的核酸分子。
优选地,所述重组载体表达第一方面所述的含有降解决定子的重组病毒。
第四方面,本发明提供了一种第一方面所述的含有降解决定子的重组病毒的制备方法,所述制备方法包括:
构建蛋白质降解系统缺陷的细胞系;
在病毒蛋白的编码基因中引入编码降解决定子的核苷酸序列;
构建第三方面所述的重组载体,导入所述的蛋白质降解系统缺陷的细胞系,包装得到所述含有降解决定子的重组病毒。
本发明中,由于蛋白质降解系统广泛分布于宿主细胞中,为了避免重组病毒在制备过程中被细胞内的蛋白质降解系统降解导致生产效率降低,本发明提供了一种蛋白质降解系统缺陷的人工改造细胞系。在该人工改造细胞系中,降解决定子不会被识别、病毒蛋白不会被蛋白质降解系统降解而得以保留,因此重组病毒可以在该特定的人工改造的细胞系中高效复制、大量制备。而在正常细胞中,蛋白质降解系统会识别与病毒蛋白融合的降解决定子,从而降解病毒蛋白,病毒的复制能力被减弱甚至完全失去复制能力,因此重组病毒具备极高的安全性。
利用重组病毒对该特定病毒生产体系的依赖,可以在该系统中进行重组病毒的大量制备。由于人体和动物等的正常细胞中存在蛋白质降解系统,可以识别与病毒蛋白融合表达的降解决定子,从而将病毒蛋白降解,因此制备出来的重组病毒在动物和人体中复制能力降低或者不能进行复制繁殖,增加了病毒的安全性,从而使得该重组病毒成了名副其实的减毒活病毒疫苗。
本发明中,所述重组病毒的制备原理在于:(1)引入病毒蛋白特定位点的降解决定子可以被正常宿主细胞中的蛋白质降解系统识别,从而诱导相关的病毒蛋白降解、失活;(2)引入病毒蛋白特定位点的降解决定子可以在特定的病毒生产系统中不被识别或者被抑制,从而避免或减少病毒蛋白被宿主细胞的蛋白质降解系统降解;(3)引入病毒蛋白特定位点的降解决定子在正常宿主细胞中被蛋白质降解系统识别,因此制备出来的病毒在动物和人体等的宿主细胞中可以被蛋白质降解系统识别、降解,因而复制能力降低甚至完全失去复制繁殖能力,增加了病毒的安全性。
优选地,所述蛋白质降解系统缺陷包括泛素-蛋白酶体系统缺陷,包括E3连接酶敲除或敲降、蛋白酶体敲除或敲降中的任意一种或至少两种的组合。
优选地,所述细胞系包括哺乳动物细胞系,包括CHO细胞系、Vero细胞系、MDCK细胞系、HEK293T细胞系、MDCK细胞系、A549细胞系、BHK细胞系、BHK-21/BRS细胞系、Sp2/0细胞系、HEK293细胞系、293F细胞系、HeLa细胞系、TZM-bl细胞系、Sup-T1细胞系、MRC-5细胞系、VMK细胞系、LLC-MK2细胞系、HCT-8细胞系、Huh-7细胞系或Caco2细胞系中的任意一种,优选为HEK293T细胞系、MDCK细胞系或A549细胞系中的任意一种。
本发明中,选用哺乳动物细胞系还解决了传统方法中使用鸡胚繁殖病毒易引起人体过敏等不良反应的缺点。
优选地,所述含有降解决定子的重组病毒在制备过程中加入蛋白质降解系统抑制剂。
优选地,所述蛋白质降解系统抑制剂包括蛋白酶体抑制剂,所述蛋白酶体抑制剂包括MG132、MG-341或乳胞素(lactacystin)中的任意一种或至少两种的组合。
优选地,所述制备方法还包括检测所述含有降解决定子的重组病毒在所述蛋白质降解系统缺陷的细胞系以及未经改造的细胞系中的复制能力、安全性以及免疫原性的步骤。
本发明中,通过检测所述含有降解决定子的重组病毒在所述蛋白质降解系统缺陷的细胞系以及未经改造的细胞系中的复制能力,来确定所述的重组病毒是否改造成功。其中,在所述蛋白质降解系统缺陷的细胞系中正常复制,在未经改造的正常宿主细胞中复制能力降低或不能复制的重组病毒为改造成功的重组病毒。
优选地,所述制备方法还包括大规模生产的步骤。
作为优选技术方案,本发明所述含有降解决定子的重组病毒的制备方法,包括以下步骤:
(1)构建蛋白质降解系统缺陷的哺乳动物细胞系:
通过基因编辑技术,将细胞系中的蛋白质降解系统的关键元件敲除;
(2)确定引入降解决定子的病毒蛋白以及所述降解决定子的种类、数量和引入位点,在病毒蛋白的编码基因中引入编码降解决定子的核苷酸序列,得到重组病毒序列;
(3)构建重组载体:
将步骤(2)中的重组病毒序列与质粒连接,得到所述重组载体;
(4)重组载体导入所述的蛋白质降解系统缺陷的细胞系,包装得到所述含有降解决定子的重组病毒:
通过反向遗传技术,将步骤(3)中的重组载体与病毒拯救质粒共转染至所述蛋白质降解系统缺陷的细胞系中,加入蛋白质降解系统抑制剂,包装得到所述含有降解决定子的重组病毒;
检测所述含有降解决定子的重组病毒在所述蛋白质降解系统缺陷的细胞系以及未经改造的细胞系中的复制能力、安全性以及免疫原性,并进行大规模生产。
本发明步骤(2)中,通过对流感病毒进行生物信息学分析和蛋白质结构预测,预测并分析在病毒的各个蛋白中引入降解决定子序列后的病毒的蛋白结构,以筛选引入降解决定子的病毒蛋白并确定所引入的降解决定子的种类、数量和具体位点。
本发明步骤(4)中,利用反向遗传技术,可以将现有的病毒模型的任意基因替换成其他亚型或者毒株的基因,或者将现用的病毒模型替换成其他亚型或者毒株,从而制备出其他亚型或者毒株的重组病毒,使得该方法可以应用于任意亚型或毒株的病毒,而且制备出的病毒在蛋白质降解系统缺陷的细胞株中大量复制,而在正常的宿主细胞中会被蛋白质降解系统识别降解。
本发明中,对于已经改造成功的重组病毒,可以重复步骤(2)~(4),实现在重组病毒的多个病毒蛋白上均引入降解决定子,或者在重组病毒的任一病毒蛋白上引入多个降解决定子。
此外,利用反向遗传技术,还可以制备多价病毒,更重要的是,制备出的突变型强毒和多价病毒具有非常高的安全性和有效性。
第五方面,本发明提供了一种第一方面所述的含有降解决定子的重组病毒的制备系统,所述制备系统包括蛋白质降解系统缺陷的细胞系、重组载体以及病毒拯救质粒。
第六方面,本发明提供了第一方面所述的含有降解决定子的重组病毒、第二方面所述的核酸分子、第三方面所述的重组载体、第四方面所述的含有降解决定子的重组病毒的制备方法或第五方面所述的含有降解决定子的重组病毒的制备系统中的任意一种或至少两种的组合在制备疫苗和/或药物中的应用。
第七方面,本发明提供了一种疫苗,所述疫苗含有第一方面所述的含有降解决定子的重组病毒。
优选地,所述疫苗包括减毒活疫苗、复制无能活疫苗、复制可控活疫苗或溶瘤病毒疫苗中的任意一种。
优选地,所述疫苗还包括佐剂和辅料。
第八方面,本发明提供了一种溶瘤病毒,所述溶瘤病毒含有第一方面所述的含有降解决定子的重组病毒。
第九方面,本发明提供了一种药物,所述药物含有第一方面所述的含有降解决定子的重组病毒。
优选地,所述药物还包括药学上可以接受的载体、稀释剂或赋形剂中的任意一种或至少两种的组合。
相比于现有技术,本发明具有如下有益效果:
(1)通用性:只需在病毒蛋白中引入降解决定子,就可以控制病毒的复制,因此本发明的技术方案可对所有的病毒进行改造,可用于所有病毒疫苗的制备;可供选择的蛋白质降解系统及其对应的降解决定子有多种,限制因素少,适用性更强;
(2)操作简单:只需要简单的病毒载体的构建和病毒的包装技术,技术成熟,成功率高,促进了相关产品的制备与推广;
(3)效果好:根据本发明的技术方案可以设计出具有不同失活程度的疫苗,具有安全可控性;制备得到的疫苗具有极好的免疫原性,应用前景广阔。
具体实施方式
为进一步阐述本发明所采取的技术手段及其效果,以下结合实施例对本发明作进一步地说明。可以理解的是,此处所描述的具体实施方式仅仅用于解释本发明,而非对本发明的限定。
实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件,或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可通过正规渠道商购获得的常规产品。
材料:
pHH21、pCDNA3(neo)和pcAAGGS/MCS载体购自北京中科裕博生物技术有限公司;
实施例1
本实施例提供一种表达含有降解决定子的重组流感病毒的重组载体,所述重组载体通过如下方法进行制备:
(1)病毒拯救质粒的构建
根据pubmed公布的流感病毒A/WSN/1933的基因序列:
https://www.ncbi.nlm.nih.gov/nuccore/?term=WSN+PB2,
https://www.ncbi.nlm.nih.gov/nuccore/?term=WSN+PB1,
https://www.ncbi.nlm.nih.gov/nuccore/?term=WSN+PA,
https://www.ncbi.nlm.nih.gov/nuccore/?term=WSN+HA,
https://www.ncbi.nlm.nih.gov/nuccore/?term=WSN+NA,
https://www.ncbi.nlm.nih.gov/nuccore/?term=WSN+NP,
https://www.ncbi.nlm.nih.gov/nuccore/?term=WSN+M,
https://www.ncbi.nlm.nih.gov/nuccore/?term=WSN+NS。
经全基因合成,获得该流感病毒各个基因片段的基因。分别连接在pHH21、pCDNA3(neo)、pcAAGGS/MCS载体上,获得野生型流感病毒拯救质粒。获得的质粒的命名及构成如表1所示。
表1
(2)构建重组载体
在病毒蛋白中引入降解决定子的编码序列,并与质粒连接,构建了一系列的重组质粒。这一工作委托北京擎科生物科技有限公司协助完成,并经测序验证突变构建成功。
重组载体的命名原则如下:
1.在病毒蛋白N端引入降解决定子,构建的病毒载体命名为“病毒蛋白名称-N-降解决定子名称”;
2.在病毒蛋白C端引入降解决定子,构建的病毒载体命名为“病毒蛋白名称-C-降解决定子名称”;
3.在病毒蛋白的编码区内部引入降解决定子,构建的病毒载体,命名为“病毒蛋白名称-与引入位点相邻的上游氨基酸的名称和氨基酸编号-降解决定子名称”。
构建的重组质粒如下:
PB2-N-Degron1、PB2-R70-Degron1、PB2-I176-Degron1、PB2-V457-Degron1、PB2-N510-Degron1、PB2-Y531-Degron1、PB2-A623-Degron1、PB2-D680-Degron1、PB2-E700-Degron1、PB2-C-Degron1、PB1-N-Degron1、PB1-D70-Degron1、PB1-D295-Degron1、PB1-R327-Degron1、PB1-R430-Degron1、PB1-F490-Degron1、PB1-T566 Degron1、PB1-N626-Degron1、PB1-G710-Degron1、PB1-C-Degron1、PA-N-Degron1、PA-D294-Degron1、PA-N350-Degron1、PA-E372-Degron1、PA-L425-Degron1、PA-H510-Degron1、PA-A553-Degron1、PA-E604-Degron1、PA-S624-Degron1、PA-C-Degron1、NP-N-Degron1、NP-G126-Degron1、NP-N247-Degron1、NP-R317-Degron1、NP-V353-Degron1、NP-A366-Degron1、NP-Q409-Degron1、NP-E465-Degron1、NP-M481-Degron1、NP-C-Degron1、M1-N-Degron1、M1-A33-Degron1、M1-V68-Degron1、M1-D89-Degron1、M1-R105-Degron1、M1-M135-Degron1、M1-Q164-Degron1、M1-H222-Degron1、M1-A239-Degron1、M1-C-Degron1、M2-C-Degron1、NEP-C-Degron1、NS1-N-Degron1、NS1-A76-Degron1、NS1-A82-Degron1、NS1-H101-Degron1、NS1-A122-Degron1、NS1-T151-Degron1、NS1-L163-Degron1、NS1-C-Degron1、HA-N-Degron1、HA-C-Degron1、NA-N-Degron1、NA-C-Degron1、PB2-N-Degron2、PB2-R70-Degron2、PB2-I176-Degron2、PB2-V457-Degron2、PB2-N510-Degron2、PB2-Y531-Degron2、PB2-A623-Degron2、PB2-D680-Degron2、PB2-E700-Degron2、PB2-C-Degron2、PB1-N-Degron2、PB1-D70-Degron2、PB1-D295-Degron2、PB1-R327-Degron2、PB1-R430-Degron2、PB1-F490-Degron2、PB1-T566Degron2、PB1-N626-Degron2、PB1-G710-Degron2、PB1-C-Degron2、PA-N-Degron2、PA-D294-Degron2、PA-N350-Degron2、PA-E372-Degron2、PA-L425-Degron2、PA-H510-Degron2、PA-A553-Degron2、PA-E604-Degron2、PA-S624-Degron2、PA-C-Degron2、NP-N-Degron2、NP-G126-Degron2、NP-N247-Degron2、NP-R317-Degron2、NP-V353-Degron2、NP-A366-Degron2、NP-Q409-Degron2、NP-E465-Degron2、NP-M481-Degron2、NP-C-Degron2、M1-N-Degron2、M1-A33-Degron2、M1-V68-Degron2、M1-D89-Degron2、M1-R105-Degron2、M1-M135-Degron2、M1-Q164-Degron2、M1-H222-Degron2、M1-A239-Degron2、M1-C-Degron2、M2-C-Degron2、NEP-C-Degron2、NS1-N-Degron2、NS1-A76-Degron2、NS1-A82-Degron2、NS1-H101-Degron2、NS1-A122-Degron2、NS1-T151-Degron2、NS1-L163-Degron2、NS1-C-Degron2、HA-N-Degron2、HA-C-Degron2、NA-N-Degron2和NA-C-Degron2。
其中,Degron1的序列如SEQ ID No.1所示,编码核苷酸序列如SEQ ID No.111所示,Degron2的序列如SEQ ID No.2所示,编码核苷酸序列如SEQ ID No.112所示。
SEQ ID No.111:GCATTGGCCCCCTACATTCCA;
SEQ ID No.112:GATCGCCACGATTCAGGGCTCGATTCCATG。
实施例2
本实施例提供一种含有降解决定子的重组流感病毒,所示含有降解决定子的重组流感病毒通过如下方法进行制备:
(1)构建蛋白质降解系统缺陷的哺乳动物细胞系:
利用CRISPR/Cas9基因敲除技术,将细胞系中的蛋白质降解系统的元件敲除;
(2)重组载体导入所述的蛋白质降解系统缺陷的细胞系,包装得到所述含有降解决定子的重组病毒:
使用实施例1中的重组载体替换对应的野生型质粒,并与其他11种质粒共转染蛋白质降解系统缺陷的哺乳动物细胞系(示例:重组载体PB2-N-Degron1替代质粒Ben1,与其他11种质粒共转染),每种质粒的加入量为0.2μg,转染后的细胞在含有0.5%FBS、2μg/mLTPCK-胰蛋白酶的DMEM培养基中培养。
转染4天后,宿主细胞完全病变或者90%以上病变后,收集上清,感染新的蛋白质降解系统缺陷的细胞,培养基为含有0.5%FBS、2μg/mL TPCK-胰蛋白酶的DMEM培养基,加入蛋白质降解系统抑制剂,感染4天后,宿主细胞完全病变后,收集上清。
上清离心并过0.4μm滤膜去除细胞碎片,对包装产物进行蛋白质降解系统缺陷依赖性的检测,以及包装产物的失活对蛋白质降解系统的依赖性,保留维持着蛋白质降解系统缺陷依赖性的突变体即为重组病毒。
按照与重组载体相同的方式,对制备得到的重组病毒进行命名。
综上所述,本发明通过在病毒蛋白中引入降解决定子,制备得到的重组病毒可以被宿主细胞内的蛋白质降解系统识别并降解,减弱甚至去除重组病毒的复制能力;所述重组病毒可以在蛋白质降解系统缺陷的细胞内复制,从而实现其大规模生产;所述重组病毒制成相应的疫苗或药物后,具有极好的安全性与免疫原性,应用前景广阔;所述重组病毒的制备方法适应性极强,操作简单,促进了产品的使用与推广。
申请人声明,本发明通过上述实施例来说明本发明的详细方法,但本发明并不局限于上述详细方法,即不意味着本发明必须依赖上述详细方法才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。
序列表
<110> 中国科学院深圳先进技术研究院
<120> 一种含有降解决定子的重组病毒及其制备方法和应用
<130> 2021
<160> 112
<170> PatentIn version 3.3
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Pro Ser Ser Pro Val Gln Thr Thr Pro Leu Ser Gln Ala Val Ala Thr
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His His Gly Lys Gly Phe Phe Gly Ser Gly His Tyr Thr Ala Tyr Cys
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Lys Arg Leu Leu Lys Gly Ser Gln Tyr Gly
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Pro His Lys Arg Leu Leu Lys Gly Ser Gln Tyr Gly
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Asp Cys Val Cys Arg Gly Ser Thr Gly Gly
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Val Ala Pro Arg Ser Arg Asp Glu Arg Gly
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Ala His Gln Leu Gln Ala Leu Arg Arg Gly
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Gly Gly Ser Gly Gly
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Arg Asp Glu Arg Gly
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Ser Arg Val Lys Gly
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Pro Ala Ser Gly Gly
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Gly Ala Glu Ala Gly
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Gly Ser Thr Gly Gly
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Arg Gly Met Gly Gly
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Leu Val His Ala Gly
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Ser Leu Gln Thr Gly
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Pro Val Pro Gly Gly
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Asn Tyr Lys Ser Gly
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Pro Arg Lys Gln Gly
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Gly Cys Ser Gly Gly
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Glu Ala Gln Arg Gly
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Gly Lys Ala Trp Gly
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Pro Ala Gly Gly Gly
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Val Val Leu Tyr Gly
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Leu Thr Leu Lys Gly
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Gly Phe Gln Ser Gly
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Arg Val Gln Trp Gly
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Ser Arg Thr Glu Gly Gln Phe Gly Thr Thr Gln Ser Asn Gly Thr Phe
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Phe Asn Gly Ala Ser Pro Gly Thr Pro Pro Ala Pro Ser Gln His Gln
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Gln Ser Leu Thr Ser Leu
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Tyr Arg Pro Ile Pro Phe Gln Pro Glu Gly Ala Gly Glu Gly Thr Asp
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Glu Asp Lys Ser Asn Arg Ile Gly Asn Asn Gly Leu Arg Leu Asn Asp
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Gly Asn Gly Asn Gly Gln Leu Ala Pro Ser Pro Thr Pro Gln Gly Thr
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Arg Lys Phe Ser Asn Asn Pro Gln Pro Asn Ala Ile Ser Asn Gly Thr
1 5 10 15
Ser Thr Ser Glu Arg Pro Gly Glu Gly Ala Thr Gln Gly Ile Val Glu
20 25 30
Glu Glu Val Leu Gln
35
<210> 94
<211> 37
<212> PRT
<213> 人工序列
<400> 94
Ile Arg Thr Glu Ser Ala Glu Glu Ala Glu Met Ala Ser Val Pro Asn
1 5 10 15
Gly Ser Pro Ser Trp His Pro Gly Ala Ser His Val Val Asn Gly Ala
20 25 30
Ala Gly His Ser Asn
35
<210> 95
<211> 37
<212> PRT
<213> 人工序列
<400> 95
Trp His Glu Ile Glu Met Glu Ser Gly Glu Glu Ala Met Glu Pro Ala
1 5 10 15
Asn Glu Thr Gly Asn Thr Leu Asn Gly Ser Pro Ser Trp His Pro Ser
20 25 30
Pro Ser His Val Ile
35
<210> 96
<211> 37
<212> PRT
<213> 人工序列
<400> 96
Asn Arg Thr Asp Phe Ala Gly Glu Glu Asp Glu Met Asp Gly Val Leu
1 5 10 15
Asn Gly Ser Pro Ser Trp His Ala Ala Thr Ser His Ile Val Asn Gly
20 25 30
Ala Thr Val His Gln
35
<210> 97
<211> 37
<212> PRT
<213> 人工序列
<400> 97
Asn Arg Thr Asp Thr Ala Ala Glu Ala Glu Met Asp Ser Val Leu Asn
1 5 10 15
Gly Ser Pro Ser Trp His Pro Pro Ala Gly His Val Val Asn Gly Ala
20 25 30
Thr Val His Arg Ser
35
<210> 98
<211> 37
<212> PRT
<213> 人工序列
<400> 98
Asn Arg Thr Asp Thr Ala Ala Glu Ala Glu Met Asp Ser Val Leu Asn
1 5 10 15
Gly Ser Pro Ser Trp His Pro Pro Ala Gly His Val Val Asn Gly Ala
20 25 30
Ala Val His Arg Ser
35
<210> 99
<211> 37
<212> PRT
<213> 人工序列
<400> 99
Asn Arg Thr Glu Val Leu Glu Gly Ala Glu Ile Pro Ser Thr Val Asn
1 5 10 15
Gly Ser Pro Ser Trp His Pro Ala Asp Ser Arg Ala Val Ser Gly Ala
20 25 30
Thr Gly His Ser Ser
35
<210> 100
<211> 37
<212> PRT
<213> 人工序列
<400> 100
Asn Arg Thr Glu Ala Pro Glu Gly Thr Glu Leu Pro Ser Thr Val Asn
1 5 10 15
Gly Ser Pro Ser Trp His Pro Ala Asp Ser Arg Ala Gly Ser Gly Ala
20 25 30
Thr Gly His Ser Ser
35
<210> 101
<211> 37
<212> PRT
<213> 人工序列
<400> 101
Asn Arg Thr Glu Ala Pro Glu Gly Thr Glu Ser Glu Arg Glu Thr Pro
1 5 10 15
Ser Ala Ile Asn Gly Asn Pro Ser Trp His Leu Ala Asp Ser Pro Ala
20 25 30
Val Asn Gly Ala Thr
35
<210> 102
<211> 59
<212> PRT
<213> 人工序列
<400> 102
Asn Arg Thr Glu Ala Pro Glu Gly Thr Glu Ser Glu Val Glu Thr Pro
1 5 10 15
Ser Ala Ile Asn Gly Asn Pro Ser Trp Gln Leu Ala Asp Ser Pro Ala
20 25 30
Ile Asn Gly Ala Thr Gly His Ser Ser Ser Leu Asp Ala Arg Glu Val
35 40 45
Ile Pro Met Ala Ala Val Lys Gln Gln Ala Leu
50 55
<210> 103
<211> 37
<212> PRT
<213> 人工序列
<400> 103
Asn Arg Thr Glu Ala Pro Glu Gly Thr Glu Ser Asp Met Glu Thr Pro
1 5 10 15
Ser Ala Ile Asn Gly Asn Ala Ser Trp His Leu Ala Asp Ser Pro Ala
20 25 30
Val Asn Gly Ala Thr
35
<210> 104
<211> 37
<212> PRT
<213> 人工序列
<400> 104
Asn Arg Thr Glu Ala Pro Glu Gly Thr Gly Pro Glu Met Glu Thr Pro
1 5 10 15
Ser Ala Ile Asn Gly Asn Pro Ala Trp His Pro Ala Asp Ser Pro Ala
20 25 30
Val Asn Gly Ala Thr
35
<210> 105
<211> 37
<212> PRT
<213> 人工序列
<400> 105
Asn Arg Thr Glu Ala Pro Glu Gly Thr Glu Ser Asp Met Glu Thr Pro
1 5 10 15
Ser Ala Ile Asn Gly Asn Pro Ser Trp His Leu Ala Asp Ser Pro Ala
20 25 30
Val Asn Gly Ala Thr
35
<210> 106
<211> 37
<212> PRT
<213> 人工序列
<400> 106
Asn Arg Thr Glu Ala Pro Glu Gly Thr Glu Ser Glu Ala Glu Thr Pro
1 5 10 15
Ser Ala Ile Asn Gly Asn Pro Ser Trp His Leu Ala Asp Ser Pro Ala
20 25 30
Val Asn Gly Ala Thr
35
<210> 107
<211> 37
<212> PRT
<213> 人工序列
<400> 107
Asn Arg Thr Glu Ala Pro Glu Gly Thr Glu Ser Glu Met Glu Thr Pro
1 5 10 15
Ser Ala Ile Asn Gly Asn Pro Ser Trp His Leu Ala Asp Ser Pro Pro
20 25 30
Ala Asn Gly Ala Thr
35
<210> 108
<211> 37
<212> PRT
<213> 人工序列
<400> 108
Asn Arg Thr Glu Ala Pro Glu Gly Thr Asp Ser Glu Met Glu Thr Pro
1 5 10 15
Ser Ala Ile Asn Gly Asn Pro Ala Trp His Leu Ala Asp Ser Pro Ala
20 25 30
Val Asn Gly Ala Thr
35
<210> 109
<211> 37
<212> PRT
<213> 人工序列
<400> 109
Asn Arg Thr Glu Ala Pro Glu Gly Thr Asp Ser Glu Met Glu Thr Pro
1 5 10 15
Ser Ala Ile Asn Gly Asn Pro Ser Trp His Leu Ala Asp Ser Pro Val
20 25 30
Val Asn Gly Ala Thr
35
<210> 110
<211> 37
<212> PRT
<213> 人工序列
<400> 110
Asn Arg Thr Glu Ala Pro Glu Gly Thr Glu Ser Glu Met Glu Thr Pro
1 5 10 15
Ser Ala Ile Asn Gly Asn Pro Ser Trp His Leu Ala Asp Ser Pro Ala
20 25 30
Val Asn Gly Ala Thr
35
<210> 111
<211> 21
<212> DNA
<213> 人工序列
<400> 111
gcattggccc cctacattcc a 21
<210> 112
<211> 30
<212> DNA
<213> 人工序列
<400> 112
gatcgccacg attcagggct cgattccatg 30
Claims (10)
1.一种含有降解决定子的重组病毒,其特征在于,所述含有降解决定子的重组病毒的至少一种病毒蛋白中含有至少一个能被宿主细胞的蛋白质降解系统识别的降解决定子;
所述降解决定子包括氨基酸序列、多肽或结构基序中的任意一种或至少两种的组合。
2.根据权利要求1所述的含有降解决定子的重组病毒,其特征在于,所述蛋白质降解系统包括泛素-蛋白酶体系统、溶酶体系统、细胞器水解系统、细胞膜表面水解系统或Caspase蛋白酶系统中的任意一种或至少两种的组合;
优选地,所述降解决定子的位置位于病毒蛋白的C端、N端或中间编码区域中的任意一种或至少两种的组合;
优选地,所述降解决定子包括SEQ ID No.1~110所示的氨基酸序列中的任意一种;
优选地,所述病毒包括流感病毒、艾滋病毒、新冠病毒、手足口病毒、柯萨奇病毒、丙肝病毒、乙肝病毒、甲肝病毒、丁型肝炎病毒、戊型肝炎病毒、人类疱疹病毒、人乳头瘤病毒、单纯疱疹病毒、巨细胞病毒、水痘-带状疱疹病毒、水泡性口炎病毒、呼吸道合胞病毒、登革病毒、埃博拉病毒、马尔堡病毒、寨卡病毒、严重急性呼吸综合征病毒、中东呼吸综合征病毒、轮状病毒、狂犬病毒、麻疹病毒、腺病毒、脊髓灰质炎病毒、埃可病毒、乙型脑炎病毒、森林脑炎病毒、汉坦病毒、新型肠道病毒、风疹病毒、腮腺炎病毒、副流感病毒、蓝耳病毒、猪瘟病毒、口蹄疫病毒、细小病毒、朊病毒、天花病毒、烟草花叶病毒、噬菌体、疱疹病毒、西尼罗河病毒、诺如病毒、人博卡病毒或冠状病毒中的任意一种,优选为流感病毒、艾滋病毒或新冠病毒中的任意一种。
3.一种核酸分子,其特征在于,所述核酸分子编码权利要求1或2所述的含有降解决定子的重组病毒。
4.一种重组载体,其特征在于,所述重组载体含有权利要求3所述的核酸分子;
优选地,所述重组载体表达权利要求1或2所述的含有降解决定子的重组病毒。
5.一种权利要求1或2所述的含有降解决定子的重组病毒的制备方法,其特征在于,所述制备方法包括:
构建蛋白质降解系统缺陷的细胞系;
在病毒蛋白的编码基因中引入编码降解决定子的核苷酸序列;
构建权利要求4所述的重组载体,导入所述的蛋白质降解系统缺陷的细胞系,包装得到所述含有降解决定子的重组病毒;
优选地,所述蛋白质降解系统缺陷包括泛素-蛋白酶体系统缺陷,包括E3连接酶敲除或敲降、蛋白酶体敲除或敲降中的任意一种或至少两种的组合;
优选地,所述细胞系包括哺乳动物细胞系,包括CHO细胞系、Vero细胞系、MDCK细胞系、HEK293T细胞系、MDCK细胞系、A549细胞系、BHK细胞系、BHK-21/BRS细胞系、Sp2/0细胞系、HEK293细胞系、293F细胞系、HeLa细胞系、TZM-bl细胞系、Sup-T1细胞系、MRC-5细胞系、VMK细胞系、LLC-MK2细胞系、HCT-8细胞系、Huh-7细胞系或Caco2细胞系中的任意一种,优选为HEK293T细胞系、MDCK细胞系或A549细胞系中的任意一种;
优选地,所述含有降解决定子的重组病毒在制备过程中加入蛋白质降解系统抑制剂;
优选地,所述蛋白质降解系统抑制剂包括蛋白酶体抑制剂,所述蛋白酶体抑制剂包括MG132、MG-341或乳胞素中的任意一种或至少两种的组合;
优选地,所述制备方法还包括检测所述含有降解决定子的重组病毒在所述蛋白质降解系统缺陷的细胞系以及未经改造的细胞系中的复制能力、安全性以及免疫原性的步骤;
优选地,所述制备方法还包括大规模生产的步骤;
优选地,所述制备方法包括:
(1)构建蛋白质降解系统缺陷的哺乳动物细胞系:
通过基因编辑技术,将细胞系中的蛋白质降解系统的关键元件敲除;
(2)确定引入降解决定子的病毒蛋白以及所述降解决定子的种类、数量和引入位点,在病毒蛋白的编码基因中引入编码降解决定子的核苷酸序列,得到重组病毒序列;
(3)构建重组载体:
将步骤(2)中的重组病毒序列与质粒连接,得到所述重组载体;
(4)重组载体导入所述的蛋白质降解系统缺陷的细胞系,包装得到所述含有降解决定子的重组病毒:
通过反向遗传技术,将步骤(3)中的重组载体与病毒拯救质粒共转染至所述蛋白质降解系统缺陷的细胞系中,加入蛋白质降解系统抑制剂,包装得到所述含有降解决定子的重组病毒;
检测所述含有降解决定子的重组病毒在所述蛋白质降解系统缺陷的细胞系以及未经改造的细胞系中的复制能力、安全性以及免疫原性,并进行大规模生产。
6.一种权利要求1或2所述的含有降解决定子的重组病毒的制备系统,其特征在于,所述制备系统包括蛋白质降解系统缺陷的细胞系、重组载体以及病毒拯救质粒。
7.权利要求1或2所述的含有降解决定子的重组病毒、权利要求3所述的核酸分子、权利要求4所述的重组载体、权利要求5所述的含有降解决定子的重组病毒的制备方法或权利要求6所述的含有降解决定子的重组病毒的制备系统中的任意一种或至少两种的组合在制备疫苗、溶瘤病毒和/或药物中的应用。
8.一种疫苗,其特征在于,所述疫苗含有权利要求1或2所述的含有降解决定子的重组病毒;
优选地,所述疫苗包括减毒活疫苗、复制无能活疫苗、复制可控活疫苗或溶瘤病毒疫苗中的任意一种;
优选地,所述疫苗还包括佐剂和辅料。
9.一种溶瘤病毒,其特征在于,所述溶瘤病毒含有权利要求1或2所述的含有降解决定子的重组病毒。
10.一种药物,其特征在于,所述药物含有权利要求1或2所述的含有降解决定子的重组病毒;
优选地,所述药物还包括药学上可以接受的载体、稀释剂或赋形剂中的任意一种或至少两种的组合。
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PCT/CN2022/110258 WO2023016336A1 (zh) | 2021-08-12 | 2022-08-04 | 一种含有降解决定子的重组病毒及其制备方法和应用 |
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