CN113557240A - 具有提高的稳定性的诺如病毒样颗粒 - Google Patents

具有提高的稳定性的诺如病毒样颗粒 Download PDF

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CN113557240A
CN113557240A CN202080020212.XA CN202080020212A CN113557240A CN 113557240 A CN113557240 A CN 113557240A CN 202080020212 A CN202080020212 A CN 202080020212A CN 113557240 A CN113557240 A CN 113557240A
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F·贾佐夫斯基
A·迪斯纳
F·蒂梅
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Abstract

本发明提供了诺如病毒基因组I VP1衣壳蛋白，其具有其中P结构域中的氨基酸序列区段Ala‑Ala‑Leu‑Leu/Val‑His‑Tyr被修饰为Ala‑Ala‑Leu‑Leu/Val‑Arg/Lys‑Tyr的氨基酸序列。

Description

具有提高的稳定性的诺如病毒样颗粒
技术领域
本发明提供了能够形成VLP(virus-like particle，病毒样颗粒)的诺如病毒(Norovirus，NoV)基因组(genogroup)I VP1衣壳蛋白。本发明进一步提供了含有所述衣壳蛋白的VLP，以及含有所述衣壳蛋白或所述VLP的免疫原性组合物和疫苗。本发明进一步提供了含有所述衣壳蛋白或所述VLP和基因组II或基因组IV衣壳蛋白或VLP的免疫原性组合物和疫苗。本发明进一步提供了组合物和疫苗在预防或治疗受试者，优选人类中的诺如病毒感染中的用途。进一步提供了一种预防或治疗受试者(优选人类)中的诺如病毒感染的方法，包括向受试者施用所述组合物或疫苗。还提供了一种提高诺如病毒基因组I VLP稳定性的方法。
背景技术
诺如病毒是全球肠胃炎爆发的主要原因。他们每年导致6.85亿病例，包括2亿例为5岁或以下的儿童(www.cdc.gov/norovirus/worldwide.html)。迄今为止，市场上还没有诺如病毒疫苗。而且，还没有用于诺如病毒培养的既定规程，这大大减缓了诺如病毒疫苗开发的进展。此外，循环诺如病毒的快速遗传变化率导致新的诺如病毒毒株每2-4年出现一次，导致流行病爆发并使应对这些挑战所需的疫苗和疗法的开发复杂化(de Graaf,M,vanBeek,J,&Koopmans,PG,2016,Nature Rev Microbiol,14:421-433)。很明显，基因组GI和GII代表株是过去二十年中大多数具有GII基因组基因型4(GII.4)流行的爆发的主要原因(Matthews等,2012,Epidemiol.Infect,140:1161-1172)。例如，自2014年以来，东亚已经报告了新的GII.17毒株的出现，且老的GII.4毒株重新出现(Chan等,2015,Nat Commun,doi:10.1038/ncomms10061；Choi等,2017,Food Environ Virol,doi:10.1007/s12560-017-9278-4)。这种不断变化的情况增加了定义有效疫苗组合物的复杂性，因为通常优选的方法是使用多价疫苗。目前的诺如病毒疫苗开发主要依赖于病毒样颗粒(VLP)疫苗的使用(近期综述请参见：Tan,M.&Jiang,X.,2014,Hum.Vaccin Immunother,10:1449-1456；Debbink,K.,Lindesmith,L.&Baric,R.S.,2014,Clin Infect Dis,58:1746-1752；Ramani,S.,Estes,M.K.&Atmar,R.L.,2016,PLoS Pathog,12:e1005334)，其主要在动物细胞培养中生产，尤其是使用杆状病毒表达系统在昆虫细胞中生产(Huhti,L.,等,2013,Arch.Virol.,158:933-942；Koho,T.,等,2012,J.Virol.Methods,181:6-11)。
开发多价疫苗的一个主要问题是，即使是遗传上相对密切相关的诺如病毒分离株仍表现出不同的VLP稳定性概况(Pogan,R,等,2018,Curr Opin Virol,in press；Pogan,R,等,2018 J.Phys.:Condens.Matter,30:064006)。因此，制备由不同VLP的混合物组成的多价疫苗时，由于它们的稳定性概况不同，需要不同的缓冲条件，这对制剂来说是一个严峻的挑战。在一些情况下，这个问题可以通过向VLP混合物中添加明矾作为稳定剂和佐剂来解决(Leroux-Roels,G.,等,2018,The J.Infect.Diseases,217:597-607)。然而，尽管含明矾的疫苗通常具有良好的耐受性，但明矾在体内具有长时间的生物持久性，能够在淋巴器官中迁移并在大脑中积累，这引起了担忧，尤其是对于儿科应用(Petrovsky,N.&Aguilar,JC.,2004,Immunol.&Cell Biol.,82:488-496；Gherardi R.K.,等,2014,Front.Neurol,6:4；Gherardi R.K.,等,2016,Morphologie,100:85-94)。另一种方法是关键残基的氨基酸取代，导致更均质的VLP(Someya,Y.,等,2011,Journal of General Virology,92:2320–2323)并且还可以提高VLP的稳定性(Pogan,R.,等,2018,J.Phys.:Condens.Matter,30:064006)，即使是在更复杂的VLP混合物的制剂中。
与现有技术不同，本发明的一个目的是提供稳定性提高的诺如病毒VLP，尤其是基因组I的VLP，以及此类VLP的衣壳蛋白。另一个目的是提供解决诺如病毒VLP的相容性和稳定性问题的二价或多价免疫原性组合物和疫苗，以允许在不需要稳定剂如明矾的情况下配制疫苗组合物。因此，另一个目的是提供包含具有相当或相似稳定性的不同基因组的NoVVLP的组合物。另一个目的是提供用于纯化、制备和配制VLP，尤其是不同基因组例如基因组I和II的VLP的方案。
发明内容
这些目的通过以下解决：
1.一种诺如病毒基因组I VP1衣壳蛋白，其中所述蛋白的氨基酸序列在对应于SEQID NO：3中Arg472的位置处具有Arg或Lys残基。
2.一种诺如病毒基因组I VP1衣壳蛋白，其具有其中氨基酸序列区段Ala-Ala-Leu-Leu/Val-His-Tyr(SEQ ID NO：57)被修饰为Ala-Ala-Leu-Leu/Val-Arg/Lys-Tyr(SEQID NO：58)的氨基酸序列，其中Leu/Val意指Leu或Val之一，并且Arg/Lys意指Arg或Lys之一。
3.如第2项所述的衣壳蛋白，其中氨基酸序列区段Ala-Ala-Leu-Leu/Val-His-Tyr-Val/Leu/Ile-Asp(SEQ ID NO：59)被修饰为Ala-Ala-Leu-Leu/Val-Arg/Lys-Tyr-Val/Leu/Ile-Asp(SEQ ID NO：60)，其中Val/Leu/Ile意指Val或Leu或Ile之一。
4.如第1至3项中任一项所述的衣壳蛋白，其中所述衣壳蛋白属于基因组I的以下任一基因型：GI.1、GI.2、GI.3、GI.4、GI.5、GI.6、GI.7、GI.8或GI.9。
5.如第1至4项中任一项所述的衣壳蛋白，其中所述衣壳蛋白能够组装形成诺如病毒样颗粒(诺如病毒病毒样颗粒)。
6.如第1至5项中任一项所述的衣壳蛋白，其中所述衣壳蛋白具有如SEQ ID NO：6至21中任一项所定义的氨基酸序列，只不过(except for)对应于SEQ ID NO：3中Arg472位置处的氨基酸残基是Arg或Lys；或所述蛋白具有如SEQ ID NO：3至5中任一项所定义的氨基酸序列。
7.如第1至6项中任一项所述的衣壳蛋白，其中
(i)所述蛋白的氨基酸序列包含SEQ ID NO：6至21中任一项的氨基酸序列的至少480个，优选至少500个连续氨基酸残基或由其组成，只不过对应于SEQ ID NO：3中Arg472位置处的氨基酸残基是Arg或Lys；或
(ii)所述蛋白的氨基酸序列包含至少480个，优选至少500个氨基酸残基或由其组成，并且在这个长度上与SEQ ID NO：6至21中任一项的氨基酸序列的至少500个连续氨基酸残基的序列区段具有至少80％，优选至少85％，更优选至少90％的序列同一性；或
(iii)所述蛋白的氨基酸序列与SEQ ID NO：6至21中任一项的氨基酸序列的至少480个，优选至少500个连续氨基酸残基的序列区段相比具有1至50个，优选1至40个，更优选1至30个缺失、取代、添加或插入；
其中在第(ii)或(iii)项中，对应于SEQ ID NO：3中Arg472位置处的氨基酸残基是Arg或Lys。
8.如第7项所述的衣壳蛋白，其中所述蛋白的氨基酸序列包含至少510个，优选至少520个，更优选至少530个，且最优选至少540个氨基酸残基。
9.如第1至6项中任一项所述的衣壳蛋白，其中
(i')所述蛋白的氨基酸序列包含来自SEQ ID NO：3、4或5的残基43至残基540的氨基酸序列或由其组成；或
(ii')所述蛋白的氨基酸序列与来自SEQ ID NO：3、4或5的残基43至残基540的氨基酸序列具有至少80％，优选至少85％，更优选至少90％的序列同一性；或
(iii')所述蛋白的氨基酸序列与SEQ ID NO：3、4或5的残基43至残基540的氨基酸序列相比具有1至50个，优选1至40个，更优选1至30个缺失、取代、添加或插入；
其中在第(ii')或(iii')项中，对应于SEQ ID NO：3中Arg472位置处的氨基酸，或对应于SEQ ID NO：2中His472位置处的氨基酸是Arg或Lys。
10.如第1至9项中任一项所述的衣壳蛋白，其中
(i”)所述蛋白的氨基酸序列包含SEQ ID NO：3、4或5的氨基酸序列或由其组成；或
(ii”)所述蛋白的氨基酸序列与SEQ ID NO：3、4或5的氨基酸序列具有至少80％，优选至少85％，更优选至少90％的序列同一性；或
(iii”)所述蛋白的氨基酸序列与SEQ ID NO：3、4或5的氨基酸序列相比具有1至50个，优选1至40个，更优选1至30个缺失、取代、添加或插入；
其中在第(ii”)或(iii”)项中，对应于SEQ ID NO：3中Arg472位置处的氨基酸，或对应于SEQ ID NO：2中His472位置处的氨基酸是Arg或Lys。
11.如第1至6项中任一项所述的衣壳蛋白，所述蛋白
(i”')包含含有来自SEQ ID NO：3、4或5的残基43至残基540的氨基酸序列的氨基酸序列的多肽；或
(ii”')包含与来自SEQ ID NO：3、4或5的残基43至残基540的氨基酸序列具有至少80％，优选至少85％，更优选至少90％的序列同一性的氨基酸序列的多肽；或
(iii”')包含与SEQ ID NO：3、4或5的残基43至残基540的氨基酸序列相比具有1至50个，优选1至40个，更优选1至30个缺失、取代、添加或插入的氨基酸序列的多肽；
其中在第(ii”')或(iii”')项中，对应于SEQ ID NO：3中Arg472位置处的氨基酸，或对应于SEQ ID NO：2中His472位置处的氨基酸是Arg或Lys。
12.如第7项的(i)至(iii)中所定义的，如第9项的(i')至(iii')中所定义的，如第10项的(i”)至(iii”)中所定义的，或如第11项的(i”')至(iii”')中所定义的VP1衣壳蛋白。
13.编码第1至12项中任一项所述的衣壳蛋白的核酸分子。
14.包含第1至12项中任一项所述的衣壳蛋白或由其组成的病毒样颗粒(VLP)。
15.如第14项所述的VLP，其中所述VLP包含至少60个，优选至少90个，更优选约180个所述蛋白的分子。
16.包含第1至12项中任一项所定义的衣壳蛋白或第14或15项所述的VLP以及任选的药学上可接受的载体的免疫原性组合物。
17.如第16项所述的免疫原性组合物，其进一步包含诺如病毒基因组II VP1衣壳蛋白，或包含基因组II VP1衣壳蛋白或由其组成的VLP。
18.一种针对诺如病毒感染的疫苗，其包含第16或17项所述的免疫原性组合物。
19.一种针对诺如病毒感染的疫苗，其包含第1至12项中任一项所定义的衣壳蛋白或第14或15项所述的VLP。
20.如第18或19项所述的疫苗，其包含诺如病毒基因组II VP1衣壳蛋白，或含有基因组II VP1衣壳蛋白或由其组成的VLP。
21.如第20项所述的疫苗，其包含质量比为5:1至1:5，优选3:1至1:3，更优选2:1至1:2的基因组I VP1衣壳蛋白和所述基因组II VP1衣壳蛋白。
22.如第18至21项中任一项所述的疫苗，其进一步包含佐剂。
23.如第1至12项中任一项所定义的衣壳蛋白，或如第14或15项所述的VLP，或如第18至22项中任一项所述的疫苗，用于预防或治疗受试者中的诺如病毒感染。
24.一种预防或治疗受试者中的诺如病毒感染的方法，包括向所述受试者施用第1至12项中任一项所定义的衣壳蛋白，或第14或15项所述的VLP，或第18至22项中任一项所述的疫苗一次或多次。
25.一种提高诺如病毒基因组I VLP稳定性的方法，包括将基因组I VP1衣壳蛋白的P结构域中的序列区段Ala-Ala-Leu-Leu/Val-His-Tyr(SEQ ID NO：57)中的His残基替换为Arg或Lys。
26.如第25项所述的方法，包括从编码第1至12项中任一项所定义的衣壳蛋白的核酸分子中表达所述衣壳蛋白，并允许所表达的衣壳蛋白组装以形成VLP。
27.一种生产诺如病毒基因组I VLP的方法，包括从编码第1至12项中任一项所定义的衣壳蛋白的核酸分子中表达所述衣壳蛋白，并允许所表达的衣壳蛋白组装以形成VLP。
发明人已发现，诺如病毒(NoV)基因组I VLP的稳定性通常低于基因组II NoV VLP的稳定性，这对于提供稳定的VLP组合物和含有基因组I VLP的疫苗来说是有问题的。发明人已进一步发现一种通过修饰基因组I VP1衣壳蛋白的氨基酸序列来提高NoV基因组I VLP的稳定性的方法。修饰的VP1衣壳蛋白是本发明的衣壳蛋白或抗原。因此，由本发明的VP1蛋白形成的VLP具有提高的稳定性。提高的稳定性在实施例3中以及由图9和图10中报告的结果得到证实。图9显示通过尺寸排阻色谱提高了本发明VLP的均质性和纯度。图10显示了与原始衣壳蛋白(A)相比，本发明的衣壳蛋白(B)的稳定性趋势和纯度提高。
此外，如果制备含有基因组I和基因组II或IV VLP两者的免疫原性组合物或疫苗，则能够使基因组I VLP和基因组II或IV VLP的稳定性更加相似，由此含有两种类型的VLP的组合物也更稳定，这增加了储存时间，并且允许在本发明疫苗的储存和递送期间使用较不苛刻的储存条件(例如冷藏温度而不是冷冻温度)。
附图说明
图1：来自基因组I诺如病毒的不同毒株的诺如病毒衣壳蛋白VP1的比对。基因组I序列的(S/A/T/V)TA(V/A/T/L)ATA基序和保守性组氨酸残基用方框表示。图1A显示了VP1蛋白N末端部分的诺如病毒GI比对。图1B显示了VP1蛋白C末端部分的诺如病毒GI比对。所示序列是以下“氨基酸序列”部分和电子序列表中给出的完整VP1氨基酸序列的部分序列。
图2：来自基因组I、II和IV的不同毒株的诺如病毒衣壳蛋白VP1的N末端部分的比对。不同基因组的序列由水平线隔开。基因组I的(S/A/T/V)TA(V/A/T/L)ATA基序和基因组II和IV序列中的相应区域用方框表示。所示序列是以下“氨基酸序列”部分和电子序列表中给出的完整VP1氨基酸序列的部分序列。
图3：小图A显示了穿过GI诺如病毒样颗粒结构的切片(PDB:1IHM；白色：伸出结构域(protruding domain)；灰色：壳结构域(shell domain)；黑色：内表面)。小图B显示仅VLP的内表面(PDB：1IHM氨基酸残基29-45)。小图C显示了小图B的一个部分，表明了VLP内表面处的基因组I(S/A/T/V)TA(V/A/T/L)ATA基序的两个保守性苏氨酸残基的构型。在VLP的内表面处用赖氨酸和天冬氨酸残基取代两个苏氨酸残基可导致形成稳定性离子相互作用或盐桥的形成。
图4：来自基因组I、II和IV的不同毒株的诺如病毒衣壳蛋白VP1的C末端部分的比对。不同基因组的序列由水平线隔开。基因组I的保守性组氨酸残基和基因组II和IV序列中的保守性精氨酸残基用方框表示。所示序列是以下“氨基酸序列”部分和电子序列表中给出的完整VP1氨基酸序列的部分序列。
图5：基因组I VP1(PDB:1IHM)的伸出结构域(上部)和壳结构域(下部)部分的结构和基因组II VP1同一区域的理论结构。基因组I中的保守性组氨酸残基和基因组II中的保守性精氨酸残基用箭头表示。基因组II VP1中的精氨酸残基能参与离子相互作用或在伸出结构域和壳结构域之间形成盐桥，并且从而导致基于基因组II VP1的病毒样颗粒的组装和稳定性更好。
图6：诺如病毒GI.4 Chiba VP1野生型、NC和NCHR(图6A)以及NCHRKD和NCHRDK(图6B)的克隆方案。使用IIS型酶Bsal将诺如病毒GI.4 Chiba VP1的序列模块克隆到基于TMV的病毒双运表达载体中。指示了由模块编码的氨基酸序列范围。显示了Bsal限制性消化后模块侧翼的悬突(overhang)。
图7：使用
Figure BDA0003256086200000081
在本氏烟草(Nicotiana benthamiana)中表达野生型和突变型GI.4 Chiba 407 VP1。Laemmli总蛋白提取物在12％聚丙烯酰胺凝胶上分离，并随后用考马斯染色(M：大小参照物；0：未渗入的植物组织；1：GI.4 Chiba 407 VP1野生型；2：具有单个起始甲硫氨酸残基且缺失两个C末端精氨酸残基的GI.4 Chiba 407 VP1；3：具有单个起始甲硫氨酸残基、H472R且缺失两个C末端精氨酸残基的GI.4 Chiba 407 VP1；4：具有单个起始甲硫氨酸残基、T39K、T43D、H472R且缺失两个C末端精氨酸残基的GI.4 Chiba 407VP1；5：具有单个起始甲硫氨酸残基、T39D、T43K、H472R且缺失两个C末端精氨酸残基的GI.4Chiba 407 VP1)。星号表示对应于GI.4 Chiba 407 VP1的信号。
图8：两个独立VLP批次的透射电子显微照片，每个均使用GI.4 Chiba 407 VP1野生型、NC或NCHR版本制备。从GI.4 Chiba 407 VP1的A)野生型、B)NC和C)NCHR版本制备的UranyLess染色的VLP样品的透射电子显微镜术。图像右下方的条形代表500nm。
图9：衍生自GI.4 Chiba 407 VP1 NC和NCHR版本的VLP的SE-HPLC。体积排阻高效液相色谱法分析从GI.4 Chiba 407 VP1的A)NC和B)NCHR版本制备的样品中的VLP形成。黑色箭头表示GI.4 Chiba 407 VP1 NC样品中的第二个、较小的VLP种类。
图10：GI.4 Chiba 407 NC和NCHR版本的稳定性。GI.4 Chiba 407的A)NC和B)NCHR版本的稳定性趋势表示为VLP含量百分比(使用SE-HPLC测量)和VP1纯度百分比(使用毛细管凝胶电泳测量)。
图11：GI.4 Chiba 407 NC和NCHR版本的免疫原性比较。A)同源诺如病毒VP1抗原特异性血清IgG滴定。在第5周在ELISA中分析免疫小鼠的单独、连续稀释的血清样品的抗体水平。显示了在10μg GI.4 Chiba NC或GI.4 Chiba NCHR的VLP剂量后针对GI.4 Chiba诱导的抗体的平均终点滴定曲线。B)使用基于猪胃粘蛋白的阻断测定，测试分组合并和两倍滴定的血清样品针对同源GI.4 Chiba变体VLP的基因型特异性阻断(中和)活性。阻断指数(％)计算为100％-[(含VLP和血清的OD孔/不含血清的OD孔，“最大结合”)x 100％]。
具体实施方式
诺如病毒是无包膜的单链正义RNA病毒。它们属于嵌杯病毒(Calciviridae)科。诺如病毒基因组由三个开放阅读框(ORF)组成。ORF1编码病毒复制所必需的非结构蛋白，而ORF2和ORF3分别编码主要衣壳蛋白VP1和次要结构蛋白VP2。VP1自组装为病毒样颗粒(VLP)，其在形态和抗原性上与天然病毒粒(virion)相似。由于NoV在细胞培养中不可培养，因此对人NoV生物学的大部分理解来自于使用VLP的研究。
诺如病毒有五个不同的基因组(GI、GII、GIII、GIV和GV)，其可以进一步分为基因型。基因型按阿拉伯数字分类和引用，通常遵循罗马数字的基因组指示。诺如病毒的示例是诺沃克病毒(Norwalk virus，GenBank：AF093797.1)、GI.1毒株Aichi/124-89/JP(GenBank：BAA834130)、GI.2毒株Funabashi258/96/JP(GenBank：BAC05516)、马里兰病毒(Marylandvirus，MV)，AY032605)、GI.3毒株Shimizu/KK2866/JP(GenBank：AII73765)、GI.4毒株Chiba407/87/JP(GenBank：BAA82106)、GI.7毒株TCH-060/USA/2003(GenBank：AEQ77282)、GII.3毒株Kashiwa336/00/JP(GenBank：AAZ66774)、GII.4毒株NL/2014/GII.4/Groningen01(GeneBank：CRL46961)、GII.4毒株Sydney/NSW0514/2012/AU(GenBank：AFV08795)、GII.4毒株Aomori2/2006/JP(GenBank：BAG70446)、GII.17毒株JP/2002/Saitama/T87(GenBank：AII73747)、耶拿病毒(Jena virus，JV，AJ01099)、GII.17毒株JP/2013//Saitama 5203(GenBank：BAR63715)、濑户病毒(Seto virus，GenBank：AB031013)、GII.17毒株C142/1978/GUF(GenBank：AGI17592)、GIV.1毒株Ahrenshoop246/DEU/2012(GenBank：AFN61315)。还有许多其他诺如病毒毒株，其完整基因组在公共数据库(www.viprbrc.org)中有注释。
诺如病毒颗粒的关键结构组分是VP1衣壳蛋白。另一种衣壳蛋白是VP2，但它不是组装病毒颗粒或VLP所必需的。NoV颗粒的大小在直径23至40nm之间变化。根据大小，每个病毒颗粒的VP1分子数量通常为60个或180个分子(http://viralzone.expasy.org/194)。
在不存在病毒遗传物质的情况下，VP1衣壳蛋白能组装为大小和形状与病毒颗粒相似，但不含NoV基因组的病毒样颗粒(VLP)。单独的VP1(不存在VP2)就足以形成VLP。因此，在本文中，VLP包含VP1蛋白分子并且可以进一步包含VP2蛋白分子。在优选的实施方案中，本发明的VLP包含VP1衣壳蛋白分子但不包含VP2蛋白分子。
NoV衣壳蛋白VP1具有两个结构域，其中壳(S)结构域对于诺瓦克病毒衣壳蛋白(SEQ ID NO：10)而言由氨基酸残基1-225形成，且伸出(P)结构域由残基225-530形成(Choi等,PNAS 105(2008)9175-9180)，另参见图3。S结构域参与NoV衣壳的二十面体壳的形成，而P结构域参与VP1蛋白的二聚体接触。P结构域的二聚体从二十面体壳伸出。P结构域进一步细分为P1和P2子结构域(sub-domain)。诺沃克病毒VP1衣壳蛋白的氨基酸残基225-278和406-519形成P1子结构域，且残基279-405形成远端P2子结构域(Choi等，同上)。对于SEQ IDNO：3的Chiba蛋白而言，残基1-224构成S结构域，残基224-540构成P结构域，残基224-277和414-531构成P1结构域，且残基278-413构成P2结构域。其他基因组I VP1蛋白例如SEQ IDNO：6至21的那些的S、P、P1和P2结构域可以通过序列比对来确定，以找到形成上述结构域的相应一级序列区段。
本发明的诺如病毒基因组I VP1衣壳蛋白
发明人已发现能够组装为稳定性提高的VLP的NoV基因组I VP1蛋白的变体。本发明因此提供了NoV基因组I VP1蛋白。这些VP1蛋白能够组装为，或者能够被组装为更稳定的VLP。在一个实施方案中，本发明的基因组I VP1蛋白在基因组I VP1蛋白中高度保守的组氨酸残基位置处具有Arg或Lys残基，优选Arg残基。这个位置是SEQ ID NO：1中的第474位或SEQ ID NO：2或3中的第472位。可以通过将至少500个氨基酸的氨基酸序列与SEQ ID NO：3进行比对来鉴定其他基因组I VP1蛋白中的相应位置。因此，本发明提供了NoV基因组I VP1衣壳蛋白，其中所述蛋白的氨基酸序列在对应于SEQ ID NO：2的His472的位置处或在对应于SEQ ID NO：3、4或5中Arg472的位置处具有Arg或Lys残基，优选Arg残基。在此，SEQ IDNO：3中所示的氨基酸序列是鉴定本发明的衣壳蛋白在VP1序列中具有Arg或Lys残基的位置的优选参考序列。
在NoV基因组I VP1蛋白中，对应于SEQ ID NO：1中第474位或SEQ ID NO：2中第472位的His氨基酸是序列区段Ala-Ala-Leu-Leu/Val-His-(SEQ ID NO：61)，优选Ala-Ala-Leu-Leu/Val-His-Tyr(SEQ ID NO：57)的一部分。这个序列区段存在于VP1蛋白的P结构域中，优选VP1蛋白的P1子结构域中。因此，本发明的NoV基因组I VP1衣壳蛋白可以定义如下。其氨基酸序中的P结构域，优选P1结构域中的氨基酸序列区段Ala-Ala-Leu-Leu/Val-His-Tyr(SEQ ID NO：57)被修饰为Ala-Ala-Leu-Leu/Val-Arg/Lys-Tyr(SEQ ID NO：58)，其中Leu/Val意指Leu或Val之一，且Arg-/Lys意指Arg或Lys。优选地，P结构域中的氨基酸序列区段Ala-Ala-Leu-Leu/Val-His-Tyr-Val/Leu/Ile-Asp(SEQ ID NO：59)被修饰为Ala-Ala-Leu-Leu/Val-Arg/Lys-Tyr-Val/Leu/Ile-Asp(SEQ ID NO：60)，其中Val/Leu/Ile意指Val或Leu或Ile之一。所述蛋白的氨基酸序列优选包含至少510个，优选至少520个，更优选至少530个氨基酸残基。
本发明的VP1衣壳蛋白是NoV基因组I蛋白。诺如病毒的分类基于VP1蛋白(Hansman等,Journal of General Virology(2006),87,909–919)。因此，NoV的既定分类可用于确定给定的NoV VP1衣壳蛋白是否是基因组I衣壳蛋白。
本发明的VP1衣壳蛋白的实施方案如下：
(i)所述蛋白的氨基酸序列包含SEQ ID NO：6至21中任一项的氨基酸序列的至少500个连续氨基酸残基或由其组成，只不过对应于SEQ ID NO：3中Arg472位置处的氨基酸残基是Arg或Lys；或
(ii)所述蛋白的氨基酸序列包含至少500个氨基酸残基或由其组成，并且在这个长度上与SEQ ID NO：6至21中任一项的氨基酸序列的至少500个连续氨基酸残基的序列区段具有至少80％，优选至少85％，更优选至少90％，甚至更优选至少95％的序列同一性；或
(iii)所述蛋白的氨基酸序列与SEQ ID NO：6至21中任一项的氨基酸序列的至少500个连续氨基酸残基的序列区段相比具有1至50个，优选1至40个，更优选1至30个，且甚至更优选1至20个缺失、取代、添加或插入；
其中在第(ii)或(iii)项中，对应于SEQ ID NO：3中Arg472(或SEQ ID NO：6的残基469)位置处的氨基酸残基是Arg或Lys，优选Arg。在这些实施方案中，连续氨基酸残基的最小数目优选为510个，更优选为520个，甚至更优选为530个，且最优选为540个氨基酸残基。
本发明的VP1衣壳蛋白的其他实施方案如下：
(i')所述蛋白的氨基酸序列包含SEQ ID NO：3、4或5的残基43至残基540的氨基酸序列或由其组成；或
(ii')所述蛋白的氨基酸序列与SEQ ID NO：3、4或5的残基43至残基540的氨基酸序列具有至少80％，优选至少85％，更优选至少90％，且最优选至少95％的序列同一性；或
(iii')所述蛋白的氨基酸序列与SEQ ID NO：3、4或5的残基43至残基540的氨基酸序列相比具有1至50个，优选1至40个，更优选1至30个，且甚至更优选1至20个缺失、取代、添加或插入；
其中在第(ii')或(iii')项中，对应于SEQ ID NO：3、4或5中Arg472位置处的氨基酸分别是Arg或Lys，优选Arg。
VP1衣壳蛋白的氨基酸序列的更优选实施方案如下：
(i”)所述蛋白的氨基酸序列包含SEQ ID NO：3、4或5的氨基酸序列或由其组成；
(ii”)所述蛋白的氨基酸序列与SEQ ID NO：3、4或5的氨基酸序列具有至少80％，优选至少85％，更优选至少90％，且最优选至少95％的序列同一性；
(iii”)所述蛋白的氨基酸序列与SEQ ID NO：3、4或5的氨基酸序列相比具有1至50个，优选1至40个，更优选1至30个，且甚至更优选1至20个缺失、取代、添加或插入；
其中在第(ii”)或(iii”)项中，对应于SEQ ID NO：3、4或5中Arg472位置处的氨基酸分别是Arg或Lys，优选Arg。
在其他实施方案中，衣壳蛋白定义为
(i”')包含含有SEQ ID NO：3、4或5的残基43至残基540的氨基酸序列的氨基酸序列的多肽分子；或
(ii”')包含与SEQ ID NO：3、4或5的残基43至残基540的氨基酸序列具有至少80％，优选至少85％，更优选至少90％，且最优选至少95％的序列同一性的氨基酸序列的多肽分子；或
(iii”')包含与SEQ ID NO：3、4或5的残基43至残基540的氨基酸序列相比具有1至50个，优选1至40个，更优选1至30个，且甚至更优选1至20个缺失、取代、添加或插入的氨基酸序列的多肽分子；
其中在第(ii”')或(iii”')项中，对应于SEQ ID NO：3、4或5中Arg472位置处的氨基酸分别是Arg或Lys，优选Arg。
本发明所述的基因组I的VP1蛋白，例如上文所定义的那些，可以是以下基因型的任意一个或多个：I.1、I.2、I.3、I.4、I.5、I.6、I.7、I.8或I.9。优选为基因型I.1和I.4。
SEQ ID NO：1至21在本文中也称为“参考序列”。氨基酸序列的“区段”或“部分”是所提及的氨基酸序列的任何给定数目的氨基酸残基的连续氨基酸残基的部分序列(或片段)。氨基酸序列的长度通过组成其的氨基酸残基数目(包括末端残基)来测定。氨基酸序列同一性可以通过可从互联网免费访问的蛋白质序列搜索和比对程序来确定，例如PROTEINBLAST(https://blast.ncbi.nlm.nih.gov/Blast.cgi？PAGE＝Proteins)和ExPASy(http://web.expasy.org/sim/)。可以在http://molbiol-tools.ca/Alignments.htm上找到序列比对工具的综合列表。
本发明的NoV VP1蛋白可以是任意NoV基因组I基因型的VP1蛋白、此类蛋白的片段、蛋白或片段的衍生物、或包含基因组I NoV VP1蛋白或衍生物的氨基酸序列的蛋白，如上文所定义。
VP1蛋白与上述参考序列相比可具有氨基酸缺失、取代、添加或插入。其中，优选缺失、取代和添加。上述此类改变的数量是指所有缺失、取代、添加和插入的总和。术语“插入”是指在参考序列的氨基酸序列内的插入，即排除在C或N末端的添加。术语“添加”意指在参考序列的氨基酸序列的C和/或N末端的添加。缺失可以是参考序列的末端或内部氨基酸残基的缺失。
本发明的VP1蛋白可以具有天然基因组I VP1蛋白的长度，或可以是其片段或其衍生物。然而，本发明的VP1蛋白应该能够组装形成VLP。在此，如上所述，本发明的VP1蛋白优选具有500个氨基酸残基的最小长度以及与天然基因组I VP1蛋白的最小同一性或相似性，也如上所述。VLP是否形成可以通过已建立的方法确定，例如通过电子显微镜(Laue M &Bannert N.,2010,J Applied Microbiol.,109:1159-1168；Harris JR,1999,Methods MolBiol.,117:13-30；Pogan R等,2018,J Phys.:Condens.Matter,30:064006)或通过尺寸排阻色谱法(Effio CL等,2016,Vaccine,34:1259-1267)。
本发明还提供了编码本发明的衣壳蛋白的核酸分子。核酸分子可以是用于在宿主细胞或宿主生物体中表达本发明的蛋白的载体。核酸分子可以包含含有编码本发明的蛋白的核苷酸序列的核酸构建体；核酸分子可以进一步含有用于表达核苷酸序列的遗传元件。关于核酸分子和构建体的进一步信息在下文关于本发明的蛋白的生产的部分中给出。
本发明的病毒样颗粒(VLP)
本发明还提供了包含本发明的VP1衣壳蛋白或由其组成的VLP。VLP是由病毒结构蛋白组成，但不含病毒核酸的颗粒。优选地，VLP是由病毒结构蛋白组成，但不含编码所述VLP的VP1或VP1和VP2的诺如病毒核酸的颗粒。对于诺如病毒而言，VLP由结构蛋白VP1或VP1和VP2蛋白(或本文所述的任何片段或衍生物)组成。本发明的VLP包含本发明的VP1衣壳蛋白或由其组成，例如以上项目(i)至(iii)、项目(i')至(iii')、项目(i”)至(iii”)或(i”')至(iii”')项中任一项中所定义的那些。这些蛋白优选能够形成VLP。
本发明的VLP优选包含至少60个，优选至少90个，更优选约180个VP1蛋白分子。本发明的VLP的所有VP1蛋白分子不一定都是本发明所述的基因组I VP1衣壳蛋白分子。VLP也可能含有其他VP1蛋白分子，优选基因组I的VP1蛋白分子。然而，为了提供本发明的VP1蛋白对VLP的高稳定作用，至少50％、优选至少70％、更优选至少90％的VLP的VP1蛋白分子数目应该是本发明所述的VP1衣壳蛋白分子。在优选的实施方案中，VLP的所有VP1蛋白分子都是本发明所述的VP1衣壳蛋白分子。因此，在一个实施方案中，本发明的VLP包含至少60个，优选至少90个，更优选约180个本发明所述的VP1衣壳蛋白分子。VLP可进一步包含一个或多个VP2蛋白分子，优选基因组I VP2蛋白分子。
本发明的VP1衣壳蛋白能自发组装为本发明的VLP。本发明的VP1蛋白的表达和产生以及VLP的产生在下文进一步解释。
本发明还提供了一种提高NoV基因组I VLP稳定性的方法，包括将基因组I VP1衣壳蛋白的P结构域中的序列区段Ala-Ala-Leu-Leu/Val-His-Tyr(SEQ ID NO：57)中的His残基替换为Arg或Lys。替换通常通过适当改变编码基因组I VP1蛋白的核酸并在合适的表达宿主中表达编码修饰的VP1的核酸来进行(下文进一步描述)。在存在或不存在相同或不同基因组I基因型的其他基因组I VP1蛋白的情况下，优选将表达的VP1蛋白组装为本发明的VLP。
本发明的免疫原性组合物
本发明进一步提供了包含一种或多种NoV抗原的免疫原性组合物，其中至少一种NoV抗原是本发明的基因组I VP1衣壳蛋白。因此，本发明的VP1衣壳蛋白在本文中也称为“本发明的抗原”。免疫原性组合物能够在哺乳动物中产生针对组合物中的一种或多种NoV抗原的免疫应答。免疫原性组合物包含本发明的VP1衣壳蛋白或优选本发明的VLP作为NoV抗原。免疫原性组合物可进一步包含药学上可接受的载体和/或疫苗佐剂。
免疫原性组合物可包含两种或更多种不同的NoV抗原，例如两种或更多种VP1蛋白，以在受试者中同时产生针对多种NoV抗原的免疫应答，例如两种、三种或四种不同的NoV抗原。本发明的免疫原性组合物中使用的NoV抗原取决于使用本发明的疫苗在受试者中应对其实现的免疫的NoV或NoV。随着在哺乳动物中引起感染的诺如病毒(NoV)的进化，免疫原性组合物中使用的抗原可被改变或改造，以在哺乳动物中引起针对在给定时间或在给定季节被认为具有健康风险的NoV的免疫应答。本发明的免疫原性组合物至少含有本发明的VP1衣壳或VLP。因此，它至少含有一种NoV基因组I抗原。免疫原性组合物可含有第二种或另外的NoV基因组抗原，其可以是或可以不是本发明的基因组I VP1抗原；优选地，另外的NoV基因组I抗原也是本发明的基因组I VP1抗原。因此，在一个实施方案中，免疫原性组合物包含两种或更多种基因组I VP1抗原，优选不同基因型，其中两种或更多种基因组I VP1抗原均是本发明的基因组I VP1抗原。
免疫原性组合物可进一步含有来自NoV基因组GII和/或GIV的NoV抗原。优选地，免疫原性组合物另外含有来自NoV基因组II(GII)的NoV抗原。基因组GII和/或GIV的NoV抗原优选为VP1衣壳蛋白。
免疫原性组合物中可含有的基因组GII和/或GIV VP1衣壳蛋白如下：
(a)所述蛋白的氨基酸序列包含SEQ ID NO：22至53中任一项的氨基酸序列的至少500个连续氨基酸残基或由其组成；或
(b)所述蛋白的氨基酸序列包含至少500个氨基酸残基或由其组成，并且在这个长度上与SEQ ID NO：22至53中任一项的氨基酸序列的至少500个连续氨基酸残基的序列区段具有至少80％，优选至少85％，更优选至少90％的序列同一性；或
(c)所述蛋白的氨基酸序列与SEQ ID NO：22至53中任一项的氨基酸序列的至少500个连续氨基酸残基的序列区段相比具有1至50个，优选1至40个，更优选1至30个缺失、取代、添加或插入。
基因组II或IV抗原的VP1衣壳蛋白的其他实施方案如下：
(a')所述蛋白的氨基酸序列包含SEQ ID NO：22至53中任一项的氨基酸序列或由其组成；或
(b')所述蛋白的氨基酸序列与SEQ ID NO：22至53中任一项的氨基酸序列具有至少80％，优选至少85％，更优选至少90％，且最优选至少95％的序列同一性；或
(c')所述蛋白的氨基酸序列与SEQ ID NO：22至53中任一项的氨基酸序列相比具有1至50个，优选1至40个，更优选1至30个，甚至更优选1至20个缺失、取代、添加或插入。
这些GII或GII衣壳蛋白的基因型显示在氨基酸序列部分。
本发明的免疫原性组合物中使用的NoV抗原的基因型没有特别限定。基因组I的优选基因型是以上给出的任意基因组I基因型，优选基因型I.1和I.4，且最优选基因型I.4。基因组II的抗原可以是任意一种或多种以下基因型的抗原：II.1、II.2、II.3、II.4、II.5、II.6、II.7、II.8、II.12、II.13、II.14、II.17、II.21、II.22、II.24或II.25，优选II.4和II.17，更优选II.4。基因组IV的抗原可以是任意一种或多种以下基因型的抗原：IV.1或IV.3。与基因组I抗原相似，其他基因组的抗原优选是VP1蛋白。
关于其中来自NoV基因组I的抗原与来自NoV基因组II的抗原组合的实施方案，可以提及免疫原性组合物的以下示例：
包含基因型I.1的抗原和基因型II.1的抗原的免疫原性组合物；
包含基因型I.1的抗原和基因型II.4的抗原的免疫原性组合物；
包含基因型I.1的抗原和基因型II.6的抗原的免疫原性组合物；
包含基因型I.4的抗原和基因型II.1的抗原的免疫原性组合物；
包含基因型I.4的抗原和基因型II.4的抗原的免疫原性组合物；
包含基因型I.4的抗原和基因型II.17的抗原的免疫原性组合物；
包含基因型I.4的抗原和基因型II.2的抗原的免疫原性组合物；
包含基因型I.1的抗原和基因型II.17的抗原的免疫原性组合物；
包含基因型I.1的抗原和基因型II.2的抗原的免疫原性组合物；
和
包含基因型I.4的抗原和基因型II.6的抗原的免疫原性组合物；
在免疫原性组合物的所有这些实施方案中，组合物至少含有本发明的VP1衣壳蛋白作为基因组I抗原，优选基因组I抗原是本发明的VP1衣壳蛋白。基因组I和II的抗原可以是上文根据SEQ ID NO所定义的那些。在优选的一个实施方案中，其中免疫原性组合物含有基因型I.1或I.4(GI.4)的抗原和基因型II.4(GII.4)或GII.17(GII.17)的抗原。在更优选的一个实施方案中，其中免疫原性组合物含有基因型I.1或I.4的抗原和基因型II.4的抗原。在所有这些实施方案中，免疫原性组合物可进一步含有药学上可接受的载体或疫苗佐剂，如下文进一步解释。
在进一步的实施方案中，免疫原性组合物可以包含来自一个NoV基因组，优选基因组II的两种或更多种抗原。免疫原性组合物可以包含除本发明的基因型I VP1衣壳蛋白之外的基因组II诺如病毒的两种不同抗原，例如基因组II诺如病毒的第一基因型的抗原和基因组II诺如病毒的第二基因型的抗原。例如，组合物可以包含基因型II.1 NoV的抗原(例如VP1蛋白)和基因型II.4 NoV的抗原(例如VP1蛋白)。或者，组合物可以包含基因型II.1NoV的抗原(例如VP1蛋白)和基因型II.17 NoV的抗原(例如VP1蛋白)。或者，组合物可以包含基因型II.4 NoV的抗原(例如VP1蛋白)和基因型II.17 NoV的抗原(例如VP1蛋白)。这些基因组II抗原可以是上文根据SEQ ID NO所定义的那些。
如上所定义的抗原的衍生物被认为是天然抗原所属的基因组和/或基因型的抗原。如果抗原例如VP1蛋白使用这一规则可以属于两个不同的基因组或基因型，则抗原或衍生物属于在天然VP1蛋白例如SEQ ID NO：1至56中任一项的氨基酸序列的全长上与抗原或衍生物具有最相似的序列同一性的基因组或基因型。
本发明的免疫原性组合物优选含有NoV VLP形式的抗原。因此，这个实施方案的免疫原性组合物可以含有上文所定义的本发明的VLP。免疫原性组合物优选含有本发明的VLP和基因组II和/或基因组IV抗原的NoV VLP，优选基因组II抗原的NoV VLP。基因组II和/或基因组IV抗原的VLP优选是上述VP1蛋白和上述基因型的VP1蛋白。
本发明的免疫原性组合物可以含有包含基因组I的NoV抗原(其含有本发明的VP1衣壳蛋白)或由其组成的VLP，以及包含第二基因组(例如基因组II)的NoV抗原或由其组成的VLP。可以提及以下免疫原性组合物作为示例：
一种组合物，其包含含有基因型I.1的抗原或由其组成的VLP和含有基因型II.1的抗原或由其组成的VLP；
一种组合物，其包含含有基因型I.1的抗原或由其组成的VLP和含有基因型II.4的抗原或由其组成的VLP；
一种组合物，其包含含有基因型I.1的抗原或由其组成的VLP和含有基因型II.6的抗原或由其组成的VLP；
一种组合物，其包含含有基因型I.1的抗原或由其组成的VLP和含有基因型II.2的抗原或由其组成的VLP；
一种组合物，其包含含有基因型I.1的抗原或由其组成的VLP和含有基因型II.17的抗原或由其组成的VLP；
一种组合物，其包含含有基因型I.4的抗原或由其组成的VLP和含有基因型II.1的抗原或由其组成的VLP；
一种组合物，其包含含有基因型I.4的抗原或由其组成的VLP和含有基因型II.4的抗原或由其组成的VLP；和
一种组合物，其包含含有基因型I.4的抗原或由其组成的VLP和含有基因型II.6的抗原或由其组成的VLP；
一种组合物，其包含含有基因型I.4的抗原或由其组成的VLP和含有基因型II.2的抗原或由其组成的VLP；
一种组合物，其包含含有基因型I.4的抗原或由其组成的VLP和含有基因型II.17的抗原或由其组成的VLP；
在所有这些实施方案中，包含基因型I的抗原或由其组成的VLP是本发明的VLP，其中所述VLP的VP1蛋白分子的100％可以是本发明的VP1衣壳蛋白。
本发明的免疫原性组合物可以包含质量比范围为1:1至1:6，优选1:1.5至1:5，更优选1:2至1:4的基因组I诺如病毒抗原(优选VP1蛋白)和基因组II诺如病毒抗原(也优选VP1蛋白)。在其他实施方案中，本发明的免疫原性组合物包含质量比范围为5:1至1:5，优选3:1至1:3，且更优选2:1至1:2，且甚至更优选1.5:1至1:1.5的基因组I诺如病毒抗原和基因组II诺如病毒抗原。
在优选的实施方案中，本发明的免疫原性组合物包含质量比范围为5:1至1:5，优选3:1至1:3，且更优选2:1至1:2，且甚至更优选1.5:1至1:1.5的本发明的基因组I VP1衣壳蛋白和基因组II诺如病毒抗原(优选VP1蛋白)。
在进一步优选的实施方案中，本发明的免疫原性组合物包含质量比范围为5:1至1:5，优选3:1至1:3，且更优选2:1至1:2，且甚至更优选1.5:1至1:1.5的本发明的VLP和NoV基因组II VLP。本发明的VLP如上所定义。质量比可以例如通过对VLP进行SDS-PAGE、染色并通过商购读取器读取染色强度来测量。可以在混合VLP和随后以期望比率混合所需VLP之前进行测量。或者，可以使用质谱法例如MALDI-TOF来定量VLP。
免疫原性组合物可以进一步含有所需量和混合比例的合适的载体。对于水性液体组合物，合适的载体可以是水或水溶液，其应处于合适的pH，例如6至8，优选6.7至7.5。除了水之外，水溶液可以根据需要含有缓冲剂、张度剂和/或防腐剂。对于固体组合物，可以将液体组合物干燥或冻干。
缓冲剂的示例是磷酸盐缓冲剂、Tris缓冲剂、乙酸盐缓冲剂和柠檬酸盐缓冲剂。可能的张力剂的示例是氯化钠、蔗糖、甘油和海藻糖。可能的防腐剂的示例是硫柳汞。然而，可以在不添加防腐剂的情况下无菌提供免疫原性组合物。
组合物可以是液体或固体。如果它是液体，它可以是水溶液或水性缓冲液。如果它是固体，则它可以是含有NoV基因组I衣壳蛋白的混合物，优选含有本发明的NoV VLP的混合物。优选的固体形式是冻干形式。
免疫原性组合物是免疫原性的，因为如果将组合物施用给受试者，例如人，它会产生针对其中所含抗原的免疫应答。为了支持受试者中的免疫应答，组合物可含有疫苗佐剂。佐剂的示例是氢氧化铝(明矾，一种公知的疫苗佐剂)或其他铝盐。然而，在一个实施方案中，免疫原性组合物(和疫苗)不含佐剂。在一个优选的实施方案中，组合物(和疫苗)不含明矾或其他铝盐作为佐剂。
为了制备本发明的免疫原性组合物，一种或多种抗原(优选为VLP形式)可以优选地混合在合适的载体或介质中或与合适的载体或介质混合。载体或介质可以是水或水性介质例如溶液。水性介质可以含有缓冲剂以控制pH值，并且可以包含生理盐水和/或其他添加剂。可能的添加剂可以是但不限于蔗糖、甘油、海藻糖。NoV抗原可以储存在水性介质中直至产生本发明的免疫原性组合物或疫苗。如需更长的储存时间，可将其冷冻或冻干。在产生免疫原性组合物后，可以将其进行灭菌，例如通过无菌过滤，并储存。储存可以是以液体形式或冷冻。其也可以在冻干后作为干粉储存。
免疫原性组合物和疫苗的冻干法是本领域公知的。通常在在冻干过程中保护本发明的抗原和/或佐剂并产生具有所需特性的粉末的试剂存在下将组合物冷冻干燥。糖类例如蔗糖、甘露醇、海藻糖或乳糖(以10-200mg/mL的初始浓度存在)通常用于蛋白抗原的冷冻保护和冻干保护，并产生具有所需特性的冻干饼或粉末。冻干组合物可以是更稳定的。也可以使用其他干燥技术，例如喷雾干燥或喷雾冷冻干燥。
本发明的疫苗
本发明的疫苗包含处于适合施用给受试者的形式或处于在施用前能容易地制成适合施用给受试者的形式的本发明的免疫原性组合物。优选地，疫苗含有合适剂型的，优选含有在单次施用时施用给受试者的量的抗原的单个剂量或单位剂量剂型的免疫原性组合物。
适合施用的形式与施用方式有关。例如，疫苗可以是固体制剂，其可以在施用前通过添加预定量的水或水溶液、混悬液或乳液进行重建(reconstitute)。通过这种方式，可以在施用前迅速制备用于施用，例如注射的溶液。或者，疫苗可以是用于鼻内施用给受试者的固体制剂。此外，疫苗可以是用于注射施用的液体制备物，优选水性液体制剂。在后一种情况下，疫苗可以是作为单位剂型的水溶液。
除了免疫原性组合物之外，疫苗还可以包含一种或多种药物赋形剂或载体。赋形剂可以是液体或固体。液体赋形剂包括但不限于水、酒精、盐水和缓冲溶液。其他可能的赋形剂包括但不限于防腐剂和其他添加剂，例如抗微生物剂、抗氧化剂、螯合剂、缓冲物质。本发明的免疫原性组合物本身可以是本发明意义上的疫苗。
疫苗是抗NoV疫苗。它同时是药物组合物。疫苗通常用于预防或治疗受试者中的NoV感染，或用于抑制NoV感染的严重程度。本发明还提供了预防或治疗诺如病毒感染或抑制NoV感染严重性的方法，通常包括向受试者施用本发明的免疫原性组合物或疫苗。其中NoV可以被预防或治疗或其中NoV感染严重性可以被抑制的受试者是哺乳动物，优选人类。在人类中，儿童和成人均可以是预防或治疗NoV感染的受试者。在人类中，儿童优选在生命早期进行免疫接种。16岁以下的人类受试者被认为是儿童。优选地，NoV疫苗用于1至16岁，优选2至14岁，且更优选3至12岁的儿童。
本发明对疫苗的施用途径没有限制。
本发明的疫苗优选肠胃外施用给受试者，例如通过注射。对于注射施用，疫苗可以配制为液体或配制为用于重建形成液体的固体。通过注射的肠胃外施用可以是静脉内、皮内、肌内或皮下施用。优选皮内、肌内或皮下施用，更优选皮内和肌内施用。在一个实施方案中，皮内施用疫苗。在另一个实施方案中，肌内施用疫苗。也可以鼻内施用疫苗。在这种情况下，组合物或疫苗可以是液体，优选水溶液。或者，用于鼻内施用的组合物或疫苗可以是固体形式，例如冻干形式。
当疫苗施用给人类受试者时，或在本发明的方法中，施用NoV抗原的量为10至1000μg，优选30至300μg，更优选55至150μg NoV抗原。如果疫苗含有多于一种的NoV抗原，则这些量与各NoV抗原的量的总和相关。如果疫苗含有基因组I的抗原和基因组II的抗原，则基因组II抗原的量可以等于或高于基因组I抗原的量。基因组II抗原的量在重量方面可以是基因组I抗原量的1.5至6倍，优选2.0至5倍，更优选2.5至4.5倍，且甚至更优选3.0至4.0倍。
疫苗可以以单剂量或多剂量形式包装在含有适合施用的疫苗所需量的容器中。优选为单剂量形式，其中单剂量含有如上给出的NoV抗原的施用量。单剂量形式可包含10至1000μg，优选30至300μg，更优选55至150μg的NoV抗原。如果疫苗含有基因组I的抗原和基因组II的抗原，则这些抗原的比例可以如上一段中所定义。
疫苗可以施用给受试者一次或两次以提高针对NoV感染的免疫力。如果疫苗施用两次，则第二次施用可以在疫苗第一次施用后的2至8周内，优选3至5周内进行。
本发明的疫苗还可以含有针对其他感染性疾病的抗原，以产生不仅针对NoV而且针对其他病毒的免疫保护。例如，疫苗可以包含轮状病毒抗原以产生针对NoV和轮状病毒的保护。
本发明还提供了一种生产针对NoV感染的免疫原性组合物或疫苗的方法，包括在表达宿主中表达本发明的VP1衣壳蛋白，组装表达的VP1衣壳蛋白以形成VLP，以及配制用于施用给受试者的VLP。
NoV抗原的生产
如上所述的NoV抗原可以在不同的生产宿主中进行表达和纯化，所述生产宿主包括哺乳动物细胞、昆虫细胞和植物或植物细胞(见综述：Herbst-Kralovetz,M.,Mason,H.S.&Chen,Q.2010,Exp.Rev.Vaccines,9:299-307)。已经描述了用于使用杆状病毒表达系统的昆虫细胞(Jiang,X.等,1992,J.Virol.,66:6527-6532；Prasad BVV,Hardy D,EstesM.2000,J.Infect.Dis.,181:S317–S321；Huhti,L.,等,2010,Arch.Virol.,155:1855-1858；Koho,T.,等,2012,J.Virol.Methods,181:6-11；Huhti,L.,等,2013,Arch.Virol.,158:933-942；WO2013192604)和用于植物(Santi L.等,2008,Vaccine,26:1846–1854；Lai,H.&Chen,Q.2012,Plant Cell Rep.,31:573-584)的可靠的NoV抗原和NoV VLP纯化方案及其改良版本。关于NoV VLP的生产，也可以考虑EP2601970。
尽管在从昆虫和植物细胞分离的VLP的结构和免疫原性特性上未观察到差异，但VLP生产的优选系统是基于植物的，因为从植物组织分离的抗原或VLP中避免了杆状病毒杂质。此外，与杆状病毒表达系统不同，基于植物的瞬时表达系统易于扩展。可以使用称为
Figure BDA0003256086200000231
的基于植物病毒的表达系统在植物中成功表达NoV抗原基因(Gleba等,2005,Vaccine,23:17-18；Marillonnet等,2005,Nat.Biotechnol.,23:718-723；Gleba等,Curr.Opin.Biotechnol.,2007,18:134-141；Klimyuk,V.,等,2014,Curr.Top.Microbiol.Immunol.,375:127-154)，所述
Figure BDA0003256086200000232
可以在本氏烟草植物中容易地表达病毒VLP(Zahin,M.等,2016,PLoS One,11(8):e0160995)。
更详细地，本发明的衣壳蛋白和包含在免疫原性组合物或疫苗中的其他抗原可以通过在标准表达系统中的蛋白表达的已知方法生产。为了生产衣壳蛋白或抗原，可以将编码其的核苷酸序列在合适的宿主生物中表达。现有技术中已经描述了可用于生产和纯化目标蛋白的方法，并且可以使用任何此类方法。如果使用真核表达系统，则可以在抗原的编码序列中插入一个或多个内含子。
尤其有效的表达方法是在现有技术中也已知的植物表达系统。实现编码本发明的抗原的目的核苷酸序列在植物中表达的可能方式是使用含有编码抗原的核苷酸序列的自我复制(病毒)复制子。植物病毒表达系统已在许多出版物中进行了描述，例如WO2012019660、WO2008028661、WO2006003018、WO2005071090、WO2005049839、WO2006012906、WO02101006、WO2007137788或WO02068664中，并且这些文件中引用了许多其他出版物。将核酸分子例如DNA分子引入植物或植物部分以进行瞬时表达的多种方法是已知的。可使用农杆菌(agrobacteria)例如通过农杆菌渗入法(agroinfiltration)或喷洒农杆菌悬浮液来用核酸分子(载体)或核酸构建体(例如，核酸构建体)转染植物。参考文献参见WO 2012019660、WO 2014187571或WO 2013149726。
在其中需要强表达抗原的实施方案中，含有编码衣壳蛋白的核苷酸序列的核酸构建体可以编码可以在植物细胞中复制以形成病毒载体的复制子的病毒载体。为了进行复制，病毒载体和复制子可以含有可以被存在于植物细胞中的核酸聚合酶，例如从复制子表达的病毒聚合酶识别的复制起点。对于RNA病毒载体(称为“RNA复制子”)而言，复制子可以通过在植物细胞中有活性的启动子的控制下从DNA构建体(在其被引入植物细胞核之后)转录而形成。对于DNA复制子而言，复制子可以通过DNA构建体中编码病毒复制子的序列侧翼的两个重组位点之间的重组而形成，例如WO00/17365和WO 99/22003中所述。如果复制子由DNA构建体编码，则优选RNA复制子。多年来，文献中已经广泛描述了DNA和RNA病毒载体(DNA或RNA复制子)的使用。一些示例是以下专利公开：WO2008028661、WO2007137788、WO2006003018、WO2005071090、WO2005049839、WO02097080、WO02088369、WO02068664。DNA病毒载体的示例是基于双生病毒(geminivirus)的那些。对于本发明，可以优选使用基于植物RNA病毒的病毒载体或复制子，尤其是基于正义单链RNA病毒的那些。因此，病毒复制子可以是正义单链RNA复制子。此类病毒载体的示例是基于烟草花叶病毒(tobacco mosaicvirus，TMV)和马铃薯病毒X(potexvirus X，PVX)的那些。“基于”意指病毒载体使用复制系统例如复制酶和/或参与这些病毒的复制的其他蛋白。基于马铃薯病毒的病毒载体和表达系统描述在EP2061890或WO2008/028661中。
衣壳蛋白可以在多细胞植物或其部分，尤其是高等植物或其部分中表达。可以使用单子叶植物和双子叶植物(作物)植物。可用于表达蛋白的常见植物包括烟草(Nicotianatabacum)和本氏烟草。然而，也可以使用许多其他的植物。
通常，衣壳蛋白可以在植物或植物部分的细胞的细胞溶质中表达。在这种情况下，不把引导目标蛋白至特定区室(compartment)中的信号肽添加到酶中。或者，衣壳蛋白或抗原可以在植物的叶绿体中表达或靶向植物的叶绿体或分泌至细胞外空间；在这些情况下，将N末端前序列(pre-sequence)，例如质体转运肽(plastid transit peptide)或靶向细胞外空间的信号序列添加到作为目的蛋白的衣壳蛋白的N末端或C末端，优选C末端。
在下一步中，从具有表达的抗原的植物中收获含有表达的衣壳蛋白的植物材料(plant material)。植物材料可以例如是叶、根、块茎或种子，或叶、根、块茎或种子的压碎、研磨或粉碎产物。然后可以使用水性缓冲液从植物材料中提取衣壳蛋白。这可以包括将植物材料均质化并且可以通过离心或过滤去除不溶性物质。将包括衣壳蛋白的可溶性组分提取至水性缓冲液中，以在水性缓冲液中产生衣壳蛋白溶液。水性缓冲液可以含有无机或有机酸或其盐，并且可以具有如下对于作为本发明的组合物的水溶液所定义的pH。此外，水性缓冲液可以含有盐和/或巯基化合物。然后可以使用蛋白纯化的标准方法例如色谱法来进一步纯化所获得的抗原制备物中的衣壳蛋白。
衣壳蛋白作为NoV VP1蛋白或衍生物，能够形成VLP。这些VLP通常在用于提取和纯化的水性缓冲液中自发形成。可以例如使用电子显微镜来验证VLP的形成。
如果本发明的免疫原性组合物或疫苗含有两种或更多种NoV抗原，则所述两种或更多种抗原可以单独进行表达和纯化，然后在制备组合物或疫苗时以所需比例混合。还可以在同一植物细胞或植物中共表达两种或更多种衣壳蛋白或抗原，并将它们作为混合物一起纯化。
实施例1和2中描述了用于抗原表达(包括VP1抗原)的构建体工程化、抗原的表达和纯化。图6显示了含有GI.4抗原编码序列的表达载体的生成。使用IIS型限制酶的类似方法可用于将任何目的序列克隆到表达载体中。图7显示了考马斯染色凝胶上的野生型和突变型GI.4 VP1蛋白表达。
实施例
实施例1：用于诺如病毒VP1野生型和突变型版本的表达载体的构建和功能性测试
对应于诺如病毒GI.4 Chiba 407(日本，1987)的VP1衣壳蛋白的序列(GenBank登录号：BAB18267，544个氨基酸残基，SEQ ID No：1，图1)是使用基因合成生成的，并且在侧翼添加IIS型限制酶BsaI位点用于克隆。使用IIS型限制酶BsaI将诺如病毒GI.4 Chiba 407模块克隆到基于TMV的病毒表达载体(
Figure BDA0003256086200000251
系统，见下文)中，所述IIS型限制酶BsaI为每个模块生成不同的定制的悬突，从而允许通过去除这些限制位点来组装最终构建体(Engler,C.,Kandzia,R.&Marillonnet,S.2008,PLoS One,3:e3647)。
对GI.4 Chiba 407 VP1蛋白的分析表明，野生型蛋白序列缺失两个N末端甲硫氨酸残基和两个C末端精氨酸残基，导致理论上的和测定的蛋白质量间存在差异。因此，生成缺失GI.4 Chiba 407 VP1的两个N末端甲硫氨酸和两个C末端精氨酸残基的N末端和C末端的截短的NC变体(SEQ ID No：2)，以提供与理论上的和测定的质量相匹配的变体。相应的诺如病毒GI.4Chiba 407 VP1模块使用侧翼IIS型限制酶BsaI位点通过PCR来产生，并使用这些BsaI位点克隆到基于TMV的
Figure BDA0003256086200000261
病毒表达载体中。SEQ ID No：2的NC版本(与野生型序列相比：N末端ΔMM，C末端ΔRR)用作引入进一步突变的基础。
与GII.4 VLP相比，GI.4 VLP显示出较低的同质性(homogeneity)和较低的稳定性。此外，对于GI.4 Chiba 407野生型和NC版本VP1，抗原相关的高分子量产物以可重现的方式与VLP共同纯化和共同配制。由于GII.4毒株未观察到这种现象，因此进行了比较序列和结构分析。鉴定了基因组II和IV毒株的P1结构域的保守但结构灵活的区域内的单个精氨酸氨基酸残基，其能导致壳结构域和伸出结构域之间形成盐桥，从而改善VP1的构象、多聚化和组装并使所产生的VLP稳定。在基因组I毒株中，这个位置的氨基酸残基是组氨酸。因此，将GI.4 Chiba 407的VP1序列中的这个组氨酸残基替换为精氨酸(野生型中为H474R，且NC变体中为H472R)。相应的诺如病毒GI.4 Chiba 407 VP1 NC版本模块使用侧翼IIS型限制酶BsaI位点来产生通过PCR，并使用这些BsaI位点克隆到基于TMV的
Figure BDA0003256086200000262
病毒表达载体中以产生NCHR版本(SEQ ID No：3)的GI.4 Chiba 407 VP1(与野生型序列相比：N末端ΔMM，H474R，C末端ΔRR)。
为了进一步提高GI.4 Chiba 407 VLP的稳定性和完整性，通过残基的取代来修饰内壳结构域，以允许在VLP的内表面额外形成壳稳定盐桥(shell-stabilizing saltbridge)，即，将N末端STALATA基序修饰为SKALADA或SDALAKA。相应的诺如病毒GI.4 Chiba407 VP1 NCHR版本模块使用侧翼IIS型限制酶BsaI位点通过PCR来产生，并使用这些BsaI位点克隆到基于TMV的
Figure BDA0003256086200000263
病毒表达载体中以产生NCHRKD(SEQ ID No：4)和NCHRDK(SEQ ID No：5)版本的GI.4 Chiba 407 VP1(与野生型序列相比：N末端ΔMM、T41K/D、T45D/K、H474R、C末端ΔRR)。
病毒双运表达载体是基于
Figure BDA0003256086200000264
技术开发的(Gleba,Y.,Klimyuk,V.&Marillonnet,S.,2005,Vaccine,2005,23:2042-2048；Gleba,Y.,Klimyuk,V.&Marillonnet,S.2007,Curr.Opin.Biotechnol.,18:134-141)，其使用来自Tobamo病毒(烟草花叶病毒，TMV)的元件，即来自两种密切相关的植物病毒TVCV(郁金香脉明病毒，turnipvein clearing virus；Lartey,R.T.,Lane,L.C.&Melcher,U.1994,Arch.Virol.,138:287-298；Lartey,R.T.,Voss,T.C.&Melcher,U.1995,Gene,166:331-332)和crTMV(感染十字花科植物烟草病毒，crucifer-infecting tobamovirus；Dorokhov,Y.L.,Ivanov,P.A.,Novikov,V.K.,等,1994,FEBS Lett.,350:5-8)的cDNA。所产生的载体称为“基于TMV的”，因为这两种亲本病毒均是烟草病毒，并且与公知的烟草花叶病毒(TMV)相关。所有三种病毒(TVCV、crTMV和TMV)均是正链RNA病毒，并且具有相同的整体结构和复制模式。基本上，病毒编码RNA依赖的RNA聚合酶(RNA-dependent RNA polymerase，RdRP)、运动蛋白(MovementProtein，MP)和外壳蛋白(Coat Protein，CP)。RdRP复制完整的病毒RNA转录物(基因组RNA)以及表达其他两种病毒蛋白MP和CP所需的两种亚基因组RNA(sgRNA)。MP是被渗入的叶片内的病毒基因组RNA的短距离细胞间运动所必需的。CP是形成病毒颗粒和通过维管系统从叶到叶的长距离全身运动所必需的。病毒颗粒的形成不是细胞间运动所必需的。因此，从病毒载体中去除CP并替换为目的基因。因此，病毒载体不能产生病毒颗粒，并且目的基因以更高的水平表达。除了病毒蛋白基因和目的基因之外，病毒载体还含有复制所必需的5'和3'非翻译(5'ntr和3'ntr)病毒序列(Marillonnet,S.,Giritch,A.,Gils,M.等,2004,Proc.Natl.Acad.Sci.U S A.,101:6852-7)。
为了在植物细胞中有效表达基于TMV的病毒载体，将病毒载体的cDNA在植物启动子和植物终止子(Act2和nos)之间克隆(Marillonnet,S.,Giritch,A.,Gils,M.等,2004,Proc.Natl.Acad.Sci.U S A.,101:6852-6857)并在RdRP和MP序列内添加植物内含子(Marillonnet,S.,Thoeringer,C.,Kandzia,R.等,2005,Nat.Biotechnol.,23:718-723)。为了将基于TMV的病毒载体有效递送至植物细胞，我们使用根癌农杆菌(Agrobacteriumtumefaciens)。因此，将完整的病毒载体(植物启动子、具有目的基因的基于TMV的病毒载体序列、植物终止子)在双运载体的T-DNA左右边界之间克隆。双运载体的元件是用于在农杆菌中进行质粒复制的pVS1起点(Hajdukiewicz,P.,Svab,Z.&Maliga,P.,1994,Plant MolBiol.,25:989-994)、用于在大肠杆菌中进行质粒复制的co/E1起点、nptIII卡那霉素(kanamycin)抗生素抗性基因(Frisch,D.A.,Harris-Haller,L.W.,Yokubaitis,N.T.等,1995,Plant Mol.Biol.,27:405-409)和界定转移至植物细胞的DNA的末端的T-DNA左右边界(Frisch,D.A.,Harris-Haller,L.W.,Yokubaitis,N.T.等,1995,Plant Mol.Biol.,27:405-409)。为了促进蓝/白选择，将从pUC19扩增的lacZα盒插入到两个BsaI限制性位点之间，这允许目的基因的无缝框内克隆。因此，在病毒载体的初始构建过程中，去除了所有天然存在的BsaI识别位点以便轻松且稳健地克隆目的基因。
为了对重组蛋白的表达进行功能性测试，使所选的带有基于TMV的表达载体的农杆菌(Agrobacterium)菌株在液体LBS培养基中生长，所述液体LBS培养基用大豆蛋白胨(Duchefa Biochemie,Haarlem,The Netherlands)代替胰蛋白胨，并补充有50mg/mL利福平(rifampicin)和50mg/mL卡那霉素。农杆菌培养物在28℃下生长，直至OD600达到2至4。通过将农杆菌培养物在渗入缓冲液(infiltration buffer)(10mM MES，pH 5.5，10mM MgSO4)中稀释至规定的细胞浓度(相当于OD600为2.0的培养物的1000倍稀释)来制备渗入溶液(infiltration solution)。
将在受控和标准化条件下生长6-8周的本氏烟草植物的叶子使用无针头注射器用农杆菌渗入溶液渗入，然后在温室中保持约7天以表达和积累重组蛋白。然后收获植物叶材料，在液氮中研磨成细粉，并使用Laemmli缓冲液提取蛋白。蛋白提取物通过SDS-聚丙烯酰胺凝胶电泳进行分析，且蛋白通过考马斯染色显现。
实施例2：从植物材料中纯化诺如病毒VLP
如下所述地纯化诺如病毒VP1 VLP。用携带基于TMV的组装的
Figure BDA0003256086200000281
载体的稀释的根癌农杆菌培养物来真空渗入(80-100mbar，3-4分钟)五周龄的本氏烟草植物(Gleba等,2005,Vaccine,23:17-18；Marillonnet等,2005,Nat.Biotechnol.,23:718-723；Gleba等,Curr.Opin.Biotechnol.,2007,18:134-141；Klimyuk,V.,等,2014,Curr.Top.Microbiol.Immunol.,375:127-154)，所述
Figure BDA0003256086200000282
载体允许在本氏烟草植物中容易地表达病毒VLP(Zahin,M.等,2016,PLoS One,11(8):e0160995)。渗入后6-14天收获植物材料。渗入后7-8天的收获时间点导致最高的表达水平。
将绿色生物质(green biomass)在两体积的中性缓冲液(即，15g生物质和30mL100mM Tris、5mM Na2S2O5 pH 7.5)存在下均质化。为了澄清，将植物匀浆以15.000xg离心20分钟。所得提取物通过使用
Figure BDA0003256086200000283
玻璃纤维过滤器(AP25)进行过滤以进一步澄清。
通过超速离心(150.000xg 90分钟)来沉淀高分子量组分。将沉淀物悬浮于1mL20mM组氨酸、137mM NaCl pH 6.0中，并通过15.000xg离心20分钟进行澄清。将含有VLP的上清液置于30％蔗糖垫(在20mM组氨酸、137mM NaCl pH 6.5中)的顶部。以150.000xg进行超速离心90分钟。将所得沉淀物重悬于20mM组氨酸、137mM NaCl pH 6.5中。
实施例3：纯化的VP1 VLP的表征
透射电子显微镜术(TEM)
通过透射电子显微镜术来监测组装的VLP的存在。拍摄TEM显微照片以观察纯化VLP的大小、分散性(dispersity)和二十面体形态。
通过使用单液滴负染色技术(J.Robbin Harris,Methods in Molecular Biology117:Electron Microscopy Methods and Protocols chapter S.13–30)来制备样品。使用预涂覆网格(Formvar-Carbon,Cu 200目,FCF200-Cu-25,Science Services GmbH,Munich,德国)作为支撑膜，并使用UranyLess(E22409,Science Services GmbH,Munich,德国)作为对比溶液(contrast solution)。将10μl的每个样品应用到网格上并温育10分钟。通过将涂覆侧与超纯水滴接触5秒来洗涤网格表面。用滤纸去除多余的水。用即用型UranyLess将VLP染色两次，每次1分钟。干燥过夜后，用在80kV下操作的EM 900透射电子显微镜(Carl ZeissMicroscopy,Oberkochen,德国)观察网格。用Variospeed SSCCD相机SM-1k-120(
Figure BDA0003256086200000291
Moorenweis,德国)使用iTEM成像软件(EMSIS GmbH,Muenster,德国)拍摄显微照片。
[参考文献]J.Robbin Harris:Negative staining of thinly spreadbiological particulates,Methods in Molecular Biology 117:Electron MicroscopyMethods and Protocols chapter S.13-30
尺寸排阻高效液相色谱(SE-HPLC)
VLP的形成、相对含量和大小(摩尔质量和半径)通过尺寸排阻高效液相色谱(SE-HPLC)进行紫外(UV)、光散射(LS)和折射率(RI)检测来确认。
SE-HPLC分析在Agilent 1200系列HPLC系统(Agilent TechnologiesDeutschland GmbH,Waldbronn,德国)上进行。HPLC由G1312A二元泵、G1379B微真空脱气机(micro vacuum degasser)、G1329A自动液体进样器(automatic liquid sampler)、G1330B自动液体进样调温器(automatic liquid sampler thermostat)、G1316A调温器柱室(thermostated column compartment)和G1314C可变波长检测器组成。具有准弹性光散射动态光散射模块(QELS-DLS(quasi-elastic light scattering dynamic lightscattering)检测器)的Wyatt Technology Europe GmbH仪器miniDAWN TREOS激光光度计和Optilab rEX折射计与SE-HPLC系统串联结合。
最大样品注射体积为100μl，且注射前将样品在自动进样器中调温至23℃。运行在25℃下一式三份地进行。通过使用TSKgel PWxl保护柱(40x6mm，12μm粒径，混合孔径，Tosoh)和TSKgel G6000 PWxl分析柱(300x7.8mm，13μm粒径，
Figure BDA0003256086200000301
孔径，TosohBioscience，Stuttgart，德国)一同作为固定相，并且25mM磷酸氢二钠/125mM氯化钠/1mM氯化钠(pH7.4)作为SE-HPLC洗脱液(流动相)，以0.8ml/min的流速来分离VLP。
SE-HPLC系统控制和用于VLP含量测定的来自UV信号的峰积分是使用软件ChemStation(B.04.03版本，Agilent)完成的。下游连接的Wyatt检测器由程序ASTRA(第5版，Wyatt)控制，并用于通过多角度光散射(MALS)、动态光散射(DLS)和折光率(RI)检测测量尺寸将VLP特征化。VLP的摩尔质量和半径的数据分析和计算也是用ASTRA的程序工具和模型来完成的。
毛细管凝胶电泳(CGE)
对于VP1的纯度测试，在Agilent 2100生物分析仪(Agilent TechnologiesDeutschland GmbH；Waldbronn,德国)组合Agilent Protein 230试剂盒(大小范围：14-230kDa)和2100 Expert Software(Kuschel,M.,等2002,J Biomol Tech 13(3):172-178)上进行芯片上CGE分析(CGE-on-a-chip analysis)。所有试剂和芯片均根据制造商的说明来制备。将用于蛋白分离的凝胶染料混合物移液至芯片上的指定库(reservoir)中，并使用芯片启动站(chip priming station)压入微流体通道。
将4μl的每个VLP样品与2μl样品缓冲液混合并在95℃下加热5分钟。用于还原条件的样品缓冲液包含十二烷硫酸锂、两个内标准和作为还原剂的3.5％(v/v)的1M DTT。向每个样品-缓冲液混合物中添加84μl水后，将6μl的每个样品与蛋白标准分子量一起上样到芯片上。芯片运行结果以凝胶样图像、电泳图并以表格形式显示。电泳图的峰基线调整和峰积分是自动完成的，并且如有必要，可根据具体情况手动调整峰基线。目的产物(完全VP1外壳蛋白)和产物相关物质(N末端截短的VP1)的蛋白峰是可以识别的，并且通过分别比较以秒为单位的迁移时间或以kDa为单位的蛋白大小可以与产品或工艺相关的杂质清楚地区分开。
[参考文献]Kuschel,M.,T.Neumann,等(2002)."Use of lab-on-a-chiptechnology for protein sizing and quantitation."J Biomol Tech 13(3):172-178.
结果
H472R氨基酸取代显著改变了VLP组装并提高了VLP同质性。在试验性规模生产的测试批次中检测到单一、高度同质的VLP产物。
SE-HPLC：与之前的Chi和Chi_NC制备物(75-85％)相比，Chi_NCHR显示出远远更高的VLP含量和纯度(95.0％)
CGE，还原：Chi_NCHR的VP1降解保持在相同水平(80-85％)，与Chi_NC制备物相比没有提高
TEM：无显著变化，可能Chi_NCHR的伸出结构域比Chi_NC-VLP或Chi-VLP的更明显
实施例4
使用肌内(IM)递送途径的纯化的GI.4 Chiba NC(野生型)和GI.4 Chiba NCHR突 变版本VP1 VLP在小鼠中免疫原性比较。
在第0周和第3周，以PBS(pH 7.3)IM向BALB/c小鼠施用重组诺如病毒VLP两次。用10μg VLP剂量的GI.4 Chiba VLP、GI.4 Chiba NC(组I)或GI.4 Chiba NCHR(组II)任一，对各组进行免疫。在研究第5周终止所有小鼠。通过基于ELISA的测定来分析体液(抗体)免疫应答。
研究动物
BALB/c Ola/Hsd雌性小鼠(Envigo，荷兰)在环境温度下运送至动物设施。动物在免疫前一周适应环境并在7周龄时进行免疫。健康监测数据总结表随小鼠的运送一起提供。动物设施的工作人员每天监测动物健康(疾病的临床迹象)和福利。所有程序均根据芬兰国家动物实验委员会(Finnish National Animal Experiment Board)的准则进行授权和执行。
免疫程序
小鼠在免疫和相关程序期间吸入异氟醚进行麻醉。在研究开始时对动物进行称重，并用组纹身(group tattoo)和对个体穿耳洞进行标记。使用0.5ml胰岛素注射器(29G x1/2"-0.33 x 12mm)在尾侧紧绷肌中IM施用测试物(50μl体积)。
终止程序和样品收集
在终止时记录动物体重。通过用1mg/kg美托咪定(medetomidine)(
Figure BDA0003256086200000321
1mg/ml，Laboratorios Syva)和75mg/kg克他命(ketamine)(
Figure BDA0003256086200000322
50mg/ml，Pfizer)麻醉小鼠并从腋窝(腋下)区域收集终末全血来终止小鼠。从单独收集的全血样品中分离血清并储存在-20℃下直至使用。
体液免疫应答测定
血清中抗原特异性IgG的滴度通过酶联免疫吸附测定(ELISA)进行检测，如先前所述(Blazevic等,2011,Vaccine,29:81268133；Tamminen等,2012,Immunology,135:89-99)。使用基于猪胃粘蛋白(PGM)的同源阻断测定(Lindesmith等,2012,J.Virol.,86:873-883)以确定免疫血清阻断NoV VLP与推定的NoV受体人类组织血型抗原(human histo-bloodgroup antigen，HBGA)结合的能力，如先前所述(Uusi-Kerttula等,2014,MicrobesInfect.,16:472-480)。
当用10μg剂量通过IM途径肠胃外施用时，两种GI.4 Chiba VLP均在BALB/c小鼠中诱导可观的基因型特异性血清IgG应答(图11)。在个体小鼠或两个实验组之间没有观察到显著差异(图11)。此外，用10μg GI.4 Chiba VLP免疫两次的两组的合并血清具有同样高的对同源GI.4 Chiba VLP与PGM HBGA受体结合的阻断活性(图11)。综上，当对诱导的免疫应答进行比较时，没有观察到GI.4 Chiba NC(组I)或GI.4 Chiba NCHR(组II)VLP的免疫原性有差异。
氨基酸序列
SEQ ID No:1:诺如病毒GI.4 Chiba 407(日本,1987)衣壳蛋白VP1野生型序列(GenBank登录号:BAB18267)
MMMASKDATPSADGATGAGQLVPEVNTADPIPIDPVAGSSTALATAGQVNLIDPWIINNFVQAPQGEFTISPNNTPGDVLFDLQLGPHLNPFLSHLSQMYNGWVGNMRVRVVLAGNAFTAGKVIICCVPPGFQSRTLSIAQATLFPHVIADVRTLDPVEVPLEDVRNVLYHNNDTQPTMRLLCMLYTPLRTGGASGGTDSFVVAGRVLTCPGPDFNFLFLVPPTVEQKTRPFTVPNIPLKYLSNSRIPNPIEGMSLSPDQTQNVQFQNGRCTIDGQPLGTTPVSVSQLCKFRGRITSGQRVLNLTELDGSPFMAFAAPAPAGFPDLGSCDWHIEMSKIPNSSTQNNPIVTNSVKPNSQQFVPHLSSITLDENVSSGGDYIGTIQWTSPPSDSGGANTNFWKIPDYGSSLAEASQLAPAVYPPGFNEVIVYFMASIPGPNQSGSPNLVPCLLPQEYITHFISEQAPIQGEAALLHYVDPDTNRNLGEFKLYPGGYLTCVPNSSSTGPQQLPLDGVFVFASWVSRFYQLKPVGTAGPARGRLGVRR
SEQ ID No:2:诺如病毒GI.4 Chiba 407(日本,1987)衣壳蛋白VP1序列，其具有单个起始密码子且缺失两个C末端精氨酸残基
MASKDATPSADGATGAGQLVPEVNTADPIPIDPVAGSSTALATAGQVNLIDPWIINNFVQAPQGEFTISPNNTPGDVLFDLQLGPHLNPFLSHLSQMYNGWVGNMRVRVVLAGNAFTAGKVIICCVPPGFQSRTLSIAQATLFPHVIADVRTLDPVEVPLEDVRNVLYHNNDTQPTMRLLCMLYTPLRTGGASGGTDSFVVAGRVLTCPGPDFNFLFLVPPTVEQKTRPFTVPNIPLKYLSNSRIPNPIEGMSLSPDQTQNVQFQNGRCTIDGQPLGTTPVSVSQLCKFRGRITSGQRVLNLTELDGSPFMAFAAPAPAGFPDLGSCDWHIEMSKIPNSSTQNNPIVTNSVKPNSQQFVPHLSSITLDENVSSGGDYIGTIQWTSPPSDSGGANTNFWKIPDYGSSLAEASQLAPAVYPPGFNEVIVYFMASIPGPNQSGSPNLVPCLLPQEYITHFISEQAPIQGEAALLHYVDPDTNRNLGEFKLYPGGYLTCVPNSSSTGPQQLPLDGVFVFASWVSRFYQLKPVGTAGPARGRLGV
SEQ ID No:3:诺如病毒GI.4 Chiba 407(日本,1987)衣壳蛋白VP1序列，其具有单个起始密码子、缺失两个C末端精氨酸残基且具有H472R突变
MASKDATPSADGATGAGQLVPEVNTADPIPIDPVAGSSTALATAGQVNLIDPWIINNFVQAPQGEFTISPNNTPGDVLFDLQLGPHLNPFLSHLSQMYNGWVGNMRVRVVLAGNAFTAGKVIICCVPPGFQSRTLSIAQATLFPHVIADVRTLDPVEVPLEDVRNVLYHNNDTQPTMRLLCMLYTPLRTGGASGGTDSFVVAGRVLTCPGPDFNFLFLVPPTVEQKTRPFTVPNIPLKYLSNSRIPNPIEGMSLSPDQTQNVQFQNGRCTIDGQPLGTTPVSVSQLCKFRGRITSGQRVLNLTELDGSPFMAFAAPAPAGFPDLGSCDWHIEMSKIPNSSTQNNPIVTNSVKPNSQQFVPHLSSITLDENVSSGGDYIGTIQWTSPPSDSGGANTNFWKIPDYGSSLAEASQLAPAVYPPGFNEVIVYFMASIPGPNQSGSPNLVPCLLPQEYITHFISEQAPIQGEAALLRYVDPDTNRNLGEFKLYPGGYLTCVPNSSSTGPQQLPLDGVFVFASWVSRFYQLKPVGTAGPARGRLGV
SEQ ID No:4:诺如病毒GI.4 Chiba 407(日本,1987)衣壳蛋白VP1序列，其具有单个起始密码子、缺失两个C末端精氨酸残基且具有T39K、T43D、H472R突变
MASKDATPSADGATGAGQLVPEVNTADPIPIDPVAGSSKALADAGQVNLIDPWIINNFVQAPQGEFTISPNNTPGDVLFDLQLGPHLNPFLSHLSQMYNGWVGNMRVRVVLAGNAFTAGKVIICCVPPGFQSRTLSIAQATLFPHVIADVRTLDPVEVPLEDVRNVLYHNNDTQPTMRLLCMLYTPLRTGGASGGTDSFVVAGRVLTCPGPDFNFLFLVPPTVEQKTRPFTVPNIPLKYLSNSRIPNPIEGMSLSPDQTQNVQFQNGRCTIDGQPLGTTPVSVSQLCKFRGRITSGQRVLNLTELDGSPFMAFAAPAPAGFPDLGSCDWHIEMSKIPNSSTQNNPIVTNSVKPNSQQFVPHLSSITLDENVSSGGDYIGTIQWTSPPSDSGGANTNFWKIPDYGSSLAEASQLAPAVYPPGFNEVIVYFMASIPGPNQSGSPNLVPCLLPQEYITHFISEQAPIQGEAALLRYVDPDTNRNLGEFKLYPGGYLTCVPNSSSTGPQQLPLDGVFVFASWVSRFYQLKPVGTAGPARGRLGV
SEQ ID No:5:诺如病毒GI.4 Chiba 407(日本,1987)衣壳蛋白VP1序列，其具有单个起始密码子、缺失两个C末端精氨酸残基且具有T39D、T43K、H472R突变
MASKDATPSADGATGAGQLVPEVNTADPIPIDPVAGSSDALAKAGQVNLIDPWIINNFVQAPQGEFTISPNNTPGDVLFDLQLGPHLNPFLSHLSQMYNGWVGNMRVRVVLAGNAFTAGKVIICCVPPGFQSRTLSIAQATLFPHVIADVRTLDPVEVPLEDVRNVLYHNNDTQPTMRLLCMLYTPLRTGGASGGTDSFVVAGRVLTCPGPDFNFLFLVPPTVEQKTRPFTVPNIPLKYLSNSRIPNPIEGMSLSPDQTQNVQFQNGRCTIDGQPLGTTPVSVSQLCKFRGRITSGQRVLNLTELDGSPFMAFAAPAPAGFPDLGSCDWHIEMSKIPNSSTQNNPIVTNSVKPNSQQFVPHLSSITLDENVSSGGDYIGTIQWTSPPSDSGGANTNFWKIPDYGSSLAEASQLAPAVYPPGFNEVIVYFMASIPGPNQSGSPNLVPCLLPQEYITHFISEQAPIQGEAALLRYVDPDTNRNLGEFKLYPGGYLTCVPNSSSTGPQQLPLDGVFVFASWVSRFYQLKPVGTAGPARGRLGV
SEQ ID No:6:gb:AGJ52175|GI Hu/GI/HuzhouN11/2008/CHN
MMMASKDAPTSPDGASGAGQLVPEANTAEQISMDPVAGASTAVATAGQVNMIDPWIFNNFVQAPQGEFTISPNNTPGDILFDLQLGPHLNPFLAHLSQMYNGWVGNMRVRILLAGNAFTAGKIIICCVPPGFDARILTIAQATLFPHLIADVRTLEPVELPLEDVRNVLYHNSSQPQPTMRLVAMLYTPLRTGGGSGGTDAFVVAGRVLTCPAPDFSFLFLVPPSVEQKTRVFSVPNIPLKDLSNSRVPVPIQGMFMSPDVNQSVQFQNGRCQIDGQLQGTTPVSLSQLCKIRGKTSSNARVLNLSEVDGTPFIPLESPAPVGFPDLGGCDWHVNFSFQTQDRDPSQSVTFATNDASFVPYLGSVSPHNGEGFQAGDIIGSLGWISAPSDNSQFNVWAIPKYGSSLQMSPILLLLCSPRLWEVILYFYSTFPGSGQPSQLQVPCLLPQEFITHFCNEQAPIAGEAALLHYVDPDTGRNLGEFKLYPDGFMTCVPNSVSSGPQTLPINGVFVFVSWVSRFYQLKPVGTASAARRLGLRRI
SEQ ID No:7:gb:AFN06736|GI Hu/GI/E8/UG/1976
MMMASKDAPTNMDGTSGAGQLVPEANTAEPISMDPVAGAATAVATAGQINMIDPWIMSNFVQAPQGEFTVSPNNTPGDVLFDLQLGPQLNPFLAHLAQMYNGWVGNMRVKVLLAGNAFTAGKIIISCIPPGFTSQNISIAQMTMFPHVIADVRVLEPIEIPLEDVRNVLFHTNDNRPTMRLVCMLYTPLRANGSSSGTDPFVIAGRVLTCPDSNFSFLFLVPPNVEQKTRPFSVPNIPLNTLSNSRVPSLIKSMTISRDQNQIIQFQNGRVTLDGQLQGTTPTSVSQLCKIRGTTYHATGGNGINLTELNGEPYHAFESPAPIGFPDLGGCDWHLTATPTQAFNDGAKVVRLSVTQGAAFAPHLGTIHYTTTDHDYDPNTSIICTLDWLSQTTGQNNVDPWQIPTYGSTLTEAAQLAPPIFPPGFGETLVFFLSDFPISNGKNGLSVPCTLPQEFVTHFVNEQAPIRGEAALLHYVDPDTHRNLGEFKLYPEGFMTCVPNTSGGGPQTLPINGVFVFVSWVSRFYQLKPVGTAGAARRLGIRRS
SEQ ID No:8:gb:AUF81820|GI Hu/ETH/2016/P15
MMMASKDAPTNMDGTSGAGQLVPEANTAEPISMEPVAGAATAAATAGQVNMIDPWIMNNYVQAPQGEFTISPNNTPGDILFDLQLGPHLNPFLSHLAQMYNGWVGNMKVKVLLAGNAFTAGKIIISCIPPGFAAQNISIAQATMFPHVIADVRVLEPIEIPLEDVRNVLFHNNDNTPTMRLVCMLYTPLRASGSSSGTDPFVIAGRVLTCPSPDFSFLFLVPPNVEQKTKPFSVPNLPLNILSSSRVPSLIKSMMISRDHGQMVQFQNGRVTLDGQLQGTTPTSASQLCKIRGSVFHANGGNGYNLTELDGSPYHAFESPAPIGFPDLGECDWHMEASPTIQFDTGDVIKQINVKQESAFAPHLGTVQADGLDGVSANTNMIAKLGWVSPVSDGHRRDVDPWVIPRYGSTLTEAAQLAPPIYPPGFGEAIVFFMSDFPIAHGTNGLSVPCTIPQEFVTHFVNEQAPTRGEAALLHYLDPDTHRNLGEFKLYPDGFMTCVPNSSGSGPQTLPINGVFVFVSWVSRFYQLKPVGTAGPARRLGIRRS
SEQ ID No:9:gb:BAV21674|GI Hu/GI/46-2/Tokyo/1977/JPN
MMMASKDAPSNMDGTSGAGQLVPEANTAEPINMESVVGAATATATAGQVNLIDPWIMNNYVQAPQGEFTISPNNTPGDVLFDLQLGPHLNPFLSHLSRMYNGWVGNMKVRVMLAGNAFSAGKIIICCIPPGFTSQSISIAQATMFPHVIADVRVLEPIDVPLDDVRNVLFHNNDNAQTMRLLCMLYTPLRTGASSSGSDPFVIAGRVLTCPTQDFNFLFLVPPDVEQKTKPFSVPNIPLNLMSNSRVPALIDGMTVSSDQNQVVQFQNGRVTLDGQLQGTTAVSASCVAKIRGRIFSNASHYGINLTEVDGTQYHAFDSPAPLGFPDFGNCDWHVTGTKASQGDLQTDNPTISGTIKSYESSFAPHLGTVRIEGDDNELARFNGKDVLLNLTWFSQRNGSQLNLWTIPSYGSNLTEASQLAPPIYPPGFGEAIVYFTSTFPAISRPSVPCTMPQEFVSHFVNEQAPTRGEAALLHYLDPDTHRNLGEFKMYPEGFFTCVPNAGGSGPQTLPINGVFVFVSWVSRYYQLKPVGTVGMTRRLGLMKQ
SEQ ID No:10:gb:NP_056821GI.1 GI/Human/United States/Norwalk/1968
MMMASKDATSSVDGASGAGQLVPEVNASDPLAMDPVAGSSTAVATAGQVNPIDPWIINNFVQAPQGEFTISPNNTPGDVLFDLSLGPHLNPFLLHLSQMYNGWVGNMRVRIMLAGNAFTAGKIIVSCIPPGFGSHNLTIAQATLFPHVIADVRTLDPIEVPLEDVRNVLFHNNDRNQQTMRLVCMLYTPLRTGGGTGDSFVVAGRVMTCPSPDFNFLFLVPPTVEQKTRPFTLPNLPLSSLSNSRAPLPISSMGISPDNVQSVQFQNGRCTLDGRLVGTTPVSLSHVAKIRGTSNGTVINLTELDGTPFHPFEGPAPIGFPDLGGCDWHINMTQFGHSSQTQYDVDTTPDTFVPHLGSIQANGIGSGNYVGVLSWISPPSHPSGSQVDLWKIPNYGSSITEATHLAPSVYPPGFGEVLVFFMSKMPGPGAYNLPCLLPQEYISHLASEQAPTVGEAALLHYVDPDTGRNLGEFKAYPDGFLTCVPNGASSGPQQLPINGVFVFVSWVSRFYQLKPVGTASSARGRLGLRR
SEQ ID No:11:gb:ARC53064|GI.2 Hu/GI.2/Kaohsiung/16-AF-2/2016/TW
MMMASKDAPQSADGASGAGQLVPEVNTADPLPMEPVAGPTTAVATAGQVNMIDPWIVNNFVQSPQGEFTISPNNTPGDILFDLQLGPHLNPFLSHLSQMYNGWVGNMRVRILLAGNAFSAGKIIVCCVPPGFTSSSLTIAQATLFPHVIADVRTLEPIEMPLEDVRNVLYHTNDNQPTMRLVCMLYTPLRTGGGSGSSDSFVVAGRVLTAPSSDFSFLFLVPPTIEQKTRAFTVPNIPLQTLSNSRFPSLIQGMILSPDASQVVQFQNGRCLIDGQLLGTTPATSGQLFRVRGKINQGARTLNLTEVDGKPFMAFDSPAPVGFPDFGKCDWHMRISKTPNNTSSGDPMRSVSVQTNVQGFVPHLGSIQFDEVFNHPTGDYIGTIEWISQPSTPPGTDINLWEIPDYGSSLSQAANLAPPVFPPGFGEALVYFVSAFPGPNNRSAPNDVPCLLPQEYITHFVSEQAPTMGDAALLHYVDPDTNRNLGEFKLYPGGYLTCVPNGVGAGPQQLPLNGVFLFVSWVSRFYQLKPVGTASTARGRLGVRRI
SEQ ID No:12:gb:AFN06739|GI.3 Hu/GI.3/B8/CF/1977
MMMASKDAPTNMDGTSGAGQLVPEANTAEPISMEPVAGAATAAATAGQVNMIDPWIMNNYVQAPQGEFTISPNNTPGDILFDLQLGPHLNPFLSHLAQMYNGWVGNMKVKVLLAGNAFTAGKIIISCIPPGFASQNISIAQATMFPHVIADVRVLEPIEVPLEDVRNVLFHNNDNTPTMRLVCMLYTPLRASGSSSGTDPFVIAGRVLTCPSPDFSFLFLVPPNVEQKTKPFSVPNLPLNVLSNSRVPSLIKSMMVSQDHGQMVQFQNGRVTLDGQLQGTTPTSASQLCKMRGTVYHASGGQGLNLTEIDGTPYHAFESPAPIGFPDIGDSDWHINASPATTFDSGESIKRLDMEQGSSFAPHLGTVHYTNADYPANTDLICSLEWLSPPSGGTPNKVNPWTIPRYGSTLTEAAQLAPPIYPPGFGEAIVFFMSDFPIANGQDGLKVPCTIPQEFVTHFVNEQAPTRGEAALLHYVDPDTHRNLGEFKLYPEGFMTCVPNSSGSGPQTLPINGVFTFVSWVSRFYQLKPVGTTGPVRRLGIRRS
SEQ ID No:13:gb:AOO95034|GI.3 15-EN-3/2015
MMMASKDAPTNMDGTSGAGQLVPEANTAEPISMEPVAGAATAAATAGQVNMIDPWIMNNYVQAPQGEFTISPNNTPGDILFDLQLGPHLNPFLSHLAQMYNGWVGNMKVKVLLAGNAFTAGKIIISCIPPGFASQNISIAQATMFPHVIADVRVLEPIEVPLEDVRNVLFHNNDNSPTMRLVCMLYTPLRASGSSSGTDPFVIAGRVLTCPSPDFSFLFLVPPNVEQKTKPFSVPNLPLNTLSNSRVPSLINAMMISRDHGQMVQFQNGRVTLDGQLQGTTPTSLSQLCKIRGKVFLASGGNGLNLTELDGSAYHAFESPAPIGFPDIGDCDWHMNATATSNFTGSNDEHQILVKQESTFAPHLGHVQADHLPEVANTDLMVSLSWISPVSDQHRRDVDPWVIPRYGSTLTEAAQLAPPIYPPGFGEAIVFFMSDFPVVSGVNGMRIPCTLPQEYVAHFVNEQAPTRGEAALLHYVDPDTHRNLGEFKIYPEGFMTCVPNSSGTGPQTLPINGVFTFVSWVSRFYQLKPVGTAGPARRLGIRRS
SEQ ID No:14:gb:AEY77031|GI.4 Hu/GI.4/S14/2008/LillaEdet/Sweden
MMMASKDATPSADGATGAGQLVPEVNTADPIPIDPVAGSSTALATAGQVNLIDPWIINNFVQAPQGEFTISPNNTPGDVLFDLQLGPHLNPFLSHLSQMYNGWVGNMRVRVVLAGNAFTAGKVIICCVPPGFQSRTLSIAQATLFPHVIADVRTLDPVEVPLEDVRNVLYHNNDTQPTMRLLCMLYTPLRTGGASGGTDSFVVAGRVLTCPGPDFNFLFLVPPTVEQKTRPFTVPNIPLKYLSNSRIPNPIEGMSLSPDQTQNVQFQNGRCTIDGQPLGTTPVSVSQLCKFRGRITSGQRVLNLTELDGSPFMAFAAPAPAGFPDLGSCDWHIEMSKIPNSSTQNNPIVVNSVKPNSQQFVPHLSSITLDDNVSSGGDYIGTIQWTSPPSDSGGANTNFWKIPDYGSSLAEASQLAPAVYPPGFNEVIVYFMASIPGPNQSGSPNLVPCLLPQEYITHFISEQAPIQGEAALLHYVDPDTNRNLGEFKLYPGGYLTCVPNSSSTGPQQLPLDGVFVFASWVSRFYQLKPVGTA
SEQ ID No:15:gb:BAA82106|GI.4 Hu/Chiba407/87/JP
MMMASKDATPSADGATGAGQLVPEVNTADPIPIDPVAGSSTALATAGQVNLIDPWIINNFVQAPQGEFTISPNNTPGDVLFDLQLGPHLNPFLSHLSQMYNGWVGNMRVRVVLAGNAFTAGKVIICCVPPGFQSRTLSIAQATLFPHVIADVRTLDPVEVPLEDVRNVLYHNNDTQPTMRLLCMLYTPLRTGGASGGTDSFVVAGRVLTCPGPDFNFLFLVPPTVEQKTRPFTVPNIPLKYLSNSRIPNPIEGMSLSPDQTQNVQFQNGRCTIDGQPLGTTPVSVSQLCKFRGRITSGQRVLNLTELDGSPFMGFGAPAPAGFPDLGSCDWHIEMSKIPNSSTQNNPIVTNSVKPNSQQFVPHLSSITLDENVSSGGDYIGTIQWTSPPSDSGGANTNFWKIPDYGSSLAEASQLAPAVYPPGFNEVIVYFMASIPGPNQSGSPNLVPCLLPQEYITHFISEQAPIQGEAALLHYVDPDTNRNLGEFKLYPGGYLTCVPNSSSTGPQQLPLDGVFVFASWVSRFYQLKPVGTAGPARGRLGVRR
SEQ ID No:16:gb:AOO95019|GI.5 15-EN-8/2015/GI.5
MMMASKDATPSADGANGAGQLVPEVNNAEPLPLDPVAGASTALATAGQVNMIDPWIFNNFVQAPQGEFTISPNNTPGDILFDLQLGPHLNPFLAHLSQMYNGWVGNMRVRVILAGNAFTAGKVIICCVPPGFQSRTLSIAQATLFPHIIADVRTLEPIEIPLEDVRNTLYHTNDNQPTMRLLCMLYTPLRTGGGSGGTDAFVVAGRVLTSPSPDFNFLFLVPPTVEQKTRPFSVPNIPLQLLSNSRVPNLIQSMVPSPDQAQNVQFQNGRCTTDGQLLGTTPVSVSQILKFRGKVSAGSKVINLTELDGSPFLAFEAPAPTGFPDLGTSDWHIEMSLNSNSQSSGNPILLRDIQPNSSDFVPHLGSVAVTTAIDTAGDYTGTIQWTSQPSNVTPVPDVNFWTIPQYGSNLAEASQLAPVVYPPGFGEAIVYFMSPIPGPNTAHKPNLVPCLLPQEFVTHFVSEQAPSMGEAALVHYVDPDTNRNLGEFKLYPEGFITCVPNGTGPQQLPLNGVFVFASWVSRFYQLKPVGTANSARGRLGVRR
SEQ ID No:17:gb:BAU16307|GI.5 Hu/Jp/2002/GI.5/OC020180
MMMASKDATPSADGANGAGQLVPEVNNAEPLPLDPVAGASTALATAGQVNMIDPWIFNNFVQAPQGEFTISPNNTPGDILFDLQLGPHLNPFLAHLSQMYNGWVGNMRVRVILAGNAFTAGKVIICCVPPGFQSRTLSIAQATLFPHVIADVRTLEPLEIPLEDVRNTLYHNNDSQPTMRLLCMLYTPLRTGGGSGGTDAFVVAGRVLTCPSPDFNFLFLVPPTVEQKTRPFSVPNIPLQNLSNSRVPSLIQSMVLSSDHAQTVQFQNGRCTTDGHLLGTTPVSSGQLMKFRGKVTPGSKVLNLTELDGSPFLAFEPPAPAGFPDLGKCDWHIEMSLYQVNNQDNPIVLRAIEPNSSSFVPHLGSVSFNQNVDAAGDYVCTIQYTSPPSNSHDADVDFWSIPDYGSNLAEASQLAPVVYPPGFGEAIVYFMSRVPGWNRTNRLNLVPCLLPQEFIGHFVSEQAPAIGEAALLHYVDPDTNRNLGEFKLYPEGFITCVPNGTGPQQLPLNGVFVFSSWVSRFYQLKPVGTASSARGRLGIRR
SEQ ID No:18:gb:BAU16303|GI.6 Hu/Jp/2013/GI.6/s130147
MMMASKDVPTSPDGASGAGQLVPEVNTADQISMDPVAGASTAVATAGQVNMIDPWIFNNFVQAPQGEFTISPNNTPGDILFDLQLGPHLNPFLAHLSQMYNGWVGNMRVRILLAGNAFTAGKIIICCVPPGFDARILTIAQATLFPHLIADVRTLEPVELPLEDVRNVLYHNSSQPQPTMRLVAMLYTPLRTGGGSGGTDAFVVAGRVLTCPAPDFSFLFLVPPSVEQKTRVFSVPNIPLKDLSNSRVPTLIQGMFVSPDVNQSVQFQNGRCQIDGQLQGTTPVSLSQLCKIRGKTSSNTRVLNLSEVDGTPFVPLESPAPVGFPDIGGCDWHVGFTFEARDQGPSQNVTFATNDSSFVPYLGSISPHNGDGFHSGDIIGSLDWISAPSDGSALDVWSIPKYGSSLPDVTHLAPAVFPPGFGEVILYFHSKFPGSGPTDKLRVPCLMPQEFITHFCDEQAPIAGEAALLHYVDPDAGRNLGEFKLYPDGFMTCVPNSISSGPQTLPINGVFVFVSWVSRFYQLKPVGTASMARRLGLRRI
SEQ ID No:19:gb:APA31976|GI.7 Hu/USA/2011/GI.P7_GI.7/CS5567
MMMASKDAPSNMDGTSGAGQLVPEVNAAEPLPLEPVVGAATAVATAGQVNLIDPWIMNNFVQAPEGEFTISPNNTPGDILFDLQLGPHLNPFLQHLSQMYNGWVGNMRVRVMLAGNAFTAGKIIICCVPPGFASQNISIGQATMFPHVIADVRVLEPIEIPLDDVRNVLFHTNESRPTMRLLCMLYTPLRAGGASSGTDPFVIAGRVLTCPSPDFNFLFLVPPSVEQKTRQLTVPNIPLNNLANSRVPAMINKMTVSTDQSQVVQFQNGRCTLEGQLLGTTPVSASQVARIRGKVFSTASGKGLNLTELDGTPYHAFESPAPLGFPDIGACDWHVSTFKVDQNLSGDPMSRLDIKQNAPFAPHLGSIEFTSDQEPTGDQLGTLAWVSPSTSGARVDPWKIPSYGSTVTESTHLAPPIFPPGFGEAIVYFMSDFPIVSGNTAQVPCTLPQEFVSHFVEQQAPIRGEAALLHYVDPDTHRNLGEFKLYPDGFITCVPNTGGGPQNLPINGVFVFSSWVSRYYQLKPVGTAGPARRLGVRRV
SEQ ID No:20:gb:AKM20815|GI.8 Hu/CHN/2008/GI.P8_GI.8/Huzhou/N10
MMMASKDAPTNMDGTSGAGQLVPEANTAEPLPIKPVAGAATAVATAGQVNMIDPWIMNNFVQAPQGEFTISPNNTPGDILFDLQLGPHLNPFLAHLSRMYNGWVGNMQVRIMLAGNAFSAGKIIVCCIPPGFSSQSISIAQATMFPHVIADVRVLEPIDVPLDDVRNVLFHNNDNPQTMRLLCMLYTPLRSGGTSSGTDPFVIAGRVLTCPTPDFSFLFLVPPDIEQRTKPFSVPNIPMNLMSNSRVSMLIDGMMVSNDQNQVPQFQNGRVTLDGQLQGTTTVSAACVARMRGRIFNNNGNYGVNLTELDGNPYHAFDSPAPLGFPDFGNCDLHMTFVKINPNELSSGDPSGKVVIRSYDATFAPHLGTVKLENDDELARFVGKEVVLELTWVSNREGATLNLWAVPNYGSSLTQASQLAPPIYPPGFGEAIVYFTSTFPTVSNPKVPCTLPQEFVSHFVNEQAPTRGDAALLHYVDPDTHRNLGEFKMYPEGYMTCVPNAGGGPQTLPINGVFVFISWVSRYYQLKPVGTAGAARRLGLRRS
SEQ ID No:21:gb:APA31982|GI.9 Hu/USA/2016/GI.P9_GI.9/SC6350
MMMASKDATSNMDGTSGAGQLVPENNNTSEPINMEPVAGAVTAAATAGQVNMIDPWIMNNYVQAPQGEFTISPNNTPGDILFDLQLGPHLNPFLAHLSQMYNGWVGNMKVRVVLAGNAFSAGKIIVCCIPPGFSAPNISIAQATMFPHVIADVRVLEPIDIPLDDVRNVLFHNNDNGNQTMRLLCMLYTPLRSGGTSSGTDPFVIAGRVLTCPTPDFNFLFLVPPTVEQKTKQFSVPNLPLNVMSNSRVPSLLNAMVVSPDQAQVVQFQNGRCTLDGQMLGTTTVSASCVARFRGKTFQAPDNRLGINLAEISGEPYHAFESPAPLGFPDFGDGDWHVTATKVTPSQLEANDPVVMGNVQPYNPQFAPHLGTLVVENPTPDNVTTGTDLLFNITWLSNRANNRFNPWVIPNYGSTLTEAAQLAPSIFPPGFGETIVYFNSTFPAVGATTHAAIPCLLPQEFVAHFVNEQAPIRGEAALLHYIDPDTHRNLGEFKIYPEGFVTCVPNVGGTGPQSLPTNGIFVFVSWVSRYYQLKPVGTAGQARRLGFRRV
SEQ ID No:22:gb:AGL98416|GII Hu/GII/T091/TN/1976
MKMASNDANPSDGSAANLVPEVNNEVMALEPVVGAAIAAPVAGQQNVIDPWIRNNFVQAPGGEFTVSPRNAPGEILWSMPLSPELNPYLSHLSRMYNGYAGGFEVQVILAGNAFTAGKIIFAAIPPNFPTDGLSPSQVTMFPHIIVDVRQLEPVLIPLPDVRNNFYHYNQANDSTLKLIAMLYTPLRANNAGDDVFTVSCRVLTRPSPDFDFIFLVPPTVESRTKPFTVPILTVDEMTNSRFPTPLEKLHTGPNNSIVVQPQNGRCTIDGVLLGTTQLSTVNICNFRGSTTRAGQSHAYTMNLVSQNWNNYDPTEEIPAPLGTPDFVGKIVGMLSQTTRENSSTRAHKATVSTGDAHFTPKSGSVLFTTDTDDLQNGQNTRFTPVGVAQDGEPHQNEPQQWRLPNYSGTPGHNVHLAPPVAPTFPGEQLLFFRSTMPGCGGYPNMDLDCLLPQEWVRHFYQEAAPAQSDVALLRFVNPDTGRVLFECKLHKAGYITVSHTGPYDLVIPPNGYFRFDSWVNQFYALAPMGTGTGRRRAL
SEQ ID No:23:gb:AUD54969|GII Hu/PE/2012/GII.PNA1-GII.NA1/Loreto1041
MKMASNDAAPSNDGAAGLVPEINNETMALEPVAGGAIAAPLTGQTNFIDPWIRNNYVQAPNGEFTVSPRNSPGEILLNLELGPELNPFLAHLSRMYNGYAGGIDVQVIMAGNAFTAGKIIFAAVPPHFPIDNISPPQITMFPHIIIDVRTLEPVNIPLPDVRNSFFHYSQNNEPRMRLLAMLYTPLRSNGSADDVFTVSCRVLTKPSADFEFNYLVPPTVESRTKPFTIPILTIGEMTNSRFPVAIDMLHTSPTDNFIVQPQNGRCTLDGELQGTTQLVTSNICAFRGSISGHENNGDQHQWHFSITNPNGTPFDPTEDVPAPLGTPDFKGQLYGVISQRNREGSPGNGNQKANRSHEGVISTVAPRFTPKLGSVMIGTWTTDDIQDQPSRFTPVGLNDDDNYKQWELPNYSGALTLNMGLAPSVFPTYPGEQLLFFRSYIPMKGGYGSPYIDCLIPQEWISHFYQESAPSQTDVALIRYVNPDTGRVLFEAKLHRQGYITVAKTGDSPINVPANGYFRFDSWVSQFYSLAPMGTGNGRRRIQ
SEQ ID No:24:gb:AUO28670|GII 768/2002/TUN
MRMASSDAPVSGTDGAAGLVPESQQEVLPLEPVAGVQLAAPVAGQSNIIDPWIRMNFVQAPAGEFTVSPRNAPGEVLIDLELGPELNPYLNHLARMYNGYVGGMEVEVVLAGNAFTAGKILFAAVPPSFPTHGISAAQATMLPHVIVDVRQLEPVRLPLPDVRNVMFHFCQENKEPRMRIVAILYTPLRANGAGDDVFTVSCRVLTRPSPDFDFIFLVPPSVESKLKQFTLPNLQPNEMTNSRFPTGITQLYTSPNTNLVVQFQNGRCLLDGTLLGTTPVRAADICSFRGVTSTEVDATDSPRVAGSHRIMVQLKEPDGEEFSPTGPNPAPVGTPDFQAAIFGTLSQRNTGGTGQNSNRAHFAYFYTRNPTFAPGIGTVVFSFDTTDFQNRQPTKFSPSGVFDDDSSEPFNQFSLPYYNGSLGAVDAGKLAPPVAPNYPGEQILYFRGNIPFKGGYGEGEIDSLLPQEWITHFYAEQAPTQGDAALLRYYNPDTGRVLFECKLHREGFITINYTGSNALAVPVNGVFRFEGWVNKFYTLTPMGNGNGRRGRRREL
SEQ ID No:25:gb:BAJ25074|GII Hu/OC07118/2007/JP
MKMASNDANPSSDGSANLVPEISNEVMALEPVAGAAIAAPVAGQQNIIDPWIRNNFVQAPGGEFTVSPRNAPGEVLLNLPLSPDINPYLAHLSRMYNGYAGGVEVEVVLAGNAFTAGKIIFAAVPPNFPPENLSPSQITMLPHIIVDVRQLEPVRIPLPDVRNNFYHYSRENDSTLRLIAMLYTPLRANNAGDDVFTVSCRVLTRPSPDFDFIFLVPPTVESKSKPFTIPMLTIEEMTNSRFPAPLELMTTGPSHDIVVQPQNGRCTIDGVLLGTTQLSPVNICSLRGVPTKRTNGNDNCFVQLENPNGSAYDPTEDIPAVLGSPDFVGELYGTITQRSSDNSTRAHPFTLNTGSPRYTPKIGSVDIRVTDVSDLQDHDPVKLTPVGLSGDRGSIHQWQLPNYSGVATHNMHLAPSVAPLFPGEQILFFRSTVPGCGGYPNSNIDCLIPQEWVQHFYQEGAPARTDVALLRFINPDTGRVLFECKLHKHGFITVAYSGNHDLVMPPNGYFRFESWVNQFHTLAPMGTGSGRRRIQ
SEQ ID No:26:gb:AII73762|GII Hu/JP/2011/GII/Yuzawa/Gira2HS
MKMASKDASPSTDGTANLVPESQQEVLALQPVAGAQIAAPVAGQFNVIDPWIYQNFVQAPEGEFTVSPRNSTGEILMNLELGPQLNPYLAHLARMYNAYAGGFEVQVLLAGNAFTAGKIIVCAVPPNFPLQNISAAQATQLPHVVVDVRQLEPVVLPLPDVRAGFYHYNQVEESRMRLVAILYTPLRTNSAGDDAFTVSCRILTRPAPDFSFFFLIPPTIESKTTPFTLPRLPISEMTNSRFPLVIKGMVVDPNLPLQANFQNGRITLDGELQGTTLPTSTSIGRISGTHMSSTPSRIIQHEDSGDSTQPRVFNPVWMDLTENNWTEFQPFNDQPAPLGCPDFKAKILGTLIRQPNNGSYYFDAYLDTRQHGTFAPYTGHAAVHSDQQAGHLAQGYKIQFSPTGIESDQNTDLNQLPDYGGAMTVSKGLAPAAAPDFPGEMILYFVSDMPVRNPNGERRDTEILCLLPQEMVTHFYEQQAPSQGDVALVRYINAETGRVMFEGKLHRNGFFTVSATARTLIVPDGYFRFDSWVNRFYTLSPMGTGNGRRRARMLE
SEQ ID No:27:gb:ASW22508|GII.1 Hu/IDN/ITD11-3/2015/GII.Pg/GII.1
MKMASNDVAPSNDGAAGLVPEVSNETMALEPVAGASIAAPLTGQNNVIDPWIRMNFVQAPNGEFTVSPRNSPGEVLLNLELGPELNPFLAHLARMYNGYAGGVEVQVLLAGNAFTAGKLVFAAIPPHFPLENLSPGQITMFPHVIIDVRTLEPVLLPLPDVRNNFFHYNQQPEPRMRLVAMLYTPLRSNGSGDDVFTVSCRVLTRPSPDFDFNYLVPPTVESKTKPFTLPILTIGELSNSRFPVPIDELYTSPNEGVVVQPQNGRSTLDGELLGTTQLVPSNICALRGRINAQVPDDHHQWNLQVTNANGTSFDPTEDVPAPLGTPDFLANIYGVTSQRNPDNTCRAHDGVLATWSPKFTPKLGSVVLGTWEESDLDLNQPTRFTPVGLYDTNHFDQWILPNYSGRLTLNMNLAPSVAPLFPGEQILFFRSHIPLKGGTSNGAIDCLLPQEWIQHFYQESAPSPTDVALIRYTNPDTGRVLFEAKLHRQGFITVANSGSRPIVVPPNGYFRFDSWVNQFYSLAPMGTGNGRRRVQ
SEQ ID No:28:gb:BBB86933|GII.2 Hu/GII/JP/2004/GII.P2_GII.2/Tochigi-86
MKMASIDAAPSTDGAAGLVPESNNEVMALEPVAGAALAAPVTGQTNIIDPWIRANFVQAPNGEFTVSPRNAPGEVLLNLELGPELNPYLAHLARMYNGYAGGMEVQVMLAGNAFTAGKLVFAAVPPHFPVENLSPQQITMFPHVIIDVRTLEPVLLPLPDVRNNFFHYNQKDDPKMRIVAMLYTPLRSNGSGDDVFTVSCRVLTRPSPDFDFTYLVPPTVESKTKPFTLPILTLGELSNSRFPVSIDQMYTSPNEVISVQCQNGRCTLDGELQGTTQLQVSGICAFKGEVTAHLHDNDHLYNVTITNLNGSPFDPSEDIPAPLGVPDFQGRVFGVISQRDKHNSPGHNEPANRGHDAVVPTYTSQYTPKLGQIQIGTWQTDDLTVNQPVKFTPVGLNDTEHFNQWVVPRYAGALNLNTNLAPSVAPVFPGERLLFFRSYIPLKGGYGNPAIDCLLPQEWVQHFYQEAAPSMSEVALVRYINPDTGRALFEAKLHRAGFMTVSSNTSAPVVVPANGYFRFDSWVNQFYSLAPMGTGNGRRRVQ
SEQ ID No:29:gb:AUD54972|GII Hu/PE/2013/GII.PNA2-GII.NA2/Loreto1257
MKMASNDAAPSNDGAAGLVPEINNETMALEPVAGGAIAAPLTGQTNFIDPWIRGNYVQAPNGEFTVSPRNSPGEILLNLELGPELNPFLAHLSRMYNGYAGGIDVQVIMAGNAFTAGKIIFAAVPPHFPVENISPPQITMFPHIIVDVRTLEPINIPVPDVRNNFFHYNQDRDSRMRLVAMLYTPLRSNGSTDDVFTVSCRVLTKPSADFEFNYLVPPTVESRTKPFSIPILTIGEMTNSRFPLPIDMLYTSPTENLVVQPQNGRCTTEGELLGTTQLVTPSICSLRGAITGHEGNDDDHKWHMTVTSPNGAAFDPTEDVPAPLGTPDFTGDIYGVLSQRDRNINPGQTAPANRAHEAVVSTRSNKFTPKLGSVMIATWETTDVLQQPTKFTPVGLESPNHYNQWQLPNYSGALTLNMGLAPSVFPTYPGEQILFFRSFIPLKGGYGNSAIDCLVPQEWIQHFYQESAPSQTDVALIRYVNPETGRVLFEAKLHRQGFITVAKTGDSPINVPANGYFRFDSWVNPFYSLAPMGTGNGRRRNQ
SEQ ID No:30:gb:BAK43275|GII.3 Hu/Tokyo/10-1105/2010/JPN
MKMASNDAAPSNDGAAGLVPEINNEAMALEPVAGAAIAAPLTGQQNIIDPWIMNNFVQAPGGEFTVSPRNSPGEVLLNLELGPEINPYLAHLARMYNGYAGGFEVQVVLAGNAFTAGKIIFAAIPPNFPIDNLSAAQITMCPHVIVDVRQLEPVNLPMPDVRNNFFHYNQGSDSRLRLVAMLYTPLRANNSGDDVFTVSCRVLTRPSPDFSFNFLVPPTVESKTKPFTLPILTISEMSNSRFPVPIDSLHTSPTENIVVQCQNGRVTLDGELMGTTQLLPSQICAFRGVLTRSTSRASDQADTATPRLFNYYWHIQLANLNGTPYDPAEDIPGPLGTPDFRGKVFGVACQRNPDCTTRAHEAKVDTTAGRFTPKLGSLEISTESGDFDQNQPTRFTPVGIGVDHEADFQQWSLPDYSGQFTHNMNLAPAVAPNFPGEQLLFFRSQLPSSGGRSNGILDCLVPQEWVQHFYQESAPAQTQVALVRYVNPDTGRVLFEAKLHKLGFMTIAKNGDSPITVPPNGYFRFESWVNPFYTLAPMGTGNGRRRIQ
SEQ ID No:31:gb:BAG70446|GII.4 Aomori2/2006/JP
MKMASSDANPSDGSTANLVPEVNNEVMALEPVVGAAIAAPVAGQQNVIDPWIRNNFVQAPGGEFTVSPRNAPGEILWSAPLGPDLNPYLSHLARMYNSYAGGFEVQVILAGNAFTAGKIIFAAVPPNFPTEGLSPSQVTMFPHIIVDVRQLEPVLIPLPDVRNNFYHYNQSNDPTIKLIAMLYTPLRANNAGDDVFTVSCRVLTRPSPDFDFIFLVPPTVESRTKPFSVPILTVEEMTNSRFPIPLEKLFTGPSSAFVVQPQNGRCTTDGVLLGTTQLSPVNICTFRGDVTHIAGTQEYTMNLASQNWNNYDPTEEIPAPLGTPDFVGKIQGVLTQTTRRDGSTRGHKATVSTGSVHFTPKLGRIQFSTDTSNDFETGQNTRFTPVGVVQDGSTTHQNEPQQWVLPNYSGRDSHNVHLAPAVAPSFPGEQLLFFRSTMPGCSGYPNMNLDCLLPQEWVQHFYQEAAPAQSDVALLRFVNPDTGRVLFECKLHKSGYVTVAHTGQHDLVIPPNGYFRFDSWVNQFYTLAPMGNGTGRRRAL
SEQ ID No:32:gb:AND99841|GII.4 32-15
MKMASSDANPSDGSTASLVPEVNNEVMALEPVVGAAIAAPVAGQQNVIDPWIRNNFVQAPGGEFTVSPRNAPGEILWSAPLGPDLNPYLSHLARMYNGYAGGFEVQVILAGNAFTAGKIIFAAVPPNFPTEGLSPSQVTMFPHIIVDVRQLEPVLIPLPDVRNNFYHYNQSNDSTIKLIAMLYTPLRANNAGDDVFTVSCRVLTRPSPDFDFIFLVPPTVESRTKPFSVPILTVEEMTNSRFPIPLEKLFTGPSSTFVVQPQNGRCTTDGVLLGTTQLSPVNICTFRGGITRIGQSESYKMNLASQNWNNYDPTEEIPAPLGTPDFKGRIRGLLTQTTKGAGSTRGHKATVLTGGSDFTPKLGTVRFDTKSIDFENNQNTKFTPVGVVQDGNNHDEPTQWVLPNYSGPDTHNVHLAPAVAPTFPGEQLLFFRSTMPGCSGYPKMELDCLLPQEWVQHFYQEAAPAQTDVALLRFVNPDTGRVLFECKLHKSGYVTVAHTGDHDLVIPPNGYFRFDSWVNQFYTLAPMGNGTGRRRAL
SEQ ID No:33:gb:AEG79288|GII.4 Hu/GII.4/Hong Kong/CUB001/2010/CHN
MKMASNDANPSDGSAANLVPEVNNEVMALEPVAGAALAAPVAGQQNVIDPWIRNNFVQAPGGEFTVSPRNAPGEILWSAPLSPDLNPYLSHLARMYNSYAGGFEVQVILAGNAFTAGKIIFAAVPPNFPIEGLSPSQVTMFPHIIVDVRQLEPVLIPLPDVRNNFYHYNQTNEPTIKLIAMLYTPLRANNAGEDVFTVSCRVLTRPSPDFDFIFLVPPTVESRTKPFTVPILTVEEMTNSRFPIPLEKLFTGPSSSFVVQPQNGRCTTDGVLLGTTQLSPVNICTFRGDVTHIAGSRNYTMNLASINWNNYDPTEEIPAPLGTPDFVGKIQGMLTQTTRGEGSTRAHRATVYTGSAPFTPKLGSVQFTTDTDNDFDANQNTKFTPVGVIQDGDTAHRNEPQQWVLPSYSGRNVQNVHLAPAVAPTFPGEQLLFFRSTMPGCSGYPNMDLDCLLPQEWVQHFYQEAAPAQSDVALLRFVNPDTGRVLFECKLHKSGYVTVAHTGQHDLVIPPNGYFRFDSWVNQFYTLAPMGNGAGRRRAL
SEQ ID No:34:gb:AQU14484|GII.4 3.10
MKMASNDANPSDGSAANLVPEVNNEVMALEPVVGAAIAAPVAGQQNVIDPWIRNNFVQAPGGEFTVSPRNAPGEILWSAPLGPDLNPYLSHLARMYNGYAGGFEVQVILAGNAFTAGKIIFAAVPPNFPTEGLSPSQVTMFPHIIVDVRQLEPVLIPLPDVRNNFYHYNQSNDSTIKLIAMLYTPLRANNAGDDVFTVSCRVLTRPSPDFDFIFLVPPTVESRSKPFSVPVLTVEEMTNSRFPATLDKLFTGPSSTFVVQPQNGRCMIDGVLLGTTQLSPVNICTFRGDVTHLRDSPIYTMNLASPNWNNYDSTEEIPAPLGTPDFVGKIQGVLTQTTKGEGSTRGHRATVYVGSANYTPKLGKVQFETNTTNDLYAHQNTKFTPVGVVQGGESAHRSEPQQWVLPGYSGRDTPNVHLAPAVAPTFPGEQLLFFRSTIPGCGGHPNMDLDCLLPQEWVQHFYQEAAPAQSDVALLRFVNPDTSRVLFECKLHKSGYVTVAHTGQHDLVIPPNGYFRFDSWVNQFYTLAPMGNGTGRKRAI
SEQ ID No:35:gb:AQU14462|GII.4 2.8b
MKMASSDANPSDGSAANLVPEVNNEVMALEPVVGAAIAAPVAGQQNVIDPWIRNNFVQAPGGEFTVSPRNAPGEILWSAPLGPDLNPYLSHLARMYNGYAGGFEVQVILAGNAFTAGKIIFAAVPPTFPTEGLSPSQVTMFPHIIVDVRQLEPVLIPLPDVRNNFYHYNQSNDSTIKLIAMLYTPLRANNPGDDVFTVSCRVLTRPSPDFDFIFLVPPTVESRTKPFSVPILTVGEMTNSRFPINLERLFTGPSSANVVQPQNGRCTIDGELLGTTQLSSVNICTFRGDVTHIGSTHHWTMNLASPNWNNYDPTEETPAPLGTPDFVGKIHGMLTQTTQGNGSTRGHRATVYVGSAEFTPKLGKVQFKTETDHDLAIRQNTKFTPVGVIQESDHHRDEPQQWRLPNYSGANTFNVHLAPAVAPNFPGEQLLFFRSTLPGCGGHPNMDLDCLLPQEWVQHFYQEAAPAQSDVALLRFVNPDTSRVLFECKLHKSGYVTVAHTGQYDLVLPSNGYFRFDSWVNQFYTLAPMGNGTGRRRAL
SEQ ID No:36:gb:AHH44895|GII.4 Hu/GII.4/patient_C/2010/USA
MKMASNDASPSDGSAANLVPEVNNEVMALEPVVGAAIAAPVAGQQNVIDPWIRNNFVQAPGGEFTVSPRNAPGEILWSAPLGPDLNPYLSHLARMYNGYAGGFEVQVILAGNAFTAGKIIFAAVPPNFPTEGLSPSQVTMFPHIVVDVRQLEPVLIPLPDVRNNFYHYNQSKDPTIKLIAMLYTPLRANNAGEDVFTVSCRVLTRPSPDFDFIFLVPPTVESRSKPFTVPILTVEEMTNSRFPIPLEKLFTGPSGAFVVQPQNGRCTTDGVLLGTTQLSPVNICTFRGDLTHFTGTSEYAMNLASQNWDNYDPTEEIPAPLGAPDFVGKIRGMLTQTTRRDGSTRGHRATLSTGSAHFTPKLGNIRFSTDTNNDFEAGQNTKFTPVGVFQEGDNHQNEPQQWVLPNYSGATAHNVHLAPAVAPAFPGEQLLFFRSTMPGCGGYPNMNLDCLLPQEWVQHFYQEAAPAQSDVALLRFVNPDTSRVLFECKLHKSGYVTVAHTGQHDLVIPPNGYFRFDSWVNQFYTLAPMGNGTGRRRAL
SEQ ID No:37:gb:AGX85889|GII.4 Hu/GII.4/NIHIC1.8/2012/USA
MKMASSDANPSDGSTANLVPEANNEVMALEPVVGAAIAAPVAGQQNVIDPWIRNNFVQAPGGEFTVSPRNAPGEILWSAPLGPDLNPYLSHLSRMYNGYAGGFEVQVILAGNAFAAGKIIFAAVPPNFPTEGLSPSQVTMFPHLIVDVRQLEPVMIPLPDIRNNFYHYNQSNDPTIKLIAMLYTPLRANNVGDDVFTVSCRVLTRPSPDFDFIFLVPPTVESKTNPFSVPILTIEEMTNSRFPIPLEKLFTGPSSALVVQPQNGRCTTDGVLLGTTQLSPVNICTFRGDVTHTTKTHTYQMNLAAQNWNSYDPTEEIPAPLGTPDFVGKIQGVLTQTTKGNGSTRAHKATVYTGSAEFTPKLGRIQLFTDTDNDLEANQNTKFTPVGVIQDGDTHQNEPQQWVLPSYSGRNNHNVHLAPAVAPTFPGEQLLFFRSTMPGCSGYPNMNLDCLLPQEWVQYFYQEAAPAQSDVALLRFVNPDTGRVLFECKLHKSGYVTVAHTGHHDLFIPPNGYFRFDSWVSPFYTLAPMGNGTGRRRAL
SEQ ID No:38:gb:AHH44878|GII.4 Hu/GII.4/patient_A/2010/USA
MKMASSDANPSDGSAANLVPEVNNEVMALEPVVGAAIAAPVAGQQNVIDPWIRNNFVQAPGGEFTISPRNAPGEILWSAPLGPDLNPYLSHLARMYNGYAGGFEVQVVLAGNAFTAGKIIFAAVPPNFPTEGLSPSQVTMFPHIIVDVRQLEPVLIPLPDVRNNFYHYNQSKDSTIKLIAMLYTPLRANNAGDDVFTVSCRVLTRPSPDFDFIFLVPPTVESRTKPFSVPVLTVEEMTNSRFPIPLEKLFTGPSSAFVVQPQNGRCTTDGVLLGTTQLSAVNICTFRGDVTHVAGDTFAMNLASLNWNNYDPTEETPAPLGTPDFVGRIHGMLTQTTRSDGATRAHKATVSTGGADFTPKLGSVRYSTDTSSDLEVRENTKFTPIGVLHSSGGHRAEPDQWRLPEYSGRNVHNVHLAPAVAPTFPGEQLLFFRSTMPGCGGYPNMDLDCLLPQEWVQHFYQEAAPAQSDVALLRFVNPDTGRVLFECKLHKSGYVTVAHTGPHDLVIPPNGYFRFDSWVNQFYTLAPMGNGTGRRRAL
SEQ ID No:39:gb:BAW33648|GII.4 Hu/GII/3-157/Tokyo/1994/JPN
MKMASSDANPSDGSAANLVPEVNNEVMALEPVVGAAIAAPVAGQQNIIDPWIRNNFVQAPGGEFTVSPRNAPGEILWSAPLGPDLNPYLSHLSRMYNGYAGGFEVQVILAGNAFTAGKVIFAAVPPNFPTEGLSPSQVTMFPHIIVDVRQLEPVLIPLPDVRNNFYHYNQSHDSTLKLIAVLYTPLRTNNAGDDVFTVSCRVLTRPSPDFDFIFLVPPTVESRTKPFTVPILTVEEMSNSRFPIPLEKLYTGPSSAFVVQPQNGRCTTDGVLLGTTQLSAVNICNFRGDVTHIVGSHETTMNLASQNWSNYDPTQKIPAPLGTPHFVGKIQGLLTQTTRAHGSTRAHKATVSTGSVHFTPKLGSVQFTTDTNNDFQTGQNTKFTPVGVIQDGDHHQNEPQQWVLPNYSGRTGHNVHLAPAVAPTFPGEQLLFFRSTMPGCSGYPNMNLDCLLPHEWVLHFYQEAAPAQSDVALLRFVNPDTGRVLFECKLHKSGYITVAHTGPFDLGIPPNGYFRFDSWVNQFYTLAPMGNGTGRRRAL
SEQ ID No:40:gb:ABD77588|GII.4 Hu/Beijing/CR2905/2004/CHN
MKMASNDASPSDGSTANLVPEVNNEVMALEPVVGAAIAAPVAGQQNVIDPWIRNSSVQAPGGEFTVSPRDAPGEILWSAPLGPDLNPYLSHLARMYNGYAGGFEVQVILAGNAFTAGKIIFAAAPPNFPTEGLSPSQVTMFPHIIVGVRQLEPVLIPLPDVRNNFYHYNQSNDSTIKLIAMLYTPLRANNAGDDVFTVSCRVLTRPSPDFDFIFLVPPTVESRTKPFTVPILTVEEMTNSRFPIPLENCSRVPAVPLSSNHKMQCTTDGVLLGTTQLSPVNICTFRGDVTHIPGTRTYRMNLASQNWNNYDPTEEIPAPLGTPDFVGKIQGMLTQTTKGDGSTRGHKATVSTGSVDFTPKLGSVQFATDTDNDFETGQNTRFTPVGVIQDGSSTHRNEPQQWVLPDYSGRTVHNVHLAPAVAPTFPGEQLLFFRSTMPGCSGYPNMDLDCLLPQEWVQHFYQEAAPSQSDVALLRFVNPDTGRVLFECKLHKAGYVTVAHTGQHDLVIPPNGYFRFDSWVNQFYTLAPMGNGAGRRRAL
SEQ ID No:41:gb:AGE99612|GII.4 Hu/GII.4/KL45/1978/MYS
MKMASSDANPSDGSSANLVPEVNNEVMALEPVVGAAIAAPVAGQQNIIDPWIRNNFVQAPGGEFTVSPRNAPGEILWSAPLSPDLNPYLSHLSRMYNGYAGGFEVQVILAGNAFTAGKIVFAAVPPNFPTEGLSPSQVTMFPHIIVDVRQLEPVLIPLPDVRNNFYHYNQANDSTLKLIAMLYTPLRANNAGDDVFTVSCRVLTRPSPDFDFIFLVPPTVESRTKPFTVPVLTVEEMTNSRFPIPLERLFTGPSTAFVVQPQNGRCTTDGVLLGTTQLSAVNICNFRGEVNHIAGTHDYTMRLTSQNWNNYDPTEEIPAPLGTPDFVGRIQGVLTQTTRSDGSTRSHKATVSTGSVHFTPKLGSVQFTTDTTNDLNAGQNTKFTPVGVEQTSGDHQSEPQQWTLPNYSGTPNHNVHLAPAVAPTFPGEQLLFFRSTLPGCGGYPNMNLDCLLPQEWVLHFYQEAAPAQSDVALLRFVNPDTGRVLFECKLHRSGFITVAHSGSHDLVIPPNGYFRFDSWVNQFYTLAPMGNGSGRRRVV
SEQ ID No:42:gb:AII73753|GII.5 Hu/JP/2002/GII.P5_GII.5/Saitama/T52
MKMASNDATPSNDGAAGLVPESNNEAMALEPVVGASLAAPVTGQTNIIDPWIRTNFVQAPNGEFTVSPRNSPGEILVNLELGPELNPYLAHLARMYNGYAGGMEVQVMLAGNAFTAGKIIFAAVPPYFPVENLSPSQITMFPHVIIDVRTLEPVLLPMPDVRSTLFHFNQKDEPKMRLVAMLYTPLRSNGSGDDVFTVSCRILTRPSPEFDFTYLVPPTVESKTKPFTLPVLTLGELSNSRFPLSIDEMVTSPNESIVVQPQNGRVTLDGELLGTTQLQACNICSIRGKVTGQVPNEQHMWNLQITNLNGTQFDPTDDVPAPLGVPDFAGEVFGVLSQRNRGESNPANRAHDAVVATYSDKYTPKLGLVQIGTWNTNDVENQPTKFTPIGLNEVANGHRFEQWTLPRYSGALTLNMNLAPAVAPLFPGERLLFFRSYVPLKGGFGNPAIDCLVPQEWVQHFYQESAPSLGDVALVRYVNPDTGRVLFEAKLHKGGFLTVSSTSTGPVVVPANGYFRFDSWVNQFYSLAPMGTGNGRRRFQ
SEQ ID No:43:gb:BAN16287|GII.6 Hu/GII.6/Ehime090549/2009/JP
MKMASNDAAPSNDGAANLVPEANNEVMALEPVAGASIAAPVVGQQNIIDPWIRENFVQAPQGEFTVSPRNSPGEMLLNLELGPELNPYLSHLSRMYNGYAGGMQVQVVLAGNAFTAGKIIFAAVPPHFPVKNISAAQITMCPHVIVDVRQLEPVLLPLPDIRNRFFHYNQENTPRMRLVAMLYTPLRANSGEDVFTVSCRVLTRPAPDFEFTFLVPPTVESKTKPFTLPILTLGELSNSRFPAPIDMLYTDPNEGIVVQPQNGRCTLDGTLQGTTQLVPTQICAFRGTLIGQTSRSSDSTDSAPRRRDHPLHVQLKNLDGTQYDPTDEVPAVLGAIDFKGTVFGVASQRDVSGQQVGATRAHEVHINTTDPRYTPKLGSILIHSESDDFVTGQPVRFTPIGMGDNDWHQWELPDYSGHLTLNMNLAPAVAPAFPGERILFFRSMVPSAGGYGSGQIDCLIPQEWVQHFYQEAAPSQSAVALIRYVNPDTGRNIFEAKLHREGFITVANSGNNPIVVPHNGYFRFEAWVNQFYTLTPMGTGQGRRRNQ
SEQ ID No:44:gb:AII73774|GII.7 Hu/JP/2010/GII.P7_GII.7/Musashimurayama
MKMASNDAAPSNDGAAGLVPEINNEVMPLEPVAGASLATPVVGQQNIIDPWIRNNFVQAPAGEFTVSPRNSPGEILLDLELGPELNPYLAHLARMYNGHAGGMEVQIVLAGNAFTAGKIIFAAIPPGFPYENLSPSQITMCPHVIIDVRQLEPVLLPMPDIRNNFFHYNQGNDPKLRLIAMLYTPLRANNSGDDVFTVSCRVLTKPSPDFEFTFLVPPTVESKTKQFTLPILKISEMTNSRFPVPVEMMYTARNENQVVQPQNGRVTLDGELLGTTPLLAVNICKFKGEVIAKNGDVRSYRMDMEITNTDGTPIDPTEDTPGPIGSPDFQGILFGVASQRNKNEQNPATRAHEANINTGGDQYAPKLAQVKFFSESQDFEVHQPTVFTPVGVAGDTSHPFRQWVLPRYGGHLTNNTHLAPAVAPLFPGEQILFFRSQIPSSGGHELGYMDCLVPQEWVQHFYQEAATAQSEVALIRFINPDTGRVLFEAKLHKQGFITVAHTGDNPIVMPPNGYFRFEAWVNQFYSLAPVGTGNGRRRIQ
SEQ ID No:45:gb:ATI15126|GII.8 Hu/JC231/ZS/GD/CHN/2016
MKMASNDAAPSNDGAAGLVPEINHEVMAIEPVAGASLAAPVVGQLNIIDPWIRNNFVQAPAGEFTVSPRNAPGEFLLDLELGPELNPYLAHLARMYNGHAGGMEVQIVLAGNAFTAGKILFAVIPPGFPYENLSPAQLTMCPHVVVDVRQLEPILLPMPDIRNTFFHYNQSNGPKLRLVAMLYTPLRANNAGDDVFTVSCRVLTRPSPDFEFNFLVPPSVESKTKAFTLPILKISEMTNSRFPIPVDQMYTSRNENVVVQPQNGRVTLDGELQGTTTLQPVSICGFRGTLQTRLADQPNYTYQVHLENLDGSPVDPTDEVPAPLGTPDFQAQLFGVVSQRSSDNATRAHEARVNTNDPTFAPQIAQVRFKSPSHDFFDNEPIKFTPVGISVDSENSYNQWLLPRYGGHLTNNTHLAPSVSPMFPGEQILFFRSFMPGASGHTDGAIDCLLPQEWVAHFYQEAATAQTDVALIRFVNPDTGRVLFEGKLHKQGFITISNSGDHPIVMPANGYFRFEAWVNQFYSLAPVGTGSGRRRIQ
SEQ ID No:46:gb:AGT39194|GII.12 Hu/GII.12/CGMH39/2010/TW
MKMASNDAAPSNDGAAGLVPEVNNETMALEPVAGASIAAPLTGQNNVIDPWIRLNFVQAPNGEFTVSPRNSPGEVLLNLELGPELNPYLAHLSRMYNGYAGGVEVQVLLAGNAFTAGKLVFAAVPPHFPLENISPGQITMFPHVIIDVRTLEPVLLPLPDVRNNFFHYNQQNEPRMRLVAMLYTPLRSNGSGDDVFTVSCRVLTRPSPDFDFNYLVPPTVESKTKPFTLPILTIGELTNSRFPVPIDELYTSPNESLVVQPQNGRCALDGELQGTTQLLPTAICSFRGRINQKVSGENHVWNMQITNINGTPFDPTEDVPAPLGTPDFSGKLFGVLSQRDHDNACRSHDAVIATNSAKFTPKLGAIQIGTWEQDDVHINQPTKFTPVGLFESEGFNQWTLPNYSGALTLNMGLAPPVAPTFPGEQILFFRSHIPLKGGVADPVIDCLLPQEWIQHLYQESAPSQTDVALIRFTNPDTGRVLFEAKLHRSGYITVANTGSRPIVVPANGYFRFDSWVNQFYSLAPMGTGNGRRRVQ
SEQ ID No:47:gb:BAQ94581|GII.13 Hu/GII.13/10N4555/2010/NP
MKMASNDAAPSNDGAASLVPEAINETMPLEPVAGASIAAPVAGQTNIIDPWIRTNFVQAPNGEFTVSPRNSPGEILLNLELGPDLNPYLAHLSRMYNGYAGGVEVQVLLAGNAFTAGKILFAAIPPNFPVDMISPAQITMLPHLIVDVRTLEPIMIPLPDVRNVFYHFNNQPQPRMRLVAMLYTPLRSNGSGDDVFTVSCRVLTRPTPDFEFIYLVPPSVESKTKPFTLPILTISELTNSRFPIPIEQLYTAPNENNVVQCQNGRCTLDGELQGTTQLLSSAVCSYRGRTVANRGDNWDQNLLQLTYPSGASYDPTDEVPAPLGTQDFSGILYGVLTQDNVSEGTGEAKNAKGVYISTTSGKFTPKIGSIGLHSITENVHPNQQSRFTPVGVAQNENTPFQQWVLPHYAGALALNTNLAPAVAPTFPGEQLLFFRSRVPCVQGLRGQDAFIDCLLPQEWVNHFYQEAAPSQADVALIRYVNPDTGRTLFEAKLHRSGFITVSHTGAYPLVVPPNGHFRFDSWVNQFYS
SEQ ID No:48:gb:AAN05735|GII.14 Hu/NLV/M7/1999/US
MKMASNDATPSDDGAAGLVPEINNEVMALEPVAGASIAAPVVGQQNIIDPWIRNNFVQAPAGEFTVSPRNSPGELLLDLELGPELNPYLAHLARMYNGHAGGMEVQIVLAGNAFTAGKILFAAIPPSFPYENLSPAQLTMCPHVIVDVRQLEPVLLPMPDIRNVFYHYNQNNSPKLRLVAMLYTPLRANNSGDDVFTVSCRVLTRPSPDFQFTFLVPPTVESKTKNFTLPVLRVSEMTNSRFPVVLDQMYTSRNENIIVQPQNGRCTTDGELLGTTTLQSVSICNFRGTMQAKLNEQPRYQLQLTNLDGSPIDPTDDMPAPLGTPDFQAMLYGVASQRSSRDNATRAHDAQIDTAGDTFAPKIGQVRFKSSSDDFDLHDPTKFTPIGVNVDDQHPFRQWSLPNYGGHLALNNHLAPAVTPLFPGEQILFFRSHIPSAGGHTDGAIDCLLPQEWIEHFYQEAAPSQSDIALVRFINPDTGRVLLEAKLHKQGFLTVAASGDHPIVMPTNGYFRFEAWVNPFYTLAPVGTGSGRRRIQ
SEQ ID No:49:gb:AOQ30449|GII.17 E11161
MKMASNDAAPSNDGAAGLVPEGNNETLPLEPVAGAAIAAPVTGQNNIIDPWIRTNFVQAPNGEFTVSPRNSPGEILLNLELGPDLNPYLAHLSRMYNGYAGGVEVQVLLAGNAFTAGKILFAAVPPNFPVEFLSPAQITMLPHIIVDVRTLEPIMIPLPDVRNTFFHYNNQPNSRMRLVAMLYTPLRSNGSGDDVFTVSCRVLTRPTPDFEFTYLVPPSVESKTKPFSLPILTLSELTNSRFPVPIDSLFTAQNNVLQVQCQNGRCTLDGELQGTTQLLPSGICAFRGRVTAETDNPDKWHMQLQNLNGTTYDPTDDVPAPLGTPDFKGVVFGVASQRNVGNDAPGSTRAHEAVISTYSPKFVPKLGSVNFRSNDDDFQLQPTRFTPVGINDDGNHPFRQWELPDYSGVLTLNMNLAPPVAPNFPGEQLLLFRSFVPCSGGYNQGIIDCLIPQEWIQHFYQESAPSQSDVALIRYVNPDTGRTLFEAKLHRSGYITVAHSGDYPLVVPANGYFRFDSWVNQFYSLAPMGTGNGRRRAQ
SEQ ID No:50:gb:AII73747|GII.17 Hu/JP/2002/GII.P16_GII.17/Saitama/T87
MKMASNDAAPSNDGATGLVPEINNETLPLEPVAGAAIAAPVTGQNNIIDPWIRTNFVQAPNGEFTVSPRNSPGEILLNLELGPDLNPYLAHLSRMYNGYAGGVEVQVLLAGNAFTAGKILFAAVPPNFPVEFLSPAQITMLPHLIVDVRTLEPIMIPLPDVRNTFFHYNNQPANRMRLVAMLYTPLRSNGSGDDVFTVSCRVLTRPTPDFEFTYLVPPSVESKTKPFSLPILTISELTNSRFPAPIDSLFTAQNNNLNVQCQNGRCTLDGELQGTTQLLPSGICAFRGRLTADVDGSHDDRWHMQLTNLNGTPFDPTEDVPAPLGTPDFTGLLFGVASQRNVGSNPNTTRAHEAVISTTSSQFVPKLGSVNFGSTSTDFQLQQPTKFTPVGIKIESGHEFDQWALPRYSGHLTLNMNLAPPIAPNFPGEQLLFFRSNVPCAGGVSDGVIDCLLPQEWIQHFYQESAPSQSDVALIRYVNPDTGRTLFEAKLHRTGYITVAHSGDYPLVVPSNGYFRFDSWVNQFYSLAPMGTGNGRRRVQ
SEQ ID No:51:gb:ALP48670|GII.21 Hu/GII.21/CUHK-NS-290/HKG/2014
MKMASNDAAPSNDGAAGLVPEINTETLPLEPVAGAAIAAPVTGQNNIIDPWIRNNFVQAPNGEFTVSPRNSPGEILMNLELGPDLNPYLAHLSRMYNGYAGGVEVQVLLAGNAFTAGKILFAAVPPNFPVDMLSPAQITMLPHLIVDVRTLEPIMIPLPDVRNVFYHFNNQPAPRMRLVAMLYTPLRSNGSGDDVFTVSCRVLTRPTPDFEFTYLVPPSVESKTKPFTLPILTIGELTNSRFPAPIDQLYTSPNADVVVQPQNGRCTLDGELQGTTQLLTTAICSYRGTTSNPTSDYWDDHLLHLVHPNGATYDPTEDVPAPFGTQDFRGILYGVLTQNTQNPRDEVSNSRGIYISSTSDKFTPKLGTIGLHQVQGDTASNQQSKFTPVGIAVNQNTPFKQWELPNYSGALTLNTNLAPAVGPNFPGEQILFFRSNVPSVQGNHPTQEIDCLIPQEWISHFYQESAPSQSDVALVRYVNPDTGRTIFEAKLHRQGFITIAATGSNPVVVPPNGYFRFDSWVNQFYALAPMGTGNGRRRAQ
SEQ ID No:52:gb:AUD54981|GII.22 Hu/BD/2012/GII.P22-GII.22/Dhaka1940
MKMASNDAAPSNDGAAGLVPEINTEVMALEPVAGGAIAAPLTGQTNIIDPWIRNNFVQAPNGEFTISPRNSPGEILLNMELGPELNPFLAHLSRMYNGFAGGMEVQVLMAGNAFTAGKVIFAAIPPHFPVENLSPPQITMFPHIIIDVRTLEPVLLPMPDVRNQFFHYNQVNEPRMRLVAMLYTPLRSNGSTEDVFTVSCRVLTRPSPDFEFNYLVPPTVESRTKPFTLPILTIGEMTNSRFPAPIDMLYTSPNDNVVVQPQNGRCTLDGELQGSTQLVPANVCAFKGKITARIVDQAAHQWHMQIDNPNGTLFDPTEDVPAPLGTPDFKAKIFGVISQRNDYNDGSQGPANRAHDAVVPTTSAKFTPKLGSILVGTWENNDIETQPSKFTPVGLLEMNDFNQWSLPNYSGALTLNMGLAPAVFPTFPGEQILFFRSFIPLKGGHGNPAIDCLLPQEWIQHFYQESAPSQTSVALIRYVNPDTGRVLFEGKLHRQGFITIAKSGDGPIVVPPNGYFRFDSWVNQFYSLAPMGNGNGRRRIQ
SEQ ID No:53:gb:AUD54978|GII.24 Hu/PE/2014/GII.P24-GII.24/Loreto6424
MKMASNDAAPSNDGAANLVPEANKEVMALEPVAGGAIAAPLTGQTNIIDPWIMNNFVQAPNGEFTISPRNSPGEVLLNLELGPDLNPFLAHLSRMYNGYAGGVEVQVIMAGNAFTAGKVIFAAVPPHFPVDNLSPPQVTMFPHVIVDVRTFEPILLPLPDVRNSFYHYNQVNDSRMRLIAMLYTPLRSNGSSDDVFTVSCRVLTRPTPDFEFNYLVPPTVESRTKPFSVPILTIGEMTNSRFPLPIDMLYTSPTENIVVQPQNGRCTLEGELLGTTQLVTPNICALRGEIRGHEGSGDNHKWHFMVRSPNGAAFDPTEDVPAPLGTPDFIGDVFGVLSQRNRNTDSGQSGPANRSHDAVVSTRDSRFTPKLGSVMIATWETSDIQDQPTRFTPVGLENPDHYNQWQLPNYSGALTLNMGLAPSVFPTYPGEQILFFRSYIPLKGGYGDSHIDCLVPQEWIQHFYQESAPSQTDVALIRYVNPETGRVLFEAKLHRQGYITVARSGSSPINVPANGYFRFDSWVNQFYSLAPMGTGNGRRRIQ
SEQ ID No:54:gb:AUD54984|GII.25 Hu/BD/2012/GII.P22-GII.25/Dhaka1928
MKMASNDAAPSNDGAAGLVPEINNEVMALEPVAGGAIAAPLTGQTNVIDPWIRTNFVQAPNGEFTISPRNSPGEVLLNMELGPELNPFLGHLSRMYNGYAGGIEVQVLMAGNAFTAGKVIFAAVPPHFPVENLSPPQVTMFPHIIVDVRTLEPILLPLPDVRNQFFHYSQVDEPKMRLVAMLYTPLRSNGSAEDVFTVSCRVLTRPSPDFEFNYLVPPTVESRTKPFTVPILTIGEMSNSRFPAPIDMLYTSPNDNQNVQPQNGRCTLDGELQGTTQLVPSGVCAFRGRITGHEGSEQNQWHMQLTNLNGTPFDPTEDIPAPLGTPDFKGEIFGFISQRNAQNDPGQSQPANRAHDAVVSTRAPKFTPKLGSVMIGTWVNSDIENQPSKFTPVGLNSNENFRQWELPDYSGVLTLNMGLAPVVHPTYPGEQILFFRSYIPLKGGHGNPAIDCLLPQEWIQHFYQESAPSQTDVALLRYVNPDTGRVLFEAKLHRQGYITIAKSGDGPIVVPPNGYFRFDSWVNQFYSLAPMGNGNGRRRVQ
SEQ ID No:55:gb:YP_009237904|GIV.1 Hu/GIV.1/Lake Macquarie/NSW268O/2010/AU
MKMASSDAAPSTDGAGNLVPESQQEVLPLAPVAGAALAAPVVGQTNIIDPWIKENFVQAPQGEFTVSPKNSPGEILVNLELGPKLNPYLDHLSRMYNSYAGGIDVMVVLAGNAFTAGKVLIAAIPPNFPVEGVSASQATQFPHVIIDVRTLDPVRLPLPDVRSTFFHYTNDTEPKMRLVIWLYTPLRTNGSGDDSFTVSGRILTRPSQDFEFAFLIPPTVETKTTPFSVPGFSVQEMSNSRWPAAISAMVVRGNEPQVVQFQNGRAHLDGMLLGTTPVSPNYIASYRGISTGNSRSASSEADERAVGSFDVWVRLQEPDGQPYDIFGKQPAPIGTPDFKAVIVGFAARPLTSGSYANEAYVNTTASDYAPATGNMRFTVRNGGTGHISANKYWEFKSFGVEGERHTDIQYQEYELPDYSGQVASNHNLAPPVAPRMPGESLLLFQSNMPVWDDGHGESTPKKIHCLLPQEFIGHFFDRQAPSLGDAALLRYVNQETNRVLFECKLYRDGYITVAASSGLLDFPLDGFFRFDSWVSSFYILSPVGSGQGRRGRVRFQ
SEQ ID No:56:gb:APA31973|GIV.3 Hu/USA/2016/GIV.3/WI7002
MKMASNDAPPSSDGAGNLVPESHQEVLPLAPVAGAELAAPVVGQTNIIDPWIKENFVQAPQGEFTVSPKNAPGEILVNLELGPNLNPYLEHLSRMYNAYAGGIEVEIILAGNAFTAGKILIAAVPPNFPVESVSASQATQFPHAIVDVRTLEPVRLPLPDVRSNFFHYTTKDEPKMRLVIWLYTPLRTNGSGDDSFTVSGRLLTRPSMDFQFSFLVPPTVETKTVLFTVPGLTPQEMSNSRWPAQISGMVVRGNEPQVVQFQNGRCHTDGTLLGTTTVSEQCIAGFVGTSTNTRSATGSTTETRTGDTDLWLRLEEPNGQPYDIFGDQPAPLGTPDFRAVIVGFASRPQTQGSYMNEAYVNTVDSHFAPATGNTKIILRRGGTGHVGGGHLWKFRPFGVEGGEGRVSYQEYVLPNYSGATASNHNLAPPVAPRMPGELLLLFESDMPVWDDGHGAAPAQKIHCLLPQQFITHFFDSQAPALAEAALLRYVHPDSSRVLFETKLYREGFMVVSAPTGRFDFPLDGYFRFDSWVNSFYVLSPVGSGQGRRGRSKVV
SEQ ID NO:57:Ala-Ala-Leu-Leu/Val-His-Tyr
SEQ ID NO:58:Ala-Ala-Leu-Leu/Val-Arg/Lys-Tyr
SEQ ID NO:59:Ala-Ala-Leu-Leu/Val-His-Tyr-Val/Leu/Ile-Asp
SEQ ID NO:60:Ala-Ala-Leu-Leu/Val-Arg/Lys-Tyr-Val/Leu/Ile-Asp
SEQ ID NO:61:Ala-Ala-Leu-Leu/Val-His
序列表
<110> 爱康遗传有限公司（Icon Genetics GmbH）
<120> 具有提高的稳定性的诺如病毒样颗粒
<130> PCT-17702
<160> 61
<170> PatentIn version 3.5
<210> 1
<211> 544
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 1
Met Met Met Ala Ser Lys Asp Ala Thr Pro Ser Ala Asp Gly Ala Thr
1 5 10 15
Gly Ala Gly Gln Leu Val Pro Glu Val Asn Thr Ala Asp Pro Ile Pro
20 25 30
Ile Asp Pro Val Ala Gly Ser Ser Thr Ala Leu Ala Thr Ala Gly Gln
35 40 45
Val Asn Leu Ile Asp Pro Trp Ile Ile Asn Asn Phe Val Gln Ala Pro
50 55 60
Gln Gly Glu Phe Thr Ile Ser Pro Asn Asn Thr Pro Gly Asp Val Leu
65 70 75 80
Phe Asp Leu Gln Leu Gly Pro His Leu Asn Pro Phe Leu Ser His Leu
85 90 95
Ser Gln Met Tyr Asn Gly Trp Val Gly Asn Met Arg Val Arg Val Val
100 105 110
Leu Ala Gly Asn Ala Phe Thr Ala Gly Lys Val Ile Ile Cys Cys Val
115 120 125
Pro Pro Gly Phe Gln Ser Arg Thr Leu Ser Ile Ala Gln Ala Thr Leu
130 135 140
Phe Pro His Val Ile Ala Asp Val Arg Thr Leu Asp Pro Val Glu Val
145 150 155 160
Pro Leu Glu Asp Val Arg Asn Val Leu Tyr His Asn Asn Asp Thr Gln
165 170 175
Pro Thr Met Arg Leu Leu Cys Met Leu Tyr Thr Pro Leu Arg Thr Gly
180 185 190
Gly Ala Ser Gly Gly Thr Asp Ser Phe Val Val Ala Gly Arg Val Leu
195 200 205
Thr Cys Pro Gly Pro Asp Phe Asn Phe Leu Phe Leu Val Pro Pro Thr
210 215 220
Val Glu Gln Lys Thr Arg Pro Phe Thr Val Pro Asn Ile Pro Leu Lys
225 230 235 240
Tyr Leu Ser Asn Ser Arg Ile Pro Asn Pro Ile Glu Gly Met Ser Leu
245 250 255
Ser Pro Asp Gln Thr Gln Asn Val Gln Phe Gln Asn Gly Arg Cys Thr
260 265 270
Ile Asp Gly Gln Pro Leu Gly Thr Thr Pro Val Ser Val Ser Gln Leu
275 280 285
Cys Lys Phe Arg Gly Arg Ile Thr Ser Gly Gln Arg Val Leu Asn Leu
290 295 300
Thr Glu Leu Asp Gly Ser Pro Phe Met Ala Phe Ala Ala Pro Ala Pro
305 310 315 320
Ala Gly Phe Pro Asp Leu Gly Ser Cys Asp Trp His Ile Glu Met Ser
325 330 335
Lys Ile Pro Asn Ser Ser Thr Gln Asn Asn Pro Ile Val Thr Asn Ser
340 345 350
Val Lys Pro Asn Ser Gln Gln Phe Val Pro His Leu Ser Ser Ile Thr
355 360 365
Leu Asp Glu Asn Val Ser Ser Gly Gly Asp Tyr Ile Gly Thr Ile Gln
370 375 380
Trp Thr Ser Pro Pro Ser Asp Ser Gly Gly Ala Asn Thr Asn Phe Trp
385 390 395 400
Lys Ile Pro Asp Tyr Gly Ser Ser Leu Ala Glu Ala Ser Gln Leu Ala
405 410 415
Pro Ala Val Tyr Pro Pro Gly Phe Asn Glu Val Ile Val Tyr Phe Met
420 425 430
Ala Ser Ile Pro Gly Pro Asn Gln Ser Gly Ser Pro Asn Leu Val Pro
435 440 445
Cys Leu Leu Pro Gln Glu Tyr Ile Thr His Phe Ile Ser Glu Gln Ala
450 455 460
Pro Ile Gln Gly Glu Ala Ala Leu Leu His Tyr Val Asp Pro Asp Thr
465 470 475 480
Asn Arg Asn Leu Gly Glu Phe Lys Leu Tyr Pro Gly Gly Tyr Leu Thr
485 490 495
Cys Val Pro Asn Ser Ser Ser Thr Gly Pro Gln Gln Leu Pro Leu Asp
500 505 510
Gly Val Phe Val Phe Ala Ser Trp Val Ser Arg Phe Tyr Gln Leu Lys
515 520 525
Pro Val Gly Thr Ala Gly Pro Ala Arg Gly Arg Leu Gly Val Arg Arg
530 535 540
<210> 2
<211> 540
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 2
Met Ala Ser Lys Asp Ala Thr Pro Ser Ala Asp Gly Ala Thr Gly Ala
1 5 10 15
Gly Gln Leu Val Pro Glu Val Asn Thr Ala Asp Pro Ile Pro Ile Asp
20 25 30
Pro Val Ala Gly Ser Ser Thr Ala Leu Ala Thr Ala Gly Gln Val Asn
35 40 45
Leu Ile Asp Pro Trp Ile Ile Asn Asn Phe Val Gln Ala Pro Gln Gly
50 55 60
Glu Phe Thr Ile Ser Pro Asn Asn Thr Pro Gly Asp Val Leu Phe Asp
65 70 75 80
Leu Gln Leu Gly Pro His Leu Asn Pro Phe Leu Ser His Leu Ser Gln
85 90 95
Met Tyr Asn Gly Trp Val Gly Asn Met Arg Val Arg Val Val Leu Ala
100 105 110
Gly Asn Ala Phe Thr Ala Gly Lys Val Ile Ile Cys Cys Val Pro Pro
115 120 125
Gly Phe Gln Ser Arg Thr Leu Ser Ile Ala Gln Ala Thr Leu Phe Pro
130 135 140
His Val Ile Ala Asp Val Arg Thr Leu Asp Pro Val Glu Val Pro Leu
145 150 155 160
Glu Asp Val Arg Asn Val Leu Tyr His Asn Asn Asp Thr Gln Pro Thr
165 170 175
Met Arg Leu Leu Cys Met Leu Tyr Thr Pro Leu Arg Thr Gly Gly Ala
180 185 190
Ser Gly Gly Thr Asp Ser Phe Val Val Ala Gly Arg Val Leu Thr Cys
195 200 205
Pro Gly Pro Asp Phe Asn Phe Leu Phe Leu Val Pro Pro Thr Val Glu
210 215 220
Gln Lys Thr Arg Pro Phe Thr Val Pro Asn Ile Pro Leu Lys Tyr Leu
225 230 235 240
Ser Asn Ser Arg Ile Pro Asn Pro Ile Glu Gly Met Ser Leu Ser Pro
245 250 255
Asp Gln Thr Gln Asn Val Gln Phe Gln Asn Gly Arg Cys Thr Ile Asp
260 265 270
Gly Gln Pro Leu Gly Thr Thr Pro Val Ser Val Ser Gln Leu Cys Lys
275 280 285
Phe Arg Gly Arg Ile Thr Ser Gly Gln Arg Val Leu Asn Leu Thr Glu
290 295 300
Leu Asp Gly Ser Pro Phe Met Ala Phe Ala Ala Pro Ala Pro Ala Gly
305 310 315 320
Phe Pro Asp Leu Gly Ser Cys Asp Trp His Ile Glu Met Ser Lys Ile
325 330 335
Pro Asn Ser Ser Thr Gln Asn Asn Pro Ile Val Thr Asn Ser Val Lys
340 345 350
Pro Asn Ser Gln Gln Phe Val Pro His Leu Ser Ser Ile Thr Leu Asp
355 360 365
Glu Asn Val Ser Ser Gly Gly Asp Tyr Ile Gly Thr Ile Gln Trp Thr
370 375 380
Ser Pro Pro Ser Asp Ser Gly Gly Ala Asn Thr Asn Phe Trp Lys Ile
385 390 395 400
Pro Asp Tyr Gly Ser Ser Leu Ala Glu Ala Ser Gln Leu Ala Pro Ala
405 410 415
Val Tyr Pro Pro Gly Phe Asn Glu Val Ile Val Tyr Phe Met Ala Ser
420 425 430
Ile Pro Gly Pro Asn Gln Ser Gly Ser Pro Asn Leu Val Pro Cys Leu
435 440 445
Leu Pro Gln Glu Tyr Ile Thr His Phe Ile Ser Glu Gln Ala Pro Ile
450 455 460
Gln Gly Glu Ala Ala Leu Leu His Tyr Val Asp Pro Asp Thr Asn Arg
465 470 475 480
Asn Leu Gly Glu Phe Lys Leu Tyr Pro Gly Gly Tyr Leu Thr Cys Val
485 490 495
Pro Asn Ser Ser Ser Thr Gly Pro Gln Gln Leu Pro Leu Asp Gly Val
500 505 510
Phe Val Phe Ala Ser Trp Val Ser Arg Phe Tyr Gln Leu Lys Pro Val
515 520 525
Gly Thr Ala Gly Pro Ala Arg Gly Arg Leu Gly Val
530 535 540
<210> 3
<211> 540
<212> PRT
<213> 人工序列（artificial）
<220>
<223> H472R突变
<400> 3
Met Ala Ser Lys Asp Ala Thr Pro Ser Ala Asp Gly Ala Thr Gly Ala
1 5 10 15
Gly Gln Leu Val Pro Glu Val Asn Thr Ala Asp Pro Ile Pro Ile Asp
20 25 30
Pro Val Ala Gly Ser Ser Thr Ala Leu Ala Thr Ala Gly Gln Val Asn
35 40 45
Leu Ile Asp Pro Trp Ile Ile Asn Asn Phe Val Gln Ala Pro Gln Gly
50 55 60
Glu Phe Thr Ile Ser Pro Asn Asn Thr Pro Gly Asp Val Leu Phe Asp
65 70 75 80
Leu Gln Leu Gly Pro His Leu Asn Pro Phe Leu Ser His Leu Ser Gln
85 90 95
Met Tyr Asn Gly Trp Val Gly Asn Met Arg Val Arg Val Val Leu Ala
100 105 110
Gly Asn Ala Phe Thr Ala Gly Lys Val Ile Ile Cys Cys Val Pro Pro
115 120 125
Gly Phe Gln Ser Arg Thr Leu Ser Ile Ala Gln Ala Thr Leu Phe Pro
130 135 140
His Val Ile Ala Asp Val Arg Thr Leu Asp Pro Val Glu Val Pro Leu
145 150 155 160
Glu Asp Val Arg Asn Val Leu Tyr His Asn Asn Asp Thr Gln Pro Thr
165 170 175
Met Arg Leu Leu Cys Met Leu Tyr Thr Pro Leu Arg Thr Gly Gly Ala
180 185 190
Ser Gly Gly Thr Asp Ser Phe Val Val Ala Gly Arg Val Leu Thr Cys
195 200 205
Pro Gly Pro Asp Phe Asn Phe Leu Phe Leu Val Pro Pro Thr Val Glu
210 215 220
Gln Lys Thr Arg Pro Phe Thr Val Pro Asn Ile Pro Leu Lys Tyr Leu
225 230 235 240
Ser Asn Ser Arg Ile Pro Asn Pro Ile Glu Gly Met Ser Leu Ser Pro
245 250 255
Asp Gln Thr Gln Asn Val Gln Phe Gln Asn Gly Arg Cys Thr Ile Asp
260 265 270
Gly Gln Pro Leu Gly Thr Thr Pro Val Ser Val Ser Gln Leu Cys Lys
275 280 285
Phe Arg Gly Arg Ile Thr Ser Gly Gln Arg Val Leu Asn Leu Thr Glu
290 295 300
Leu Asp Gly Ser Pro Phe Met Ala Phe Ala Ala Pro Ala Pro Ala Gly
305 310 315 320
Phe Pro Asp Leu Gly Ser Cys Asp Trp His Ile Glu Met Ser Lys Ile
325 330 335
Pro Asn Ser Ser Thr Gln Asn Asn Pro Ile Val Thr Asn Ser Val Lys
340 345 350
Pro Asn Ser Gln Gln Phe Val Pro His Leu Ser Ser Ile Thr Leu Asp
355 360 365
Glu Asn Val Ser Ser Gly Gly Asp Tyr Ile Gly Thr Ile Gln Trp Thr
370 375 380
Ser Pro Pro Ser Asp Ser Gly Gly Ala Asn Thr Asn Phe Trp Lys Ile
385 390 395 400
Pro Asp Tyr Gly Ser Ser Leu Ala Glu Ala Ser Gln Leu Ala Pro Ala
405 410 415
Val Tyr Pro Pro Gly Phe Asn Glu Val Ile Val Tyr Phe Met Ala Ser
420 425 430
Ile Pro Gly Pro Asn Gln Ser Gly Ser Pro Asn Leu Val Pro Cys Leu
435 440 445
Leu Pro Gln Glu Tyr Ile Thr His Phe Ile Ser Glu Gln Ala Pro Ile
450 455 460
Gln Gly Glu Ala Ala Leu Leu Arg Tyr Val Asp Pro Asp Thr Asn Arg
465 470 475 480
Asn Leu Gly Glu Phe Lys Leu Tyr Pro Gly Gly Tyr Leu Thr Cys Val
485 490 495
Pro Asn Ser Ser Ser Thr Gly Pro Gln Gln Leu Pro Leu Asp Gly Val
500 505 510
Phe Val Phe Ala Ser Trp Val Ser Arg Phe Tyr Gln Leu Lys Pro Val
515 520 525
Gly Thr Ala Gly Pro Ala Arg Gly Arg Leu Gly Val
530 535 540
<210> 4
<211> 540
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> T39K、T43D、H472R突变
<400> 4
Met Ala Ser Lys Asp Ala Thr Pro Ser Ala Asp Gly Ala Thr Gly Ala
1 5 10 15
Gly Gln Leu Val Pro Glu Val Asn Thr Ala Asp Pro Ile Pro Ile Asp
20 25 30
Pro Val Ala Gly Ser Ser Lys Ala Leu Ala Asp Ala Gly Gln Val Asn
35 40 45
Leu Ile Asp Pro Trp Ile Ile Asn Asn Phe Val Gln Ala Pro Gln Gly
50 55 60
Glu Phe Thr Ile Ser Pro Asn Asn Thr Pro Gly Asp Val Leu Phe Asp
65 70 75 80
Leu Gln Leu Gly Pro His Leu Asn Pro Phe Leu Ser His Leu Ser Gln
85 90 95
Met Tyr Asn Gly Trp Val Gly Asn Met Arg Val Arg Val Val Leu Ala
100 105 110
Gly Asn Ala Phe Thr Ala Gly Lys Val Ile Ile Cys Cys Val Pro Pro
115 120 125
Gly Phe Gln Ser Arg Thr Leu Ser Ile Ala Gln Ala Thr Leu Phe Pro
130 135 140
His Val Ile Ala Asp Val Arg Thr Leu Asp Pro Val Glu Val Pro Leu
145 150 155 160
Glu Asp Val Arg Asn Val Leu Tyr His Asn Asn Asp Thr Gln Pro Thr
165 170 175
Met Arg Leu Leu Cys Met Leu Tyr Thr Pro Leu Arg Thr Gly Gly Ala
180 185 190
Ser Gly Gly Thr Asp Ser Phe Val Val Ala Gly Arg Val Leu Thr Cys
195 200 205
Pro Gly Pro Asp Phe Asn Phe Leu Phe Leu Val Pro Pro Thr Val Glu
210 215 220
Gln Lys Thr Arg Pro Phe Thr Val Pro Asn Ile Pro Leu Lys Tyr Leu
225 230 235 240
Ser Asn Ser Arg Ile Pro Asn Pro Ile Glu Gly Met Ser Leu Ser Pro
245 250 255
Asp Gln Thr Gln Asn Val Gln Phe Gln Asn Gly Arg Cys Thr Ile Asp
260 265 270
Gly Gln Pro Leu Gly Thr Thr Pro Val Ser Val Ser Gln Leu Cys Lys
275 280 285
Phe Arg Gly Arg Ile Thr Ser Gly Gln Arg Val Leu Asn Leu Thr Glu
290 295 300
Leu Asp Gly Ser Pro Phe Met Ala Phe Ala Ala Pro Ala Pro Ala Gly
305 310 315 320
Phe Pro Asp Leu Gly Ser Cys Asp Trp His Ile Glu Met Ser Lys Ile
325 330 335
Pro Asn Ser Ser Thr Gln Asn Asn Pro Ile Val Thr Asn Ser Val Lys
340 345 350
Pro Asn Ser Gln Gln Phe Val Pro His Leu Ser Ser Ile Thr Leu Asp
355 360 365
Glu Asn Val Ser Ser Gly Gly Asp Tyr Ile Gly Thr Ile Gln Trp Thr
370 375 380
Ser Pro Pro Ser Asp Ser Gly Gly Ala Asn Thr Asn Phe Trp Lys Ile
385 390 395 400
Pro Asp Tyr Gly Ser Ser Leu Ala Glu Ala Ser Gln Leu Ala Pro Ala
405 410 415
Val Tyr Pro Pro Gly Phe Asn Glu Val Ile Val Tyr Phe Met Ala Ser
420 425 430
Ile Pro Gly Pro Asn Gln Ser Gly Ser Pro Asn Leu Val Pro Cys Leu
435 440 445
Leu Pro Gln Glu Tyr Ile Thr His Phe Ile Ser Glu Gln Ala Pro Ile
450 455 460
Gln Gly Glu Ala Ala Leu Leu Arg Tyr Val Asp Pro Asp Thr Asn Arg
465 470 475 480
Asn Leu Gly Glu Phe Lys Leu Tyr Pro Gly Gly Tyr Leu Thr Cys Val
485 490 495
Pro Asn Ser Ser Ser Thr Gly Pro Gln Gln Leu Pro Leu Asp Gly Val
500 505 510
Phe Val Phe Ala Ser Trp Val Ser Arg Phe Tyr Gln Leu Lys Pro Val
515 520 525
Gly Thr Ala Gly Pro Ala Arg Gly Arg Leu Gly Val
530 535 540
<210> 5
<211> 540
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> T39D、T43K、H472R突变
<400> 5
Met Ala Ser Lys Asp Ala Thr Pro Ser Ala Asp Gly Ala Thr Gly Ala
1 5 10 15
Gly Gln Leu Val Pro Glu Val Asn Thr Ala Asp Pro Ile Pro Ile Asp
20 25 30
Pro Val Ala Gly Ser Ser Asp Ala Leu Ala Lys Ala Gly Gln Val Asn
35 40 45
Leu Ile Asp Pro Trp Ile Ile Asn Asn Phe Val Gln Ala Pro Gln Gly
50 55 60
Glu Phe Thr Ile Ser Pro Asn Asn Thr Pro Gly Asp Val Leu Phe Asp
65 70 75 80
Leu Gln Leu Gly Pro His Leu Asn Pro Phe Leu Ser His Leu Ser Gln
85 90 95
Met Tyr Asn Gly Trp Val Gly Asn Met Arg Val Arg Val Val Leu Ala
100 105 110
Gly Asn Ala Phe Thr Ala Gly Lys Val Ile Ile Cys Cys Val Pro Pro
115 120 125
Gly Phe Gln Ser Arg Thr Leu Ser Ile Ala Gln Ala Thr Leu Phe Pro
130 135 140
His Val Ile Ala Asp Val Arg Thr Leu Asp Pro Val Glu Val Pro Leu
145 150 155 160
Glu Asp Val Arg Asn Val Leu Tyr His Asn Asn Asp Thr Gln Pro Thr
165 170 175
Met Arg Leu Leu Cys Met Leu Tyr Thr Pro Leu Arg Thr Gly Gly Ala
180 185 190
Ser Gly Gly Thr Asp Ser Phe Val Val Ala Gly Arg Val Leu Thr Cys
195 200 205
Pro Gly Pro Asp Phe Asn Phe Leu Phe Leu Val Pro Pro Thr Val Glu
210 215 220
Gln Lys Thr Arg Pro Phe Thr Val Pro Asn Ile Pro Leu Lys Tyr Leu
225 230 235 240
Ser Asn Ser Arg Ile Pro Asn Pro Ile Glu Gly Met Ser Leu Ser Pro
245 250 255
Asp Gln Thr Gln Asn Val Gln Phe Gln Asn Gly Arg Cys Thr Ile Asp
260 265 270
Gly Gln Pro Leu Gly Thr Thr Pro Val Ser Val Ser Gln Leu Cys Lys
275 280 285
Phe Arg Gly Arg Ile Thr Ser Gly Gln Arg Val Leu Asn Leu Thr Glu
290 295 300
Leu Asp Gly Ser Pro Phe Met Ala Phe Ala Ala Pro Ala Pro Ala Gly
305 310 315 320
Phe Pro Asp Leu Gly Ser Cys Asp Trp His Ile Glu Met Ser Lys Ile
325 330 335
Pro Asn Ser Ser Thr Gln Asn Asn Pro Ile Val Thr Asn Ser Val Lys
340 345 350
Pro Asn Ser Gln Gln Phe Val Pro His Leu Ser Ser Ile Thr Leu Asp
355 360 365
Glu Asn Val Ser Ser Gly Gly Asp Tyr Ile Gly Thr Ile Gln Trp Thr
370 375 380
Ser Pro Pro Ser Asp Ser Gly Gly Ala Asn Thr Asn Phe Trp Lys Ile
385 390 395 400
Pro Asp Tyr Gly Ser Ser Leu Ala Glu Ala Ser Gln Leu Ala Pro Ala
405 410 415
Val Tyr Pro Pro Gly Phe Asn Glu Val Ile Val Tyr Phe Met Ala Ser
420 425 430
Ile Pro Gly Pro Asn Gln Ser Gly Ser Pro Asn Leu Val Pro Cys Leu
435 440 445
Leu Pro Gln Glu Tyr Ile Thr His Phe Ile Ser Glu Gln Ala Pro Ile
450 455 460
Gln Gly Glu Ala Ala Leu Leu Arg Tyr Val Asp Pro Asp Thr Asn Arg
465 470 475 480
Asn Leu Gly Glu Phe Lys Leu Tyr Pro Gly Gly Tyr Leu Thr Cys Val
485 490 495
Pro Asn Ser Ser Ser Thr Gly Pro Gln Gln Leu Pro Leu Asp Gly Val
500 505 510
Phe Val Phe Ala Ser Trp Val Ser Arg Phe Tyr Gln Leu Lys Pro Val
515 520 525
Gly Thr Ala Gly Pro Ala Arg Gly Arg Leu Gly Val
530 535 540
<210> 6
<211> 539
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 6
Met Met Met Ala Ser Lys Asp Ala Pro Thr Ser Pro Asp Gly Ala Ser
1 5 10 15
Gly Ala Gly Gln Leu Val Pro Glu Ala Asn Thr Ala Glu Gln Ile Ser
20 25 30
Met Asp Pro Val Ala Gly Ala Ser Thr Ala Val Ala Thr Ala Gly Gln
35 40 45
Val Asn Met Ile Asp Pro Trp Ile Phe Asn Asn Phe Val Gln Ala Pro
50 55 60
Gln Gly Glu Phe Thr Ile Ser Pro Asn Asn Thr Pro Gly Asp Ile Leu
65 70 75 80
Phe Asp Leu Gln Leu Gly Pro His Leu Asn Pro Phe Leu Ala His Leu
85 90 95
Ser Gln Met Tyr Asn Gly Trp Val Gly Asn Met Arg Val Arg Ile Leu
100 105 110
Leu Ala Gly Asn Ala Phe Thr Ala Gly Lys Ile Ile Ile Cys Cys Val
115 120 125
Pro Pro Gly Phe Asp Ala Arg Ile Leu Thr Ile Ala Gln Ala Thr Leu
130 135 140
Phe Pro His Leu Ile Ala Asp Val Arg Thr Leu Glu Pro Val Glu Leu
145 150 155 160
Pro Leu Glu Asp Val Arg Asn Val Leu Tyr His Asn Ser Ser Gln Pro
165 170 175
Gln Pro Thr Met Arg Leu Val Ala Met Leu Tyr Thr Pro Leu Arg Thr
180 185 190
Gly Gly Gly Ser Gly Gly Thr Asp Ala Phe Val Val Ala Gly Arg Val
195 200 205
Leu Thr Cys Pro Ala Pro Asp Phe Ser Phe Leu Phe Leu Val Pro Pro
210 215 220
Ser Val Glu Gln Lys Thr Arg Val Phe Ser Val Pro Asn Ile Pro Leu
225 230 235 240
Lys Asp Leu Ser Asn Ser Arg Val Pro Val Pro Ile Gln Gly Met Phe
245 250 255
Met Ser Pro Asp Val Asn Gln Ser Val Gln Phe Gln Asn Gly Arg Cys
260 265 270
Gln Ile Asp Gly Gln Leu Gln Gly Thr Thr Pro Val Ser Leu Ser Gln
275 280 285
Leu Cys Lys Ile Arg Gly Lys Thr Ser Ser Asn Ala Arg Val Leu Asn
290 295 300
Leu Ser Glu Val Asp Gly Thr Pro Phe Ile Pro Leu Glu Ser Pro Ala
305 310 315 320
Pro Val Gly Phe Pro Asp Leu Gly Gly Cys Asp Trp His Val Asn Phe
325 330 335
Ser Phe Gln Thr Gln Asp Arg Asp Pro Ser Gln Ser Val Thr Phe Ala
340 345 350
Thr Asn Asp Ala Ser Phe Val Pro Tyr Leu Gly Ser Val Ser Pro His
355 360 365
Asn Gly Glu Gly Phe Gln Ala Gly Asp Ile Ile Gly Ser Leu Gly Trp
370 375 380
Ile Ser Ala Pro Ser Asp Asn Ser Gln Phe Asn Val Trp Ala Ile Pro
385 390 395 400
Lys Tyr Gly Ser Ser Leu Gln Met Ser Pro Ile Leu Leu Leu Leu Cys
405 410 415
Ser Pro Arg Leu Trp Glu Val Ile Leu Tyr Phe Tyr Ser Thr Phe Pro
420 425 430
Gly Ser Gly Gln Pro Ser Gln Leu Gln Val Pro Cys Leu Leu Pro Gln
435 440 445
Glu Phe Ile Thr His Phe Cys Asn Glu Gln Ala Pro Ile Ala Gly Glu
450 455 460
Ala Ala Leu Leu His Tyr Val Asp Pro Asp Thr Gly Arg Asn Leu Gly
465 470 475 480
Glu Phe Lys Leu Tyr Pro Asp Gly Phe Met Thr Cys Val Pro Asn Ser
485 490 495
Val Ser Ser Gly Pro Gln Thr Leu Pro Ile Asn Gly Val Phe Val Phe
500 505 510
Val Ser Trp Val Ser Arg Phe Tyr Gln Leu Lys Pro Val Gly Thr Ala
515 520 525
Ser Ala Ala Arg Arg Leu Gly Leu Arg Arg Ile
530 535
<210> 7
<211> 544
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 7
Met Met Met Ala Ser Lys Asp Ala Pro Thr Asn Met Asp Gly Thr Ser
1 5 10 15
Gly Ala Gly Gln Leu Val Pro Glu Ala Asn Thr Ala Glu Pro Ile Ser
20 25 30
Met Asp Pro Val Ala Gly Ala Ala Thr Ala Val Ala Thr Ala Gly Gln
35 40 45
Ile Asn Met Ile Asp Pro Trp Ile Met Ser Asn Phe Val Gln Ala Pro
50 55 60
Gln Gly Glu Phe Thr Val Ser Pro Asn Asn Thr Pro Gly Asp Val Leu
65 70 75 80
Phe Asp Leu Gln Leu Gly Pro Gln Leu Asn Pro Phe Leu Ala His Leu
85 90 95
Ala Gln Met Tyr Asn Gly Trp Val Gly Asn Met Arg Val Lys Val Leu
100 105 110
Leu Ala Gly Asn Ala Phe Thr Ala Gly Lys Ile Ile Ile Ser Cys Ile
115 120 125
Pro Pro Gly Phe Thr Ser Gln Asn Ile Ser Ile Ala Gln Met Thr Met
130 135 140
Phe Pro His Val Ile Ala Asp Val Arg Val Leu Glu Pro Ile Glu Ile
145 150 155 160
Pro Leu Glu Asp Val Arg Asn Val Leu Phe His Thr Asn Asp Asn Arg
165 170 175
Pro Thr Met Arg Leu Val Cys Met Leu Tyr Thr Pro Leu Arg Ala Asn
180 185 190
Gly Ser Ser Ser Gly Thr Asp Pro Phe Val Ile Ala Gly Arg Val Leu
195 200 205
Thr Cys Pro Asp Ser Asn Phe Ser Phe Leu Phe Leu Val Pro Pro Asn
210 215 220
Val Glu Gln Lys Thr Arg Pro Phe Ser Val Pro Asn Ile Pro Leu Asn
225 230 235 240
Thr Leu Ser Asn Ser Arg Val Pro Ser Leu Ile Lys Ser Met Thr Ile
245 250 255
Ser Arg Asp Gln Asn Gln Ile Ile Gln Phe Gln Asn Gly Arg Val Thr
260 265 270
Leu Asp Gly Gln Leu Gln Gly Thr Thr Pro Thr Ser Val Ser Gln Leu
275 280 285
Cys Lys Ile Arg Gly Thr Thr Tyr His Ala Thr Gly Gly Asn Gly Ile
290 295 300
Asn Leu Thr Glu Leu Asn Gly Glu Pro Tyr His Ala Phe Glu Ser Pro
305 310 315 320
Ala Pro Ile Gly Phe Pro Asp Leu Gly Gly Cys Asp Trp His Leu Thr
325 330 335
Ala Thr Pro Thr Gln Ala Phe Asn Asp Gly Ala Lys Val Val Arg Leu
340 345 350
Ser Val Thr Gln Gly Ala Ala Phe Ala Pro His Leu Gly Thr Ile His
355 360 365
Tyr Thr Thr Thr Asp His Asp Tyr Asp Pro Asn Thr Ser Ile Ile Cys
370 375 380
Thr Leu Asp Trp Leu Ser Gln Thr Thr Gly Gln Asn Asn Val Asp Pro
385 390 395 400
Trp Gln Ile Pro Thr Tyr Gly Ser Thr Leu Thr Glu Ala Ala Gln Leu
405 410 415
Ala Pro Pro Ile Phe Pro Pro Gly Phe Gly Glu Thr Leu Val Phe Phe
420 425 430
Leu Ser Asp Phe Pro Ile Ser Asn Gly Lys Asn Gly Leu Ser Val Pro
435 440 445
Cys Thr Leu Pro Gln Glu Phe Val Thr His Phe Val Asn Glu Gln Ala
450 455 460
Pro Ile Arg Gly Glu Ala Ala Leu Leu His Tyr Val Asp Pro Asp Thr
465 470 475 480
His Arg Asn Leu Gly Glu Phe Lys Leu Tyr Pro Glu Gly Phe Met Thr
485 490 495
Cys Val Pro Asn Thr Ser Gly Gly Gly Pro Gln Thr Leu Pro Ile Asn
500 505 510
Gly Val Phe Val Phe Val Ser Trp Val Ser Arg Phe Tyr Gln Leu Lys
515 520 525
Pro Val Gly Thr Ala Gly Ala Ala Arg Arg Leu Gly Ile Arg Arg Ser
530 535 540
<210> 8
<211> 545
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 8
Met Met Met Ala Ser Lys Asp Ala Pro Thr Asn Met Asp Gly Thr Ser
1 5 10 15
Gly Ala Gly Gln Leu Val Pro Glu Ala Asn Thr Ala Glu Pro Ile Ser
20 25 30
Met Glu Pro Val Ala Gly Ala Ala Thr Ala Ala Ala Thr Ala Gly Gln
35 40 45
Val Asn Met Ile Asp Pro Trp Ile Met Asn Asn Tyr Val Gln Ala Pro
50 55 60
Gln Gly Glu Phe Thr Ile Ser Pro Asn Asn Thr Pro Gly Asp Ile Leu
65 70 75 80
Phe Asp Leu Gln Leu Gly Pro His Leu Asn Pro Phe Leu Ser His Leu
85 90 95
Ala Gln Met Tyr Asn Gly Trp Val Gly Asn Met Lys Val Lys Val Leu
100 105 110
Leu Ala Gly Asn Ala Phe Thr Ala Gly Lys Ile Ile Ile Ser Cys Ile
115 120 125
Pro Pro Gly Phe Ala Ala Gln Asn Ile Ser Ile Ala Gln Ala Thr Met
130 135 140
Phe Pro His Val Ile Ala Asp Val Arg Val Leu Glu Pro Ile Glu Ile
145 150 155 160
Pro Leu Glu Asp Val Arg Asn Val Leu Phe His Asn Asn Asp Asn Thr
165 170 175
Pro Thr Met Arg Leu Val Cys Met Leu Tyr Thr Pro Leu Arg Ala Ser
180 185 190
Gly Ser Ser Ser Gly Thr Asp Pro Phe Val Ile Ala Gly Arg Val Leu
195 200 205
Thr Cys Pro Ser Pro Asp Phe Ser Phe Leu Phe Leu Val Pro Pro Asn
210 215 220
Val Glu Gln Lys Thr Lys Pro Phe Ser Val Pro Asn Leu Pro Leu Asn
225 230 235 240
Ile Leu Ser Ser Ser Arg Val Pro Ser Leu Ile Lys Ser Met Met Ile
245 250 255
Ser Arg Asp His Gly Gln Met Val Gln Phe Gln Asn Gly Arg Val Thr
260 265 270
Leu Asp Gly Gln Leu Gln Gly Thr Thr Pro Thr Ser Ala Ser Gln Leu
275 280 285
Cys Lys Ile Arg Gly Ser Val Phe His Ala Asn Gly Gly Asn Gly Tyr
290 295 300
Asn Leu Thr Glu Leu Asp Gly Ser Pro Tyr His Ala Phe Glu Ser Pro
305 310 315 320
Ala Pro Ile Gly Phe Pro Asp Leu Gly Glu Cys Asp Trp His Met Glu
325 330 335
Ala Ser Pro Thr Ile Gln Phe Asp Thr Gly Asp Val Ile Lys Gln Ile
340 345 350
Asn Val Lys Gln Glu Ser Ala Phe Ala Pro His Leu Gly Thr Val Gln
355 360 365
Ala Asp Gly Leu Asp Gly Val Ser Ala Asn Thr Asn Met Ile Ala Lys
370 375 380
Leu Gly Trp Val Ser Pro Val Ser Asp Gly His Arg Arg Asp Val Asp
385 390 395 400
Pro Trp Val Ile Pro Arg Tyr Gly Ser Thr Leu Thr Glu Ala Ala Gln
405 410 415
Leu Ala Pro Pro Ile Tyr Pro Pro Gly Phe Gly Glu Ala Ile Val Phe
420 425 430
Phe Met Ser Asp Phe Pro Ile Ala His Gly Thr Asn Gly Leu Ser Val
435 440 445
Pro Cys Thr Ile Pro Gln Glu Phe Val Thr His Phe Val Asn Glu Gln
450 455 460
Ala Pro Thr Arg Gly Glu Ala Ala Leu Leu His Tyr Leu Asp Pro Asp
465 470 475 480
Thr His Arg Asn Leu Gly Glu Phe Lys Leu Tyr Pro Asp Gly Phe Met
485 490 495
Thr Cys Val Pro Asn Ser Ser Gly Ser Gly Pro Gln Thr Leu Pro Ile
500 505 510
Asn Gly Val Phe Val Phe Val Ser Trp Val Ser Arg Phe Tyr Gln Leu
515 520 525
Lys Pro Val Gly Thr Ala Gly Pro Ala Arg Arg Leu Gly Ile Arg Arg
530 535 540
Ser
545
<210> 9
<211> 545
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 9
Met Met Met Ala Ser Lys Asp Ala Pro Ser Asn Met Asp Gly Thr Ser
1 5 10 15
Gly Ala Gly Gln Leu Val Pro Glu Ala Asn Thr Ala Glu Pro Ile Asn
20 25 30
Met Glu Ser Val Val Gly Ala Ala Thr Ala Thr Ala Thr Ala Gly Gln
35 40 45
Val Asn Leu Ile Asp Pro Trp Ile Met Asn Asn Tyr Val Gln Ala Pro
50 55 60
Gln Gly Glu Phe Thr Ile Ser Pro Asn Asn Thr Pro Gly Asp Val Leu
65 70 75 80
Phe Asp Leu Gln Leu Gly Pro His Leu Asn Pro Phe Leu Ser His Leu
85 90 95
Ser Arg Met Tyr Asn Gly Trp Val Gly Asn Met Lys Val Arg Val Met
100 105 110
Leu Ala Gly Asn Ala Phe Ser Ala Gly Lys Ile Ile Ile Cys Cys Ile
115 120 125
Pro Pro Gly Phe Thr Ser Gln Ser Ile Ser Ile Ala Gln Ala Thr Met
130 135 140
Phe Pro His Val Ile Ala Asp Val Arg Val Leu Glu Pro Ile Asp Val
145 150 155 160
Pro Leu Asp Asp Val Arg Asn Val Leu Phe His Asn Asn Asp Asn Ala
165 170 175
Gln Thr Met Arg Leu Leu Cys Met Leu Tyr Thr Pro Leu Arg Thr Gly
180 185 190
Ala Ser Ser Ser Gly Ser Asp Pro Phe Val Ile Ala Gly Arg Val Leu
195 200 205
Thr Cys Pro Thr Gln Asp Phe Asn Phe Leu Phe Leu Val Pro Pro Asp
210 215 220
Val Glu Gln Lys Thr Lys Pro Phe Ser Val Pro Asn Ile Pro Leu Asn
225 230 235 240
Leu Met Ser Asn Ser Arg Val Pro Ala Leu Ile Asp Gly Met Thr Val
245 250 255
Ser Ser Asp Gln Asn Gln Val Val Gln Phe Gln Asn Gly Arg Val Thr
260 265 270
Leu Asp Gly Gln Leu Gln Gly Thr Thr Ala Val Ser Ala Ser Cys Val
275 280 285
Ala Lys Ile Arg Gly Arg Ile Phe Ser Asn Ala Ser His Tyr Gly Ile
290 295 300
Asn Leu Thr Glu Val Asp Gly Thr Gln Tyr His Ala Phe Asp Ser Pro
305 310 315 320
Ala Pro Leu Gly Phe Pro Asp Phe Gly Asn Cys Asp Trp His Val Thr
325 330 335
Gly Thr Lys Ala Ser Gln Gly Asp Leu Gln Thr Asp Asn Pro Thr Ile
340 345 350
Ser Gly Thr Ile Lys Ser Tyr Glu Ser Ser Phe Ala Pro His Leu Gly
355 360 365
Thr Val Arg Ile Glu Gly Asp Asp Asn Glu Leu Ala Arg Phe Asn Gly
370 375 380
Lys Asp Val Leu Leu Asn Leu Thr Trp Phe Ser Gln Arg Asn Gly Ser
385 390 395 400
Gln Leu Asn Leu Trp Thr Ile Pro Ser Tyr Gly Ser Asn Leu Thr Glu
405 410 415
Ala Ser Gln Leu Ala Pro Pro Ile Tyr Pro Pro Gly Phe Gly Glu Ala
420 425 430
Ile Val Tyr Phe Thr Ser Thr Phe Pro Ala Ile Ser Arg Pro Ser Val
435 440 445
Pro Cys Thr Met Pro Gln Glu Phe Val Ser His Phe Val Asn Glu Gln
450 455 460
Ala Pro Thr Arg Gly Glu Ala Ala Leu Leu His Tyr Leu Asp Pro Asp
465 470 475 480
Thr His Arg Asn Leu Gly Glu Phe Lys Met Tyr Pro Glu Gly Phe Phe
485 490 495
Thr Cys Val Pro Asn Ala Gly Gly Ser Gly Pro Gln Thr Leu Pro Ile
500 505 510
Asn Gly Val Phe Val Phe Val Ser Trp Val Ser Arg Tyr Tyr Gln Leu
515 520 525
Lys Pro Val Gly Thr Val Gly Met Thr Arg Arg Leu Gly Leu Met Lys
530 535 540
Gln
545
<210> 10
<211> 530
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 10
Met Met Met Ala Ser Lys Asp Ala Thr Ser Ser Val Asp Gly Ala Ser
1 5 10 15
Gly Ala Gly Gln Leu Val Pro Glu Val Asn Ala Ser Asp Pro Leu Ala
20 25 30
Met Asp Pro Val Ala Gly Ser Ser Thr Ala Val Ala Thr Ala Gly Gln
35 40 45
Val Asn Pro Ile Asp Pro Trp Ile Ile Asn Asn Phe Val Gln Ala Pro
50 55 60
Gln Gly Glu Phe Thr Ile Ser Pro Asn Asn Thr Pro Gly Asp Val Leu
65 70 75 80
Phe Asp Leu Ser Leu Gly Pro His Leu Asn Pro Phe Leu Leu His Leu
85 90 95
Ser Gln Met Tyr Asn Gly Trp Val Gly Asn Met Arg Val Arg Ile Met
100 105 110
Leu Ala Gly Asn Ala Phe Thr Ala Gly Lys Ile Ile Val Ser Cys Ile
115 120 125
Pro Pro Gly Phe Gly Ser His Asn Leu Thr Ile Ala Gln Ala Thr Leu
130 135 140
Phe Pro His Val Ile Ala Asp Val Arg Thr Leu Asp Pro Ile Glu Val
145 150 155 160
Pro Leu Glu Asp Val Arg Asn Val Leu Phe His Asn Asn Asp Arg Asn
165 170 175
Gln Gln Thr Met Arg Leu Val Cys Met Leu Tyr Thr Pro Leu Arg Thr
180 185 190
Gly Gly Gly Thr Gly Asp Ser Phe Val Val Ala Gly Arg Val Met Thr
195 200 205
Cys Pro Ser Pro Asp Phe Asn Phe Leu Phe Leu Val Pro Pro Thr Val
210 215 220
Glu Gln Lys Thr Arg Pro Phe Thr Leu Pro Asn Leu Pro Leu Ser Ser
225 230 235 240
Leu Ser Asn Ser Arg Ala Pro Leu Pro Ile Ser Ser Met Gly Ile Ser
245 250 255
Pro Asp Asn Val Gln Ser Val Gln Phe Gln Asn Gly Arg Cys Thr Leu
260 265 270
Asp Gly Arg Leu Val Gly Thr Thr Pro Val Ser Leu Ser His Val Ala
275 280 285
Lys Ile Arg Gly Thr Ser Asn Gly Thr Val Ile Asn Leu Thr Glu Leu
290 295 300
Asp Gly Thr Pro Phe His Pro Phe Glu Gly Pro Ala Pro Ile Gly Phe
305 310 315 320
Pro Asp Leu Gly Gly Cys Asp Trp His Ile Asn Met Thr Gln Phe Gly
325 330 335
His Ser Ser Gln Thr Gln Tyr Asp Val Asp Thr Thr Pro Asp Thr Phe
340 345 350
Val Pro His Leu Gly Ser Ile Gln Ala Asn Gly Ile Gly Ser Gly Asn
355 360 365
Tyr Val Gly Val Leu Ser Trp Ile Ser Pro Pro Ser His Pro Ser Gly
370 375 380
Ser Gln Val Asp Leu Trp Lys Ile Pro Asn Tyr Gly Ser Ser Ile Thr
385 390 395 400
Glu Ala Thr His Leu Ala Pro Ser Val Tyr Pro Pro Gly Phe Gly Glu
405 410 415
Val Leu Val Phe Phe Met Ser Lys Met Pro Gly Pro Gly Ala Tyr Asn
420 425 430
Leu Pro Cys Leu Leu Pro Gln Glu Tyr Ile Ser His Leu Ala Ser Glu
435 440 445
Gln Ala Pro Thr Val Gly Glu Ala Ala Leu Leu His Tyr Val Asp Pro
450 455 460
Asp Thr Gly Arg Asn Leu Gly Glu Phe Lys Ala Tyr Pro Asp Gly Phe
465 470 475 480
Leu Thr Cys Val Pro Asn Gly Ala Ser Ser Gly Pro Gln Gln Leu Pro
485 490 495
Ile Asn Gly Val Phe Val Phe Val Ser Trp Val Ser Arg Phe Tyr Gln
500 505 510
Leu Lys Pro Val Gly Thr Ala Ser Ser Ala Arg Gly Arg Leu Gly Leu
515 520 525
Arg Arg
530
<210> 11
<211> 546
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 11
Met Met Met Ala Ser Lys Asp Ala Pro Gln Ser Ala Asp Gly Ala Ser
1 5 10 15
Gly Ala Gly Gln Leu Val Pro Glu Val Asn Thr Ala Asp Pro Leu Pro
20 25 30
Met Glu Pro Val Ala Gly Pro Thr Thr Ala Val Ala Thr Ala Gly Gln
35 40 45
Val Asn Met Ile Asp Pro Trp Ile Val Asn Asn Phe Val Gln Ser Pro
50 55 60
Gln Gly Glu Phe Thr Ile Ser Pro Asn Asn Thr Pro Gly Asp Ile Leu
65 70 75 80
Phe Asp Leu Gln Leu Gly Pro His Leu Asn Pro Phe Leu Ser His Leu
85 90 95
Ser Gln Met Tyr Asn Gly Trp Val Gly Asn Met Arg Val Arg Ile Leu
100 105 110
Leu Ala Gly Asn Ala Phe Ser Ala Gly Lys Ile Ile Val Cys Cys Val
115 120 125
Pro Pro Gly Phe Thr Ser Ser Ser Leu Thr Ile Ala Gln Ala Thr Leu
130 135 140
Phe Pro His Val Ile Ala Asp Val Arg Thr Leu Glu Pro Ile Glu Met
145 150 155 160
Pro Leu Glu Asp Val Arg Asn Val Leu Tyr His Thr Asn Asp Asn Gln
165 170 175
Pro Thr Met Arg Leu Val Cys Met Leu Tyr Thr Pro Leu Arg Thr Gly
180 185 190
Gly Gly Ser Gly Ser Ser Asp Ser Phe Val Val Ala Gly Arg Val Leu
195 200 205
Thr Ala Pro Ser Ser Asp Phe Ser Phe Leu Phe Leu Val Pro Pro Thr
210 215 220
Ile Glu Gln Lys Thr Arg Ala Phe Thr Val Pro Asn Ile Pro Leu Gln
225 230 235 240
Thr Leu Ser Asn Ser Arg Phe Pro Ser Leu Ile Gln Gly Met Ile Leu
245 250 255
Ser Pro Asp Ala Ser Gln Val Val Gln Phe Gln Asn Gly Arg Cys Leu
260 265 270
Ile Asp Gly Gln Leu Leu Gly Thr Thr Pro Ala Thr Ser Gly Gln Leu
275 280 285
Phe Arg Val Arg Gly Lys Ile Asn Gln Gly Ala Arg Thr Leu Asn Leu
290 295 300
Thr Glu Val Asp Gly Lys Pro Phe Met Ala Phe Asp Ser Pro Ala Pro
305 310 315 320
Val Gly Phe Pro Asp Phe Gly Lys Cys Asp Trp His Met Arg Ile Ser
325 330 335
Lys Thr Pro Asn Asn Thr Ser Ser Gly Asp Pro Met Arg Ser Val Ser
340 345 350
Val Gln Thr Asn Val Gln Gly Phe Val Pro His Leu Gly Ser Ile Gln
355 360 365
Phe Asp Glu Val Phe Asn His Pro Thr Gly Asp Tyr Ile Gly Thr Ile
370 375 380
Glu Trp Ile Ser Gln Pro Ser Thr Pro Pro Gly Thr Asp Ile Asn Leu
385 390 395 400
Trp Glu Ile Pro Asp Tyr Gly Ser Ser Leu Ser Gln Ala Ala Asn Leu
405 410 415
Ala Pro Pro Val Phe Pro Pro Gly Phe Gly Glu Ala Leu Val Tyr Phe
420 425 430
Val Ser Ala Phe Pro Gly Pro Asn Asn Arg Ser Ala Pro Asn Asp Val
435 440 445
Pro Cys Leu Leu Pro Gln Glu Tyr Ile Thr His Phe Val Ser Glu Gln
450 455 460
Ala Pro Thr Met Gly Asp Ala Ala Leu Leu His Tyr Val Asp Pro Asp
465 470 475 480
Thr Asn Arg Asn Leu Gly Glu Phe Lys Leu Tyr Pro Gly Gly Tyr Leu
485 490 495
Thr Cys Val Pro Asn Gly Val Gly Ala Gly Pro Gln Gln Leu Pro Leu
500 505 510
Asn Gly Val Phe Leu Phe Val Ser Trp Val Ser Arg Phe Tyr Gln Leu
515 520 525
Lys Pro Val Gly Thr Ala Ser Thr Ala Arg Gly Arg Leu Gly Val Arg
530 535 540
Arg Ile
545
<210> 12
<211> 544
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 12
Met Met Met Ala Ser Lys Asp Ala Pro Thr Asn Met Asp Gly Thr Ser
1 5 10 15
Gly Ala Gly Gln Leu Val Pro Glu Ala Asn Thr Ala Glu Pro Ile Ser
20 25 30
Met Glu Pro Val Ala Gly Ala Ala Thr Ala Ala Ala Thr Ala Gly Gln
35 40 45
Val Asn Met Ile Asp Pro Trp Ile Met Asn Asn Tyr Val Gln Ala Pro
50 55 60
Gln Gly Glu Phe Thr Ile Ser Pro Asn Asn Thr Pro Gly Asp Ile Leu
65 70 75 80
Phe Asp Leu Gln Leu Gly Pro His Leu Asn Pro Phe Leu Ser His Leu
85 90 95
Ala Gln Met Tyr Asn Gly Trp Val Gly Asn Met Lys Val Lys Val Leu
100 105 110
Leu Ala Gly Asn Ala Phe Thr Ala Gly Lys Ile Ile Ile Ser Cys Ile
115 120 125
Pro Pro Gly Phe Ala Ser Gln Asn Ile Ser Ile Ala Gln Ala Thr Met
130 135 140
Phe Pro His Val Ile Ala Asp Val Arg Val Leu Glu Pro Ile Glu Val
145 150 155 160
Pro Leu Glu Asp Val Arg Asn Val Leu Phe His Asn Asn Asp Asn Thr
165 170 175
Pro Thr Met Arg Leu Val Cys Met Leu Tyr Thr Pro Leu Arg Ala Ser
180 185 190
Gly Ser Ser Ser Gly Thr Asp Pro Phe Val Ile Ala Gly Arg Val Leu
195 200 205
Thr Cys Pro Ser Pro Asp Phe Ser Phe Leu Phe Leu Val Pro Pro Asn
210 215 220
Val Glu Gln Lys Thr Lys Pro Phe Ser Val Pro Asn Leu Pro Leu Asn
225 230 235 240
Val Leu Ser Asn Ser Arg Val Pro Ser Leu Ile Lys Ser Met Met Val
245 250 255
Ser Gln Asp His Gly Gln Met Val Gln Phe Gln Asn Gly Arg Val Thr
260 265 270
Leu Asp Gly Gln Leu Gln Gly Thr Thr Pro Thr Ser Ala Ser Gln Leu
275 280 285
Cys Lys Met Arg Gly Thr Val Tyr His Ala Ser Gly Gly Gln Gly Leu
290 295 300
Asn Leu Thr Glu Ile Asp Gly Thr Pro Tyr His Ala Phe Glu Ser Pro
305 310 315 320
Ala Pro Ile Gly Phe Pro Asp Ile Gly Asp Ser Asp Trp His Ile Asn
325 330 335
Ala Ser Pro Ala Thr Thr Phe Asp Ser Gly Glu Ser Ile Lys Arg Leu
340 345 350
Asp Met Glu Gln Gly Ser Ser Phe Ala Pro His Leu Gly Thr Val His
355 360 365
Tyr Thr Asn Ala Asp Tyr Pro Ala Asn Thr Asp Leu Ile Cys Ser Leu
370 375 380
Glu Trp Leu Ser Pro Pro Ser Gly Gly Thr Pro Asn Lys Val Asn Pro
385 390 395 400
Trp Thr Ile Pro Arg Tyr Gly Ser Thr Leu Thr Glu Ala Ala Gln Leu
405 410 415
Ala Pro Pro Ile Tyr Pro Pro Gly Phe Gly Glu Ala Ile Val Phe Phe
420 425 430
Met Ser Asp Phe Pro Ile Ala Asn Gly Gln Asp Gly Leu Lys Val Pro
435 440 445
Cys Thr Ile Pro Gln Glu Phe Val Thr His Phe Val Asn Glu Gln Ala
450 455 460
Pro Thr Arg Gly Glu Ala Ala Leu Leu His Tyr Val Asp Pro Asp Thr
465 470 475 480
His Arg Asn Leu Gly Glu Phe Lys Leu Tyr Pro Glu Gly Phe Met Thr
485 490 495
Cys Val Pro Asn Ser Ser Gly Ser Gly Pro Gln Thr Leu Pro Ile Asn
500 505 510
Gly Val Phe Thr Phe Val Ser Trp Val Ser Arg Phe Tyr Gln Leu Lys
515 520 525
Pro Val Gly Thr Thr Gly Pro Val Arg Arg Leu Gly Ile Arg Arg Ser
530 535 540
<210> 13
<211> 544
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 13
Met Met Met Ala Ser Lys Asp Ala Pro Thr Asn Met Asp Gly Thr Ser
1 5 10 15
Gly Ala Gly Gln Leu Val Pro Glu Ala Asn Thr Ala Glu Pro Ile Ser
20 25 30
Met Glu Pro Val Ala Gly Ala Ala Thr Ala Ala Ala Thr Ala Gly Gln
35 40 45
Val Asn Met Ile Asp Pro Trp Ile Met Asn Asn Tyr Val Gln Ala Pro
50 55 60
Gln Gly Glu Phe Thr Ile Ser Pro Asn Asn Thr Pro Gly Asp Ile Leu
65 70 75 80
Phe Asp Leu Gln Leu Gly Pro His Leu Asn Pro Phe Leu Ser His Leu
85 90 95
Ala Gln Met Tyr Asn Gly Trp Val Gly Asn Met Lys Val Lys Val Leu
100 105 110
Leu Ala Gly Asn Ala Phe Thr Ala Gly Lys Ile Ile Ile Ser Cys Ile
115 120 125
Pro Pro Gly Phe Ala Ser Gln Asn Ile Ser Ile Ala Gln Ala Thr Met
130 135 140
Phe Pro His Val Ile Ala Asp Val Arg Val Leu Glu Pro Ile Glu Val
145 150 155 160
Pro Leu Glu Asp Val Arg Asn Val Leu Phe His Asn Asn Asp Asn Ser
165 170 175
Pro Thr Met Arg Leu Val Cys Met Leu Tyr Thr Pro Leu Arg Ala Ser
180 185 190
Gly Ser Ser Ser Gly Thr Asp Pro Phe Val Ile Ala Gly Arg Val Leu
195 200 205
Thr Cys Pro Ser Pro Asp Phe Ser Phe Leu Phe Leu Val Pro Pro Asn
210 215 220
Val Glu Gln Lys Thr Lys Pro Phe Ser Val Pro Asn Leu Pro Leu Asn
225 230 235 240
Thr Leu Ser Asn Ser Arg Val Pro Ser Leu Ile Asn Ala Met Met Ile
245 250 255
Ser Arg Asp His Gly Gln Met Val Gln Phe Gln Asn Gly Arg Val Thr
260 265 270
Leu Asp Gly Gln Leu Gln Gly Thr Thr Pro Thr Ser Leu Ser Gln Leu
275 280 285
Cys Lys Ile Arg Gly Lys Val Phe Leu Ala Ser Gly Gly Asn Gly Leu
290 295 300
Asn Leu Thr Glu Leu Asp Gly Ser Ala Tyr His Ala Phe Glu Ser Pro
305 310 315 320
Ala Pro Ile Gly Phe Pro Asp Ile Gly Asp Cys Asp Trp His Met Asn
325 330 335
Ala Thr Ala Thr Ser Asn Phe Thr Gly Ser Asn Asp Glu His Gln Ile
340 345 350
Leu Val Lys Gln Glu Ser Thr Phe Ala Pro His Leu Gly His Val Gln
355 360 365
Ala Asp His Leu Pro Glu Val Ala Asn Thr Asp Leu Met Val Ser Leu
370 375 380
Ser Trp Ile Ser Pro Val Ser Asp Gln His Arg Arg Asp Val Asp Pro
385 390 395 400
Trp Val Ile Pro Arg Tyr Gly Ser Thr Leu Thr Glu Ala Ala Gln Leu
405 410 415
Ala Pro Pro Ile Tyr Pro Pro Gly Phe Gly Glu Ala Ile Val Phe Phe
420 425 430
Met Ser Asp Phe Pro Val Val Ser Gly Val Asn Gly Met Arg Ile Pro
435 440 445
Cys Thr Leu Pro Gln Glu Tyr Val Ala His Phe Val Asn Glu Gln Ala
450 455 460
Pro Thr Arg Gly Glu Ala Ala Leu Leu His Tyr Val Asp Pro Asp Thr
465 470 475 480
His Arg Asn Leu Gly Glu Phe Lys Ile Tyr Pro Glu Gly Phe Met Thr
485 490 495
Cys Val Pro Asn Ser Ser Gly Thr Gly Pro Gln Thr Leu Pro Ile Asn
500 505 510
Gly Val Phe Thr Phe Val Ser Trp Val Ser Arg Phe Tyr Gln Leu Lys
515 520 525
Pro Val Gly Thr Ala Gly Pro Ala Arg Arg Leu Gly Ile Arg Arg Ser
530 535 540
<210> 14
<211> 533
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 14
Met Met Met Ala Ser Lys Asp Ala Thr Pro Ser Ala Asp Gly Ala Thr
1 5 10 15
Gly Ala Gly Gln Leu Val Pro Glu Val Asn Thr Ala Asp Pro Ile Pro
20 25 30
Ile Asp Pro Val Ala Gly Ser Ser Thr Ala Leu Ala Thr Ala Gly Gln
35 40 45
Val Asn Leu Ile Asp Pro Trp Ile Ile Asn Asn Phe Val Gln Ala Pro
50 55 60
Gln Gly Glu Phe Thr Ile Ser Pro Asn Asn Thr Pro Gly Asp Val Leu
65 70 75 80
Phe Asp Leu Gln Leu Gly Pro His Leu Asn Pro Phe Leu Ser His Leu
85 90 95
Ser Gln Met Tyr Asn Gly Trp Val Gly Asn Met Arg Val Arg Val Val
100 105 110
Leu Ala Gly Asn Ala Phe Thr Ala Gly Lys Val Ile Ile Cys Cys Val
115 120 125
Pro Pro Gly Phe Gln Ser Arg Thr Leu Ser Ile Ala Gln Ala Thr Leu
130 135 140
Phe Pro His Val Ile Ala Asp Val Arg Thr Leu Asp Pro Val Glu Val
145 150 155 160
Pro Leu Glu Asp Val Arg Asn Val Leu Tyr His Asn Asn Asp Thr Gln
165 170 175
Pro Thr Met Arg Leu Leu Cys Met Leu Tyr Thr Pro Leu Arg Thr Gly
180 185 190
Gly Ala Ser Gly Gly Thr Asp Ser Phe Val Val Ala Gly Arg Val Leu
195 200 205
Thr Cys Pro Gly Pro Asp Phe Asn Phe Leu Phe Leu Val Pro Pro Thr
210 215 220
Val Glu Gln Lys Thr Arg Pro Phe Thr Val Pro Asn Ile Pro Leu Lys
225 230 235 240
Tyr Leu Ser Asn Ser Arg Ile Pro Asn Pro Ile Glu Gly Met Ser Leu
245 250 255
Ser Pro Asp Gln Thr Gln Asn Val Gln Phe Gln Asn Gly Arg Cys Thr
260 265 270
Ile Asp Gly Gln Pro Leu Gly Thr Thr Pro Val Ser Val Ser Gln Leu
275 280 285
Cys Lys Phe Arg Gly Arg Ile Thr Ser Gly Gln Arg Val Leu Asn Leu
290 295 300
Thr Glu Leu Asp Gly Ser Pro Phe Met Ala Phe Ala Ala Pro Ala Pro
305 310 315 320
Ala Gly Phe Pro Asp Leu Gly Ser Cys Asp Trp His Ile Glu Met Ser
325 330 335
Lys Ile Pro Asn Ser Ser Thr Gln Asn Asn Pro Ile Val Val Asn Ser
340 345 350
Val Lys Pro Asn Ser Gln Gln Phe Val Pro His Leu Ser Ser Ile Thr
355 360 365
Leu Asp Asp Asn Val Ser Ser Gly Gly Asp Tyr Ile Gly Thr Ile Gln
370 375 380
Trp Thr Ser Pro Pro Ser Asp Ser Gly Gly Ala Asn Thr Asn Phe Trp
385 390 395 400
Lys Ile Pro Asp Tyr Gly Ser Ser Leu Ala Glu Ala Ser Gln Leu Ala
405 410 415
Pro Ala Val Tyr Pro Pro Gly Phe Asn Glu Val Ile Val Tyr Phe Met
420 425 430
Ala Ser Ile Pro Gly Pro Asn Gln Ser Gly Ser Pro Asn Leu Val Pro
435 440 445
Cys Leu Leu Pro Gln Glu Tyr Ile Thr His Phe Ile Ser Glu Gln Ala
450 455 460
Pro Ile Gln Gly Glu Ala Ala Leu Leu His Tyr Val Asp Pro Asp Thr
465 470 475 480
Asn Arg Asn Leu Gly Glu Phe Lys Leu Tyr Pro Gly Gly Tyr Leu Thr
485 490 495
Cys Val Pro Asn Ser Ser Ser Thr Gly Pro Gln Gln Leu Pro Leu Asp
500 505 510
Gly Val Phe Val Phe Ala Ser Trp Val Ser Arg Phe Tyr Gln Leu Lys
515 520 525
Pro Val Gly Thr Ala
530
<210> 15
<211> 544
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 15
Met Met Met Ala Ser Lys Asp Ala Thr Pro Ser Ala Asp Gly Ala Thr
1 5 10 15
Gly Ala Gly Gln Leu Val Pro Glu Val Asn Thr Ala Asp Pro Ile Pro
20 25 30
Ile Asp Pro Val Ala Gly Ser Ser Thr Ala Leu Ala Thr Ala Gly Gln
35 40 45
Val Asn Leu Ile Asp Pro Trp Ile Ile Asn Asn Phe Val Gln Ala Pro
50 55 60
Gln Gly Glu Phe Thr Ile Ser Pro Asn Asn Thr Pro Gly Asp Val Leu
65 70 75 80
Phe Asp Leu Gln Leu Gly Pro His Leu Asn Pro Phe Leu Ser His Leu
85 90 95
Ser Gln Met Tyr Asn Gly Trp Val Gly Asn Met Arg Val Arg Val Val
100 105 110
Leu Ala Gly Asn Ala Phe Thr Ala Gly Lys Val Ile Ile Cys Cys Val
115 120 125
Pro Pro Gly Phe Gln Ser Arg Thr Leu Ser Ile Ala Gln Ala Thr Leu
130 135 140
Phe Pro His Val Ile Ala Asp Val Arg Thr Leu Asp Pro Val Glu Val
145 150 155 160
Pro Leu Glu Asp Val Arg Asn Val Leu Tyr His Asn Asn Asp Thr Gln
165 170 175
Pro Thr Met Arg Leu Leu Cys Met Leu Tyr Thr Pro Leu Arg Thr Gly
180 185 190
Gly Ala Ser Gly Gly Thr Asp Ser Phe Val Val Ala Gly Arg Val Leu
195 200 205
Thr Cys Pro Gly Pro Asp Phe Asn Phe Leu Phe Leu Val Pro Pro Thr
210 215 220
Val Glu Gln Lys Thr Arg Pro Phe Thr Val Pro Asn Ile Pro Leu Lys
225 230 235 240
Tyr Leu Ser Asn Ser Arg Ile Pro Asn Pro Ile Glu Gly Met Ser Leu
245 250 255
Ser Pro Asp Gln Thr Gln Asn Val Gln Phe Gln Asn Gly Arg Cys Thr
260 265 270
Ile Asp Gly Gln Pro Leu Gly Thr Thr Pro Val Ser Val Ser Gln Leu
275 280 285
Cys Lys Phe Arg Gly Arg Ile Thr Ser Gly Gln Arg Val Leu Asn Leu
290 295 300
Thr Glu Leu Asp Gly Ser Pro Phe Met Gly Phe Gly Ala Pro Ala Pro
305 310 315 320
Ala Gly Phe Pro Asp Leu Gly Ser Cys Asp Trp His Ile Glu Met Ser
325 330 335
Lys Ile Pro Asn Ser Ser Thr Gln Asn Asn Pro Ile Val Thr Asn Ser
340 345 350
Val Lys Pro Asn Ser Gln Gln Phe Val Pro His Leu Ser Ser Ile Thr
355 360 365
Leu Asp Glu Asn Val Ser Ser Gly Gly Asp Tyr Ile Gly Thr Ile Gln
370 375 380
Trp Thr Ser Pro Pro Ser Asp Ser Gly Gly Ala Asn Thr Asn Phe Trp
385 390 395 400
Lys Ile Pro Asp Tyr Gly Ser Ser Leu Ala Glu Ala Ser Gln Leu Ala
405 410 415
Pro Ala Val Tyr Pro Pro Gly Phe Asn Glu Val Ile Val Tyr Phe Met
420 425 430
Ala Ser Ile Pro Gly Pro Asn Gln Ser Gly Ser Pro Asn Leu Val Pro
435 440 445
Cys Leu Leu Pro Gln Glu Tyr Ile Thr His Phe Ile Ser Glu Gln Ala
450 455 460
Pro Ile Gln Gly Glu Ala Ala Leu Leu His Tyr Val Asp Pro Asp Thr
465 470 475 480
Asn Arg Asn Leu Gly Glu Phe Lys Leu Tyr Pro Gly Gly Tyr Leu Thr
485 490 495
Cys Val Pro Asn Ser Ser Ser Thr Gly Pro Gln Gln Leu Pro Leu Asp
500 505 510
Gly Val Phe Val Phe Ala Ser Trp Val Ser Arg Phe Tyr Gln Leu Lys
515 520 525
Pro Val Gly Thr Ala Gly Pro Ala Arg Gly Arg Leu Gly Val Arg Arg
530 535 540
<210> 16
<211> 543
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 16
Met Met Met Ala Ser Lys Asp Ala Thr Pro Ser Ala Asp Gly Ala Asn
1 5 10 15
Gly Ala Gly Gln Leu Val Pro Glu Val Asn Asn Ala Glu Pro Leu Pro
20 25 30
Leu Asp Pro Val Ala Gly Ala Ser Thr Ala Leu Ala Thr Ala Gly Gln
35 40 45
Val Asn Met Ile Asp Pro Trp Ile Phe Asn Asn Phe Val Gln Ala Pro
50 55 60
Gln Gly Glu Phe Thr Ile Ser Pro Asn Asn Thr Pro Gly Asp Ile Leu
65 70 75 80
Phe Asp Leu Gln Leu Gly Pro His Leu Asn Pro Phe Leu Ala His Leu
85 90 95
Ser Gln Met Tyr Asn Gly Trp Val Gly Asn Met Arg Val Arg Val Ile
100 105 110
Leu Ala Gly Asn Ala Phe Thr Ala Gly Lys Val Ile Ile Cys Cys Val
115 120 125
Pro Pro Gly Phe Gln Ser Arg Thr Leu Ser Ile Ala Gln Ala Thr Leu
130 135 140
Phe Pro His Ile Ile Ala Asp Val Arg Thr Leu Glu Pro Ile Glu Ile
145 150 155 160
Pro Leu Glu Asp Val Arg Asn Thr Leu Tyr His Thr Asn Asp Asn Gln
165 170 175
Pro Thr Met Arg Leu Leu Cys Met Leu Tyr Thr Pro Leu Arg Thr Gly
180 185 190
Gly Gly Ser Gly Gly Thr Asp Ala Phe Val Val Ala Gly Arg Val Leu
195 200 205
Thr Ser Pro Ser Pro Asp Phe Asn Phe Leu Phe Leu Val Pro Pro Thr
210 215 220
Val Glu Gln Lys Thr Arg Pro Phe Ser Val Pro Asn Ile Pro Leu Gln
225 230 235 240
Leu Leu Ser Asn Ser Arg Val Pro Asn Leu Ile Gln Ser Met Val Pro
245 250 255
Ser Pro Asp Gln Ala Gln Asn Val Gln Phe Gln Asn Gly Arg Cys Thr
260 265 270
Thr Asp Gly Gln Leu Leu Gly Thr Thr Pro Val Ser Val Ser Gln Ile
275 280 285
Leu Lys Phe Arg Gly Lys Val Ser Ala Gly Ser Lys Val Ile Asn Leu
290 295 300
Thr Glu Leu Asp Gly Ser Pro Phe Leu Ala Phe Glu Ala Pro Ala Pro
305 310 315 320
Thr Gly Phe Pro Asp Leu Gly Thr Ser Asp Trp His Ile Glu Met Ser
325 330 335
Leu Asn Ser Asn Ser Gln Ser Ser Gly Asn Pro Ile Leu Leu Arg Asp
340 345 350
Ile Gln Pro Asn Ser Ser Asp Phe Val Pro His Leu Gly Ser Val Ala
355 360 365
Val Thr Thr Ala Ile Asp Thr Ala Gly Asp Tyr Thr Gly Thr Ile Gln
370 375 380
Trp Thr Ser Gln Pro Ser Asn Val Thr Pro Val Pro Asp Val Asn Phe
385 390 395 400
Trp Thr Ile Pro Gln Tyr Gly Ser Asn Leu Ala Glu Ala Ser Gln Leu
405 410 415
Ala Pro Val Val Tyr Pro Pro Gly Phe Gly Glu Ala Ile Val Tyr Phe
420 425 430
Met Ser Pro Ile Pro Gly Pro Asn Thr Ala His Lys Pro Asn Leu Val
435 440 445
Pro Cys Leu Leu Pro Gln Glu Phe Val Thr His Phe Val Ser Glu Gln
450 455 460
Ala Pro Ser Met Gly Glu Ala Ala Leu Val His Tyr Val Asp Pro Asp
465 470 475 480
Thr Asn Arg Asn Leu Gly Glu Phe Lys Leu Tyr Pro Glu Gly Phe Ile
485 490 495
Thr Cys Val Pro Asn Gly Thr Gly Pro Gln Gln Leu Pro Leu Asn Gly
500 505 510
Val Phe Val Phe Ala Ser Trp Val Ser Arg Phe Tyr Gln Leu Lys Pro
515 520 525
Val Gly Thr Ala Asn Ser Ala Arg Gly Arg Leu Gly Val Arg Arg
530 535 540
<210> 17
<211> 541
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 17
Met Met Met Ala Ser Lys Asp Ala Thr Pro Ser Ala Asp Gly Ala Asn
1 5 10 15
Gly Ala Gly Gln Leu Val Pro Glu Val Asn Asn Ala Glu Pro Leu Pro
20 25 30
Leu Asp Pro Val Ala Gly Ala Ser Thr Ala Leu Ala Thr Ala Gly Gln
35 40 45
Val Asn Met Ile Asp Pro Trp Ile Phe Asn Asn Phe Val Gln Ala Pro
50 55 60
Gln Gly Glu Phe Thr Ile Ser Pro Asn Asn Thr Pro Gly Asp Ile Leu
65 70 75 80
Phe Asp Leu Gln Leu Gly Pro His Leu Asn Pro Phe Leu Ala His Leu
85 90 95
Ser Gln Met Tyr Asn Gly Trp Val Gly Asn Met Arg Val Arg Val Ile
100 105 110
Leu Ala Gly Asn Ala Phe Thr Ala Gly Lys Val Ile Ile Cys Cys Val
115 120 125
Pro Pro Gly Phe Gln Ser Arg Thr Leu Ser Ile Ala Gln Ala Thr Leu
130 135 140
Phe Pro His Val Ile Ala Asp Val Arg Thr Leu Glu Pro Leu Glu Ile
145 150 155 160
Pro Leu Glu Asp Val Arg Asn Thr Leu Tyr His Asn Asn Asp Ser Gln
165 170 175
Pro Thr Met Arg Leu Leu Cys Met Leu Tyr Thr Pro Leu Arg Thr Gly
180 185 190
Gly Gly Ser Gly Gly Thr Asp Ala Phe Val Val Ala Gly Arg Val Leu
195 200 205
Thr Cys Pro Ser Pro Asp Phe Asn Phe Leu Phe Leu Val Pro Pro Thr
210 215 220
Val Glu Gln Lys Thr Arg Pro Phe Ser Val Pro Asn Ile Pro Leu Gln
225 230 235 240
Asn Leu Ser Asn Ser Arg Val Pro Ser Leu Ile Gln Ser Met Val Leu
245 250 255
Ser Ser Asp His Ala Gln Thr Val Gln Phe Gln Asn Gly Arg Cys Thr
260 265 270
Thr Asp Gly His Leu Leu Gly Thr Thr Pro Val Ser Ser Gly Gln Leu
275 280 285
Met Lys Phe Arg Gly Lys Val Thr Pro Gly Ser Lys Val Leu Asn Leu
290 295 300
Thr Glu Leu Asp Gly Ser Pro Phe Leu Ala Phe Glu Pro Pro Ala Pro
305 310 315 320
Ala Gly Phe Pro Asp Leu Gly Lys Cys Asp Trp His Ile Glu Met Ser
325 330 335
Leu Tyr Gln Val Asn Asn Gln Asp Asn Pro Ile Val Leu Arg Ala Ile
340 345 350
Glu Pro Asn Ser Ser Ser Phe Val Pro His Leu Gly Ser Val Ser Phe
355 360 365
Asn Gln Asn Val Asp Ala Ala Gly Asp Tyr Val Cys Thr Ile Gln Tyr
370 375 380
Thr Ser Pro Pro Ser Asn Ser His Asp Ala Asp Val Asp Phe Trp Ser
385 390 395 400
Ile Pro Asp Tyr Gly Ser Asn Leu Ala Glu Ala Ser Gln Leu Ala Pro
405 410 415
Val Val Tyr Pro Pro Gly Phe Gly Glu Ala Ile Val Tyr Phe Met Ser
420 425 430
Arg Val Pro Gly Trp Asn Arg Thr Asn Arg Leu Asn Leu Val Pro Cys
435 440 445
Leu Leu Pro Gln Glu Phe Ile Gly His Phe Val Ser Glu Gln Ala Pro
450 455 460
Ala Ile Gly Glu Ala Ala Leu Leu His Tyr Val Asp Pro Asp Thr Asn
465 470 475 480
Arg Asn Leu Gly Glu Phe Lys Leu Tyr Pro Glu Gly Phe Ile Thr Cys
485 490 495
Val Pro Asn Gly Thr Gly Pro Gln Gln Leu Pro Leu Asn Gly Val Phe
500 505 510
Val Phe Ser Ser Trp Val Ser Arg Phe Tyr Gln Leu Lys Pro Val Gly
515 520 525
Thr Ala Ser Ser Ala Arg Gly Arg Leu Gly Ile Arg Arg
530 535 540
<210> 18
<211> 540
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 18
Met Met Met Ala Ser Lys Asp Val Pro Thr Ser Pro Asp Gly Ala Ser
1 5 10 15
Gly Ala Gly Gln Leu Val Pro Glu Val Asn Thr Ala Asp Gln Ile Ser
20 25 30
Met Asp Pro Val Ala Gly Ala Ser Thr Ala Val Ala Thr Ala Gly Gln
35 40 45
Val Asn Met Ile Asp Pro Trp Ile Phe Asn Asn Phe Val Gln Ala Pro
50 55 60
Gln Gly Glu Phe Thr Ile Ser Pro Asn Asn Thr Pro Gly Asp Ile Leu
65 70 75 80
Phe Asp Leu Gln Leu Gly Pro His Leu Asn Pro Phe Leu Ala His Leu
85 90 95
Ser Gln Met Tyr Asn Gly Trp Val Gly Asn Met Arg Val Arg Ile Leu
100 105 110
Leu Ala Gly Asn Ala Phe Thr Ala Gly Lys Ile Ile Ile Cys Cys Val
115 120 125
Pro Pro Gly Phe Asp Ala Arg Ile Leu Thr Ile Ala Gln Ala Thr Leu
130 135 140
Phe Pro His Leu Ile Ala Asp Val Arg Thr Leu Glu Pro Val Glu Leu
145 150 155 160
Pro Leu Glu Asp Val Arg Asn Val Leu Tyr His Asn Ser Ser Gln Pro
165 170 175
Gln Pro Thr Met Arg Leu Val Ala Met Leu Tyr Thr Pro Leu Arg Thr
180 185 190
Gly Gly Gly Ser Gly Gly Thr Asp Ala Phe Val Val Ala Gly Arg Val
195 200 205
Leu Thr Cys Pro Ala Pro Asp Phe Ser Phe Leu Phe Leu Val Pro Pro
210 215 220
Ser Val Glu Gln Lys Thr Arg Val Phe Ser Val Pro Asn Ile Pro Leu
225 230 235 240
Lys Asp Leu Ser Asn Ser Arg Val Pro Thr Leu Ile Gln Gly Met Phe
245 250 255
Val Ser Pro Asp Val Asn Gln Ser Val Gln Phe Gln Asn Gly Arg Cys
260 265 270
Gln Ile Asp Gly Gln Leu Gln Gly Thr Thr Pro Val Ser Leu Ser Gln
275 280 285
Leu Cys Lys Ile Arg Gly Lys Thr Ser Ser Asn Thr Arg Val Leu Asn
290 295 300
Leu Ser Glu Val Asp Gly Thr Pro Phe Val Pro Leu Glu Ser Pro Ala
305 310 315 320
Pro Val Gly Phe Pro Asp Ile Gly Gly Cys Asp Trp His Val Gly Phe
325 330 335
Thr Phe Glu Ala Arg Asp Gln Gly Pro Ser Gln Asn Val Thr Phe Ala
340 345 350
Thr Asn Asp Ser Ser Phe Val Pro Tyr Leu Gly Ser Ile Ser Pro His
355 360 365
Asn Gly Asp Gly Phe His Ser Gly Asp Ile Ile Gly Ser Leu Asp Trp
370 375 380
Ile Ser Ala Pro Ser Asp Gly Ser Ala Leu Asp Val Trp Ser Ile Pro
385 390 395 400
Lys Tyr Gly Ser Ser Leu Pro Asp Val Thr His Leu Ala Pro Ala Val
405 410 415
Phe Pro Pro Gly Phe Gly Glu Val Ile Leu Tyr Phe His Ser Lys Phe
420 425 430
Pro Gly Ser Gly Pro Thr Asp Lys Leu Arg Val Pro Cys Leu Met Pro
435 440 445
Gln Glu Phe Ile Thr His Phe Cys Asp Glu Gln Ala Pro Ile Ala Gly
450 455 460
Glu Ala Ala Leu Leu His Tyr Val Asp Pro Asp Ala Gly Arg Asn Leu
465 470 475 480
Gly Glu Phe Lys Leu Tyr Pro Asp Gly Phe Met Thr Cys Val Pro Asn
485 490 495
Ser Ile Ser Ser Gly Pro Gln Thr Leu Pro Ile Asn Gly Val Phe Val
500 505 510
Phe Val Ser Trp Val Ser Arg Phe Tyr Gln Leu Lys Pro Val Gly Thr
515 520 525
Ala Ser Met Ala Arg Arg Leu Gly Leu Arg Arg Ile
530 535 540
<210> 19
<211> 539
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 19
Met Met Met Ala Ser Lys Asp Ala Pro Ser Asn Met Asp Gly Thr Ser
1 5 10 15
Gly Ala Gly Gln Leu Val Pro Glu Val Asn Ala Ala Glu Pro Leu Pro
20 25 30
Leu Glu Pro Val Val Gly Ala Ala Thr Ala Val Ala Thr Ala Gly Gln
35 40 45
Val Asn Leu Ile Asp Pro Trp Ile Met Asn Asn Phe Val Gln Ala Pro
50 55 60
Glu Gly Glu Phe Thr Ile Ser Pro Asn Asn Thr Pro Gly Asp Ile Leu
65 70 75 80
Phe Asp Leu Gln Leu Gly Pro His Leu Asn Pro Phe Leu Gln His Leu
85 90 95
Ser Gln Met Tyr Asn Gly Trp Val Gly Asn Met Arg Val Arg Val Met
100 105 110
Leu Ala Gly Asn Ala Phe Thr Ala Gly Lys Ile Ile Ile Cys Cys Val
115 120 125
Pro Pro Gly Phe Ala Ser Gln Asn Ile Ser Ile Gly Gln Ala Thr Met
130 135 140
Phe Pro His Val Ile Ala Asp Val Arg Val Leu Glu Pro Ile Glu Ile
145 150 155 160
Pro Leu Asp Asp Val Arg Asn Val Leu Phe His Thr Asn Glu Ser Arg
165 170 175
Pro Thr Met Arg Leu Leu Cys Met Leu Tyr Thr Pro Leu Arg Ala Gly
180 185 190
Gly Ala Ser Ser Gly Thr Asp Pro Phe Val Ile Ala Gly Arg Val Leu
195 200 205
Thr Cys Pro Ser Pro Asp Phe Asn Phe Leu Phe Leu Val Pro Pro Ser
210 215 220
Val Glu Gln Lys Thr Arg Gln Leu Thr Val Pro Asn Ile Pro Leu Asn
225 230 235 240
Asn Leu Ala Asn Ser Arg Val Pro Ala Met Ile Asn Lys Met Thr Val
245 250 255
Ser Thr Asp Gln Ser Gln Val Val Gln Phe Gln Asn Gly Arg Cys Thr
260 265 270
Leu Glu Gly Gln Leu Leu Gly Thr Thr Pro Val Ser Ala Ser Gln Val
275 280 285
Ala Arg Ile Arg Gly Lys Val Phe Ser Thr Ala Ser Gly Lys Gly Leu
290 295 300
Asn Leu Thr Glu Leu Asp Gly Thr Pro Tyr His Ala Phe Glu Ser Pro
305 310 315 320
Ala Pro Leu Gly Phe Pro Asp Ile Gly Ala Cys Asp Trp His Val Ser
325 330 335
Thr Phe Lys Val Asp Gln Asn Leu Ser Gly Asp Pro Met Ser Arg Leu
340 345 350
Asp Ile Lys Gln Asn Ala Pro Phe Ala Pro His Leu Gly Ser Ile Glu
355 360 365
Phe Thr Ser Asp Gln Glu Pro Thr Gly Asp Gln Leu Gly Thr Leu Ala
370 375 380
Trp Val Ser Pro Ser Thr Ser Gly Ala Arg Val Asp Pro Trp Lys Ile
385 390 395 400
Pro Ser Tyr Gly Ser Thr Val Thr Glu Ser Thr His Leu Ala Pro Pro
405 410 415
Ile Phe Pro Pro Gly Phe Gly Glu Ala Ile Val Tyr Phe Met Ser Asp
420 425 430
Phe Pro Ile Val Ser Gly Asn Thr Ala Gln Val Pro Cys Thr Leu Pro
435 440 445
Gln Glu Phe Val Ser His Phe Val Glu Gln Gln Ala Pro Ile Arg Gly
450 455 460
Glu Ala Ala Leu Leu His Tyr Val Asp Pro Asp Thr His Arg Asn Leu
465 470 475 480
Gly Glu Phe Lys Leu Tyr Pro Asp Gly Phe Ile Thr Cys Val Pro Asn
485 490 495
Thr Gly Gly Gly Pro Gln Asn Leu Pro Ile Asn Gly Val Phe Val Phe
500 505 510
Ser Ser Trp Val Ser Arg Tyr Tyr Gln Leu Lys Pro Val Gly Thr Ala
515 520 525
Gly Pro Ala Arg Arg Leu Gly Val Arg Arg Val
530 535
<210> 20
<211> 543
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 20
Met Met Met Ala Ser Lys Asp Ala Pro Thr Asn Met Asp Gly Thr Ser
1 5 10 15
Gly Ala Gly Gln Leu Val Pro Glu Ala Asn Thr Ala Glu Pro Leu Pro
20 25 30
Ile Lys Pro Val Ala Gly Ala Ala Thr Ala Val Ala Thr Ala Gly Gln
35 40 45
Val Asn Met Ile Asp Pro Trp Ile Met Asn Asn Phe Val Gln Ala Pro
50 55 60
Gln Gly Glu Phe Thr Ile Ser Pro Asn Asn Thr Pro Gly Asp Ile Leu
65 70 75 80
Phe Asp Leu Gln Leu Gly Pro His Leu Asn Pro Phe Leu Ala His Leu
85 90 95
Ser Arg Met Tyr Asn Gly Trp Val Gly Asn Met Gln Val Arg Ile Met
100 105 110
Leu Ala Gly Asn Ala Phe Ser Ala Gly Lys Ile Ile Val Cys Cys Ile
115 120 125
Pro Pro Gly Phe Ser Ser Gln Ser Ile Ser Ile Ala Gln Ala Thr Met
130 135 140
Phe Pro His Val Ile Ala Asp Val Arg Val Leu Glu Pro Ile Asp Val
145 150 155 160
Pro Leu Asp Asp Val Arg Asn Val Leu Phe His Asn Asn Asp Asn Pro
165 170 175
Gln Thr Met Arg Leu Leu Cys Met Leu Tyr Thr Pro Leu Arg Ser Gly
180 185 190
Gly Thr Ser Ser Gly Thr Asp Pro Phe Val Ile Ala Gly Arg Val Leu
195 200 205
Thr Cys Pro Thr Pro Asp Phe Ser Phe Leu Phe Leu Val Pro Pro Asp
210 215 220
Ile Glu Gln Arg Thr Lys Pro Phe Ser Val Pro Asn Ile Pro Met Asn
225 230 235 240
Leu Met Ser Asn Ser Arg Val Ser Met Leu Ile Asp Gly Met Met Val
245 250 255
Ser Asn Asp Gln Asn Gln Val Pro Gln Phe Gln Asn Gly Arg Val Thr
260 265 270
Leu Asp Gly Gln Leu Gln Gly Thr Thr Thr Val Ser Ala Ala Cys Val
275 280 285
Ala Arg Met Arg Gly Arg Ile Phe Asn Asn Asn Gly Asn Tyr Gly Val
290 295 300
Asn Leu Thr Glu Leu Asp Gly Asn Pro Tyr His Ala Phe Asp Ser Pro
305 310 315 320
Ala Pro Leu Gly Phe Pro Asp Phe Gly Asn Cys Asp Leu His Met Thr
325 330 335
Phe Val Lys Ile Asn Pro Asn Glu Leu Ser Ser Gly Asp Pro Ser Gly
340 345 350
Lys Val Val Ile Arg Ser Tyr Asp Ala Thr Phe Ala Pro His Leu Gly
355 360 365
Thr Val Lys Leu Glu Asn Asp Asp Glu Leu Ala Arg Phe Val Gly Lys
370 375 380
Glu Val Val Leu Glu Leu Thr Trp Val Ser Asn Arg Glu Gly Ala Thr
385 390 395 400
Leu Asn Leu Trp Ala Val Pro Asn Tyr Gly Ser Ser Leu Thr Gln Ala
405 410 415
Ser Gln Leu Ala Pro Pro Ile Tyr Pro Pro Gly Phe Gly Glu Ala Ile
420 425 430
Val Tyr Phe Thr Ser Thr Phe Pro Thr Val Ser Asn Pro Lys Val Pro
435 440 445
Cys Thr Leu Pro Gln Glu Phe Val Ser His Phe Val Asn Glu Gln Ala
450 455 460
Pro Thr Arg Gly Asp Ala Ala Leu Leu His Tyr Val Asp Pro Asp Thr
465 470 475 480
His Arg Asn Leu Gly Glu Phe Lys Met Tyr Pro Glu Gly Tyr Met Thr
485 490 495
Cys Val Pro Asn Ala Gly Gly Gly Pro Gln Thr Leu Pro Ile Asn Gly
500 505 510
Val Phe Val Phe Ile Ser Trp Val Ser Arg Tyr Tyr Gln Leu Lys Pro
515 520 525
Val Gly Thr Ala Gly Ala Ala Arg Arg Leu Gly Leu Arg Arg Ser
530 535 540
<210> 21
<211> 550
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 21
Met Met Met Ala Ser Lys Asp Ala Thr Ser Asn Met Asp Gly Thr Ser
1 5 10 15
Gly Ala Gly Gln Leu Val Pro Glu Asn Asn Asn Thr Ser Glu Pro Ile
20 25 30
Asn Met Glu Pro Val Ala Gly Ala Val Thr Ala Ala Ala Thr Ala Gly
35 40 45
Gln Val Asn Met Ile Asp Pro Trp Ile Met Asn Asn Tyr Val Gln Ala
50 55 60
Pro Gln Gly Glu Phe Thr Ile Ser Pro Asn Asn Thr Pro Gly Asp Ile
65 70 75 80
Leu Phe Asp Leu Gln Leu Gly Pro His Leu Asn Pro Phe Leu Ala His
85 90 95
Leu Ser Gln Met Tyr Asn Gly Trp Val Gly Asn Met Lys Val Arg Val
100 105 110
Val Leu Ala Gly Asn Ala Phe Ser Ala Gly Lys Ile Ile Val Cys Cys
115 120 125
Ile Pro Pro Gly Phe Ser Ala Pro Asn Ile Ser Ile Ala Gln Ala Thr
130 135 140
Met Phe Pro His Val Ile Ala Asp Val Arg Val Leu Glu Pro Ile Asp
145 150 155 160
Ile Pro Leu Asp Asp Val Arg Asn Val Leu Phe His Asn Asn Asp Asn
165 170 175
Gly Asn Gln Thr Met Arg Leu Leu Cys Met Leu Tyr Thr Pro Leu Arg
180 185 190
Ser Gly Gly Thr Ser Ser Gly Thr Asp Pro Phe Val Ile Ala Gly Arg
195 200 205
Val Leu Thr Cys Pro Thr Pro Asp Phe Asn Phe Leu Phe Leu Val Pro
210 215 220
Pro Thr Val Glu Gln Lys Thr Lys Gln Phe Ser Val Pro Asn Leu Pro
225 230 235 240
Leu Asn Val Met Ser Asn Ser Arg Val Pro Ser Leu Leu Asn Ala Met
245 250 255
Val Val Ser Pro Asp Gln Ala Gln Val Val Gln Phe Gln Asn Gly Arg
260 265 270
Cys Thr Leu Asp Gly Gln Met Leu Gly Thr Thr Thr Val Ser Ala Ser
275 280 285
Cys Val Ala Arg Phe Arg Gly Lys Thr Phe Gln Ala Pro Asp Asn Arg
290 295 300
Leu Gly Ile Asn Leu Ala Glu Ile Ser Gly Glu Pro Tyr His Ala Phe
305 310 315 320
Glu Ser Pro Ala Pro Leu Gly Phe Pro Asp Phe Gly Asp Gly Asp Trp
325 330 335
His Val Thr Ala Thr Lys Val Thr Pro Ser Gln Leu Glu Ala Asn Asp
340 345 350
Pro Val Val Met Gly Asn Val Gln Pro Tyr Asn Pro Gln Phe Ala Pro
355 360 365
His Leu Gly Thr Leu Val Val Glu Asn Pro Thr Pro Asp Asn Val Thr
370 375 380
Thr Gly Thr Asp Leu Leu Phe Asn Ile Thr Trp Leu Ser Asn Arg Ala
385 390 395 400
Asn Asn Arg Phe Asn Pro Trp Val Ile Pro Asn Tyr Gly Ser Thr Leu
405 410 415
Thr Glu Ala Ala Gln Leu Ala Pro Ser Ile Phe Pro Pro Gly Phe Gly
420 425 430
Glu Thr Ile Val Tyr Phe Asn Ser Thr Phe Pro Ala Val Gly Ala Thr
435 440 445
Thr His Ala Ala Ile Pro Cys Leu Leu Pro Gln Glu Phe Val Ala His
450 455 460
Phe Val Asn Glu Gln Ala Pro Ile Arg Gly Glu Ala Ala Leu Leu His
465 470 475 480
Tyr Ile Asp Pro Asp Thr His Arg Asn Leu Gly Glu Phe Lys Ile Tyr
485 490 495
Pro Glu Gly Phe Val Thr Cys Val Pro Asn Val Gly Gly Thr Gly Pro
500 505 510
Gln Ser Leu Pro Thr Asn Gly Ile Phe Val Phe Val Ser Trp Val Ser
515 520 525
Arg Tyr Tyr Gln Leu Lys Pro Val Gly Thr Ala Gly Gln Ala Arg Arg
530 535 540
Leu Gly Phe Arg Arg Val
545 550
<210> 22
<211> 538
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 22
Met Lys Met Ala Ser Asn Asp Ala Asn Pro Ser Asp Gly Ser Ala Ala
1 5 10 15
Asn Leu Val Pro Glu Val Asn Asn Glu Val Met Ala Leu Glu Pro Val
20 25 30
Val Gly Ala Ala Ile Ala Ala Pro Val Ala Gly Gln Gln Asn Val Ile
35 40 45
Asp Pro Trp Ile Arg Asn Asn Phe Val Gln Ala Pro Gly Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ala Pro Gly Glu Ile Leu Trp Ser Met Pro
65 70 75 80
Leu Ser Pro Glu Leu Asn Pro Tyr Leu Ser His Leu Ser Arg Met Tyr
85 90 95
Asn Gly Tyr Ala Gly Gly Phe Glu Val Gln Val Ile Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Ile Ile Phe Ala Ala Ile Pro Pro Asn Phe
115 120 125
Pro Thr Asp Gly Leu Ser Pro Ser Gln Val Thr Met Phe Pro His Ile
130 135 140
Ile Val Asp Val Arg Gln Leu Glu Pro Val Leu Ile Pro Leu Pro Asp
145 150 155 160
Val Arg Asn Asn Phe Tyr His Tyr Asn Gln Ala Asn Asp Ser Thr Leu
165 170 175
Lys Leu Ile Ala Met Leu Tyr Thr Pro Leu Arg Ala Asn Asn Ala Gly
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Ser Pro
195 200 205
Asp Phe Asp Phe Ile Phe Leu Val Pro Pro Thr Val Glu Ser Arg Thr
210 215 220
Lys Pro Phe Thr Val Pro Ile Leu Thr Val Asp Glu Met Thr Asn Ser
225 230 235 240
Arg Phe Pro Thr Pro Leu Glu Lys Leu His Thr Gly Pro Asn Asn Ser
245 250 255
Ile Val Val Gln Pro Gln Asn Gly Arg Cys Thr Ile Asp Gly Val Leu
260 265 270
Leu Gly Thr Thr Gln Leu Ser Thr Val Asn Ile Cys Asn Phe Arg Gly
275 280 285
Ser Thr Thr Arg Ala Gly Gln Ser His Ala Tyr Thr Met Asn Leu Val
290 295 300
Ser Gln Asn Trp Asn Asn Tyr Asp Pro Thr Glu Glu Ile Pro Ala Pro
305 310 315 320
Leu Gly Thr Pro Asp Phe Val Gly Lys Ile Val Gly Met Leu Ser Gln
325 330 335
Thr Thr Arg Glu Asn Ser Ser Thr Arg Ala His Lys Ala Thr Val Ser
340 345 350
Thr Gly Asp Ala His Phe Thr Pro Lys Ser Gly Ser Val Leu Phe Thr
355 360 365
Thr Asp Thr Asp Asp Leu Gln Asn Gly Gln Asn Thr Arg Phe Thr Pro
370 375 380
Val Gly Val Ala Gln Asp Gly Glu Pro His Gln Asn Glu Pro Gln Gln
385 390 395 400
Trp Arg Leu Pro Asn Tyr Ser Gly Thr Pro Gly His Asn Val His Leu
405 410 415
Ala Pro Pro Val Ala Pro Thr Phe Pro Gly Glu Gln Leu Leu Phe Phe
420 425 430
Arg Ser Thr Met Pro Gly Cys Gly Gly Tyr Pro Asn Met Asp Leu Asp
435 440 445
Cys Leu Leu Pro Gln Glu Trp Val Arg His Phe Tyr Gln Glu Ala Ala
450 455 460
Pro Ala Gln Ser Asp Val Ala Leu Leu Arg Phe Val Asn Pro Asp Thr
465 470 475 480
Gly Arg Val Leu Phe Glu Cys Lys Leu His Lys Ala Gly Tyr Ile Thr
485 490 495
Val Ser His Thr Gly Pro Tyr Asp Leu Val Ile Pro Pro Asn Gly Tyr
500 505 510
Phe Arg Phe Asp Ser Trp Val Asn Gln Phe Tyr Ala Leu Ala Pro Met
515 520 525
Gly Thr Gly Thr Gly Arg Arg Arg Ala Leu
530 535
<210> 23
<211> 543
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 23
Met Lys Met Ala Ser Asn Asp Ala Ala Pro Ser Asn Asp Gly Ala Ala
1 5 10 15
Gly Leu Val Pro Glu Ile Asn Asn Glu Thr Met Ala Leu Glu Pro Val
20 25 30
Ala Gly Gly Ala Ile Ala Ala Pro Leu Thr Gly Gln Thr Asn Phe Ile
35 40 45
Asp Pro Trp Ile Arg Asn Asn Tyr Val Gln Ala Pro Asn Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ser Pro Gly Glu Ile Leu Leu Asn Leu Glu
65 70 75 80
Leu Gly Pro Glu Leu Asn Pro Phe Leu Ala His Leu Ser Arg Met Tyr
85 90 95
Asn Gly Tyr Ala Gly Gly Ile Asp Val Gln Val Ile Met Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Ile Ile Phe Ala Ala Val Pro Pro His Phe
115 120 125
Pro Ile Asp Asn Ile Ser Pro Pro Gln Ile Thr Met Phe Pro His Ile
130 135 140
Ile Ile Asp Val Arg Thr Leu Glu Pro Val Asn Ile Pro Leu Pro Asp
145 150 155 160
Val Arg Asn Ser Phe Phe His Tyr Ser Gln Asn Asn Glu Pro Arg Met
165 170 175
Arg Leu Leu Ala Met Leu Tyr Thr Pro Leu Arg Ser Asn Gly Ser Ala
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Lys Pro Ser Ala
195 200 205
Asp Phe Glu Phe Asn Tyr Leu Val Pro Pro Thr Val Glu Ser Arg Thr
210 215 220
Lys Pro Phe Thr Ile Pro Ile Leu Thr Ile Gly Glu Met Thr Asn Ser
225 230 235 240
Arg Phe Pro Val Ala Ile Asp Met Leu His Thr Ser Pro Thr Asp Asn
245 250 255
Phe Ile Val Gln Pro Gln Asn Gly Arg Cys Thr Leu Asp Gly Glu Leu
260 265 270
Gln Gly Thr Thr Gln Leu Val Thr Ser Asn Ile Cys Ala Phe Arg Gly
275 280 285
Ser Ile Ser Gly His Glu Asn Asn Gly Asp Gln His Gln Trp His Phe
290 295 300
Ser Ile Thr Asn Pro Asn Gly Thr Pro Phe Asp Pro Thr Glu Asp Val
305 310 315 320
Pro Ala Pro Leu Gly Thr Pro Asp Phe Lys Gly Gln Leu Tyr Gly Val
325 330 335
Ile Ser Gln Arg Asn Arg Glu Gly Ser Pro Gly Asn Gly Asn Gln Lys
340 345 350
Ala Asn Arg Ser His Glu Gly Val Ile Ser Thr Val Ala Pro Arg Phe
355 360 365
Thr Pro Lys Leu Gly Ser Val Met Ile Gly Thr Trp Thr Thr Asp Asp
370 375 380
Ile Gln Asp Gln Pro Ser Arg Phe Thr Pro Val Gly Leu Asn Asp Asp
385 390 395 400
Asp Asn Tyr Lys Gln Trp Glu Leu Pro Asn Tyr Ser Gly Ala Leu Thr
405 410 415
Leu Asn Met Gly Leu Ala Pro Ser Val Phe Pro Thr Tyr Pro Gly Glu
420 425 430
Gln Leu Leu Phe Phe Arg Ser Tyr Ile Pro Met Lys Gly Gly Tyr Gly
435 440 445
Ser Pro Tyr Ile Asp Cys Leu Ile Pro Gln Glu Trp Ile Ser His Phe
450 455 460
Tyr Gln Glu Ser Ala Pro Ser Gln Thr Asp Val Ala Leu Ile Arg Tyr
465 470 475 480
Val Asn Pro Asp Thr Gly Arg Val Leu Phe Glu Ala Lys Leu His Arg
485 490 495
Gln Gly Tyr Ile Thr Val Ala Lys Thr Gly Asp Ser Pro Ile Asn Val
500 505 510
Pro Ala Asn Gly Tyr Phe Arg Phe Asp Ser Trp Val Ser Gln Phe Tyr
515 520 525
Ser Leu Ala Pro Met Gly Thr Gly Asn Gly Arg Arg Arg Ile Gln
530 535 540
<210> 24
<211> 555
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 24
Met Arg Met Ala Ser Ser Asp Ala Pro Val Ser Gly Thr Asp Gly Ala
1 5 10 15
Ala Gly Leu Val Pro Glu Ser Gln Gln Glu Val Leu Pro Leu Glu Pro
20 25 30
Val Ala Gly Val Gln Leu Ala Ala Pro Val Ala Gly Gln Ser Asn Ile
35 40 45
Ile Asp Pro Trp Ile Arg Met Asn Phe Val Gln Ala Pro Ala Gly Glu
50 55 60
Phe Thr Val Ser Pro Arg Asn Ala Pro Gly Glu Val Leu Ile Asp Leu
65 70 75 80
Glu Leu Gly Pro Glu Leu Asn Pro Tyr Leu Asn His Leu Ala Arg Met
85 90 95
Tyr Asn Gly Tyr Val Gly Gly Met Glu Val Glu Val Val Leu Ala Gly
100 105 110
Asn Ala Phe Thr Ala Gly Lys Ile Leu Phe Ala Ala Val Pro Pro Ser
115 120 125
Phe Pro Thr His Gly Ile Ser Ala Ala Gln Ala Thr Met Leu Pro His
130 135 140
Val Ile Val Asp Val Arg Gln Leu Glu Pro Val Arg Leu Pro Leu Pro
145 150 155 160
Asp Val Arg Asn Val Met Phe His Phe Cys Gln Glu Asn Lys Glu Pro
165 170 175
Arg Met Arg Ile Val Ala Ile Leu Tyr Thr Pro Leu Arg Ala Asn Gly
180 185 190
Ala Gly Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro
195 200 205
Ser Pro Asp Phe Asp Phe Ile Phe Leu Val Pro Pro Ser Val Glu Ser
210 215 220
Lys Leu Lys Gln Phe Thr Leu Pro Asn Leu Gln Pro Asn Glu Met Thr
225 230 235 240
Asn Ser Arg Phe Pro Thr Gly Ile Thr Gln Leu Tyr Thr Ser Pro Asn
245 250 255
Thr Asn Leu Val Val Gln Phe Gln Asn Gly Arg Cys Leu Leu Asp Gly
260 265 270
Thr Leu Leu Gly Thr Thr Pro Val Arg Ala Ala Asp Ile Cys Ser Phe
275 280 285
Arg Gly Val Thr Ser Thr Glu Val Asp Ala Thr Asp Ser Pro Arg Val
290 295 300
Ala Gly Ser His Arg Ile Met Val Gln Leu Lys Glu Pro Asp Gly Glu
305 310 315 320
Glu Phe Ser Pro Thr Gly Pro Asn Pro Ala Pro Val Gly Thr Pro Asp
325 330 335
Phe Gln Ala Ala Ile Phe Gly Thr Leu Ser Gln Arg Asn Thr Gly Gly
340 345 350
Thr Gly Gln Asn Ser Asn Arg Ala His Phe Ala Tyr Phe Tyr Thr Arg
355 360 365
Asn Pro Thr Phe Ala Pro Gly Ile Gly Thr Val Val Phe Ser Phe Asp
370 375 380
Thr Thr Asp Phe Gln Asn Arg Gln Pro Thr Lys Phe Ser Pro Ser Gly
385 390 395 400
Val Phe Asp Asp Asp Ser Ser Glu Pro Phe Asn Gln Phe Ser Leu Pro
405 410 415
Tyr Tyr Asn Gly Ser Leu Gly Ala Val Asp Ala Gly Lys Leu Ala Pro
420 425 430
Pro Val Ala Pro Asn Tyr Pro Gly Glu Gln Ile Leu Tyr Phe Arg Gly
435 440 445
Asn Ile Pro Phe Lys Gly Gly Tyr Gly Glu Gly Glu Ile Asp Ser Leu
450 455 460
Leu Pro Gln Glu Trp Ile Thr His Phe Tyr Ala Glu Gln Ala Pro Thr
465 470 475 480
Gln Gly Asp Ala Ala Leu Leu Arg Tyr Tyr Asn Pro Asp Thr Gly Arg
485 490 495
Val Leu Phe Glu Cys Lys Leu His Arg Glu Gly Phe Ile Thr Ile Asn
500 505 510
Tyr Thr Gly Ser Asn Ala Leu Ala Val Pro Val Asn Gly Val Phe Arg
515 520 525
Phe Glu Gly Trp Val Asn Lys Phe Tyr Thr Leu Thr Pro Met Gly Asn
530 535 540
Gly Asn Gly Arg Arg Gly Arg Arg Arg Glu Leu
545 550 555
<210> 25
<211> 535
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 25
Met Lys Met Ala Ser Asn Asp Ala Asn Pro Ser Ser Asp Gly Ser Ala
1 5 10 15
Asn Leu Val Pro Glu Ile Ser Asn Glu Val Met Ala Leu Glu Pro Val
20 25 30
Ala Gly Ala Ala Ile Ala Ala Pro Val Ala Gly Gln Gln Asn Ile Ile
35 40 45
Asp Pro Trp Ile Arg Asn Asn Phe Val Gln Ala Pro Gly Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ala Pro Gly Glu Val Leu Leu Asn Leu Pro
65 70 75 80
Leu Ser Pro Asp Ile Asn Pro Tyr Leu Ala His Leu Ser Arg Met Tyr
85 90 95
Asn Gly Tyr Ala Gly Gly Val Glu Val Glu Val Val Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Ile Ile Phe Ala Ala Val Pro Pro Asn Phe
115 120 125
Pro Pro Glu Asn Leu Ser Pro Ser Gln Ile Thr Met Leu Pro His Ile
130 135 140
Ile Val Asp Val Arg Gln Leu Glu Pro Val Arg Ile Pro Leu Pro Asp
145 150 155 160
Val Arg Asn Asn Phe Tyr His Tyr Ser Arg Glu Asn Asp Ser Thr Leu
165 170 175
Arg Leu Ile Ala Met Leu Tyr Thr Pro Leu Arg Ala Asn Asn Ala Gly
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Ser Pro
195 200 205
Asp Phe Asp Phe Ile Phe Leu Val Pro Pro Thr Val Glu Ser Lys Ser
210 215 220
Lys Pro Phe Thr Ile Pro Met Leu Thr Ile Glu Glu Met Thr Asn Ser
225 230 235 240
Arg Phe Pro Ala Pro Leu Glu Leu Met Thr Thr Gly Pro Ser His Asp
245 250 255
Ile Val Val Gln Pro Gln Asn Gly Arg Cys Thr Ile Asp Gly Val Leu
260 265 270
Leu Gly Thr Thr Gln Leu Ser Pro Val Asn Ile Cys Ser Leu Arg Gly
275 280 285
Val Pro Thr Lys Arg Thr Asn Gly Asn Asp Asn Cys Phe Val Gln Leu
290 295 300
Glu Asn Pro Asn Gly Ser Ala Tyr Asp Pro Thr Glu Asp Ile Pro Ala
305 310 315 320
Val Leu Gly Ser Pro Asp Phe Val Gly Glu Leu Tyr Gly Thr Ile Thr
325 330 335
Gln Arg Ser Ser Asp Asn Ser Thr Arg Ala His Pro Phe Thr Leu Asn
340 345 350
Thr Gly Ser Pro Arg Tyr Thr Pro Lys Ile Gly Ser Val Asp Ile Arg
355 360 365
Val Thr Asp Val Ser Asp Leu Gln Asp His Asp Pro Val Lys Leu Thr
370 375 380
Pro Val Gly Leu Ser Gly Asp Arg Gly Ser Ile His Gln Trp Gln Leu
385 390 395 400
Pro Asn Tyr Ser Gly Val Ala Thr His Asn Met His Leu Ala Pro Ser
405 410 415
Val Ala Pro Leu Phe Pro Gly Glu Gln Ile Leu Phe Phe Arg Ser Thr
420 425 430
Val Pro Gly Cys Gly Gly Tyr Pro Asn Ser Asn Ile Asp Cys Leu Ile
435 440 445
Pro Gln Glu Trp Val Gln His Phe Tyr Gln Glu Gly Ala Pro Ala Arg
450 455 460
Thr Asp Val Ala Leu Leu Arg Phe Ile Asn Pro Asp Thr Gly Arg Val
465 470 475 480
Leu Phe Glu Cys Lys Leu His Lys His Gly Phe Ile Thr Val Ala Tyr
485 490 495
Ser Gly Asn His Asp Leu Val Met Pro Pro Asn Gly Tyr Phe Arg Phe
500 505 510
Glu Ser Trp Val Asn Gln Phe His Thr Leu Ala Pro Met Gly Thr Gly
515 520 525
Ser Gly Arg Arg Arg Ile Gln
530 535
<210> 26
<211> 555
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 26
Met Lys Met Ala Ser Lys Asp Ala Ser Pro Ser Thr Asp Gly Thr Ala
1 5 10 15
Asn Leu Val Pro Glu Ser Gln Gln Glu Val Leu Ala Leu Gln Pro Val
20 25 30
Ala Gly Ala Gln Ile Ala Ala Pro Val Ala Gly Gln Phe Asn Val Ile
35 40 45
Asp Pro Trp Ile Tyr Gln Asn Phe Val Gln Ala Pro Glu Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ser Thr Gly Glu Ile Leu Met Asn Leu Glu
65 70 75 80
Leu Gly Pro Gln Leu Asn Pro Tyr Leu Ala His Leu Ala Arg Met Tyr
85 90 95
Asn Ala Tyr Ala Gly Gly Phe Glu Val Gln Val Leu Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Ile Ile Val Cys Ala Val Pro Pro Asn Phe
115 120 125
Pro Leu Gln Asn Ile Ser Ala Ala Gln Ala Thr Gln Leu Pro His Val
130 135 140
Val Val Asp Val Arg Gln Leu Glu Pro Val Val Leu Pro Leu Pro Asp
145 150 155 160
Val Arg Ala Gly Phe Tyr His Tyr Asn Gln Val Glu Glu Ser Arg Met
165 170 175
Arg Leu Val Ala Ile Leu Tyr Thr Pro Leu Arg Thr Asn Ser Ala Gly
180 185 190
Asp Asp Ala Phe Thr Val Ser Cys Arg Ile Leu Thr Arg Pro Ala Pro
195 200 205
Asp Phe Ser Phe Phe Phe Leu Ile Pro Pro Thr Ile Glu Ser Lys Thr
210 215 220
Thr Pro Phe Thr Leu Pro Arg Leu Pro Ile Ser Glu Met Thr Asn Ser
225 230 235 240
Arg Phe Pro Leu Val Ile Lys Gly Met Val Val Asp Pro Asn Leu Pro
245 250 255
Leu Gln Ala Asn Phe Gln Asn Gly Arg Ile Thr Leu Asp Gly Glu Leu
260 265 270
Gln Gly Thr Thr Leu Pro Thr Ser Thr Ser Ile Gly Arg Ile Ser Gly
275 280 285
Thr His Met Ser Ser Thr Pro Ser Arg Ile Ile Gln His Glu Asp Ser
290 295 300
Gly Asp Ser Thr Gln Pro Arg Val Phe Asn Pro Val Trp Met Asp Leu
305 310 315 320
Thr Glu Asn Asn Trp Thr Glu Phe Gln Pro Phe Asn Asp Gln Pro Ala
325 330 335
Pro Leu Gly Cys Pro Asp Phe Lys Ala Lys Ile Leu Gly Thr Leu Ile
340 345 350
Arg Gln Pro Asn Asn Gly Ser Tyr Tyr Phe Asp Ala Tyr Leu Asp Thr
355 360 365
Arg Gln His Gly Thr Phe Ala Pro Tyr Thr Gly His Ala Ala Val His
370 375 380
Ser Asp Gln Gln Ala Gly His Leu Ala Gln Gly Tyr Lys Ile Gln Phe
385 390 395 400
Ser Pro Thr Gly Ile Glu Ser Asp Gln Asn Thr Asp Leu Asn Gln Leu
405 410 415
Pro Asp Tyr Gly Gly Ala Met Thr Val Ser Lys Gly Leu Ala Pro Ala
420 425 430
Ala Ala Pro Asp Phe Pro Gly Glu Met Ile Leu Tyr Phe Val Ser Asp
435 440 445
Met Pro Val Arg Asn Pro Asn Gly Glu Arg Arg Asp Thr Glu Ile Leu
450 455 460
Cys Leu Leu Pro Gln Glu Met Val Thr His Phe Tyr Glu Gln Gln Ala
465 470 475 480
Pro Ser Gln Gly Asp Val Ala Leu Val Arg Tyr Ile Asn Ala Glu Thr
485 490 495
Gly Arg Val Met Phe Glu Gly Lys Leu His Arg Asn Gly Phe Phe Thr
500 505 510
Val Ser Ala Thr Ala Arg Thr Leu Ile Val Pro Asp Gly Tyr Phe Arg
515 520 525
Phe Asp Ser Trp Val Asn Arg Phe Tyr Thr Leu Ser Pro Met Gly Thr
530 535 540
Gly Asn Gly Arg Arg Arg Ala Arg Met Leu Glu
545 550 555
<210> 27
<211> 535
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 27
Met Lys Met Ala Ser Asn Asp Val Ala Pro Ser Asn Asp Gly Ala Ala
1 5 10 15
Gly Leu Val Pro Glu Val Ser Asn Glu Thr Met Ala Leu Glu Pro Val
20 25 30
Ala Gly Ala Ser Ile Ala Ala Pro Leu Thr Gly Gln Asn Asn Val Ile
35 40 45
Asp Pro Trp Ile Arg Met Asn Phe Val Gln Ala Pro Asn Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ser Pro Gly Glu Val Leu Leu Asn Leu Glu
65 70 75 80
Leu Gly Pro Glu Leu Asn Pro Phe Leu Ala His Leu Ala Arg Met Tyr
85 90 95
Asn Gly Tyr Ala Gly Gly Val Glu Val Gln Val Leu Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Leu Val Phe Ala Ala Ile Pro Pro His Phe
115 120 125
Pro Leu Glu Asn Leu Ser Pro Gly Gln Ile Thr Met Phe Pro His Val
130 135 140
Ile Ile Asp Val Arg Thr Leu Glu Pro Val Leu Leu Pro Leu Pro Asp
145 150 155 160
Val Arg Asn Asn Phe Phe His Tyr Asn Gln Gln Pro Glu Pro Arg Met
165 170 175
Arg Leu Val Ala Met Leu Tyr Thr Pro Leu Arg Ser Asn Gly Ser Gly
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Ser Pro
195 200 205
Asp Phe Asp Phe Asn Tyr Leu Val Pro Pro Thr Val Glu Ser Lys Thr
210 215 220
Lys Pro Phe Thr Leu Pro Ile Leu Thr Ile Gly Glu Leu Ser Asn Ser
225 230 235 240
Arg Phe Pro Val Pro Ile Asp Glu Leu Tyr Thr Ser Pro Asn Glu Gly
245 250 255
Val Val Val Gln Pro Gln Asn Gly Arg Ser Thr Leu Asp Gly Glu Leu
260 265 270
Leu Gly Thr Thr Gln Leu Val Pro Ser Asn Ile Cys Ala Leu Arg Gly
275 280 285
Arg Ile Asn Ala Gln Val Pro Asp Asp His His Gln Trp Asn Leu Gln
290 295 300
Val Thr Asn Ala Asn Gly Thr Ser Phe Asp Pro Thr Glu Asp Val Pro
305 310 315 320
Ala Pro Leu Gly Thr Pro Asp Phe Leu Ala Asn Ile Tyr Gly Val Thr
325 330 335
Ser Gln Arg Asn Pro Asp Asn Thr Cys Arg Ala His Asp Gly Val Leu
340 345 350
Ala Thr Trp Ser Pro Lys Phe Thr Pro Lys Leu Gly Ser Val Val Leu
355 360 365
Gly Thr Trp Glu Glu Ser Asp Leu Asp Leu Asn Gln Pro Thr Arg Phe
370 375 380
Thr Pro Val Gly Leu Tyr Asp Thr Asn His Phe Asp Gln Trp Ile Leu
385 390 395 400
Pro Asn Tyr Ser Gly Arg Leu Thr Leu Asn Met Asn Leu Ala Pro Ser
405 410 415
Val Ala Pro Leu Phe Pro Gly Glu Gln Ile Leu Phe Phe Arg Ser His
420 425 430
Ile Pro Leu Lys Gly Gly Thr Ser Asn Gly Ala Ile Asp Cys Leu Leu
435 440 445
Pro Gln Glu Trp Ile Gln His Phe Tyr Gln Glu Ser Ala Pro Ser Pro
450 455 460
Thr Asp Val Ala Leu Ile Arg Tyr Thr Asn Pro Asp Thr Gly Arg Val
465 470 475 480
Leu Phe Glu Ala Lys Leu His Arg Gln Gly Phe Ile Thr Val Ala Asn
485 490 495
Ser Gly Ser Arg Pro Ile Val Val Pro Pro Asn Gly Tyr Phe Arg Phe
500 505 510
Asp Ser Trp Val Asn Gln Phe Tyr Ser Leu Ala Pro Met Gly Thr Gly
515 520 525
Asn Gly Arg Arg Arg Val Gln
530 535
<210> 28
<211> 542
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 28
Met Lys Met Ala Ser Ile Asp Ala Ala Pro Ser Thr Asp Gly Ala Ala
1 5 10 15
Gly Leu Val Pro Glu Ser Asn Asn Glu Val Met Ala Leu Glu Pro Val
20 25 30
Ala Gly Ala Ala Leu Ala Ala Pro Val Thr Gly Gln Thr Asn Ile Ile
35 40 45
Asp Pro Trp Ile Arg Ala Asn Phe Val Gln Ala Pro Asn Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ala Pro Gly Glu Val Leu Leu Asn Leu Glu
65 70 75 80
Leu Gly Pro Glu Leu Asn Pro Tyr Leu Ala His Leu Ala Arg Met Tyr
85 90 95
Asn Gly Tyr Ala Gly Gly Met Glu Val Gln Val Met Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Leu Val Phe Ala Ala Val Pro Pro His Phe
115 120 125
Pro Val Glu Asn Leu Ser Pro Gln Gln Ile Thr Met Phe Pro His Val
130 135 140
Ile Ile Asp Val Arg Thr Leu Glu Pro Val Leu Leu Pro Leu Pro Asp
145 150 155 160
Val Arg Asn Asn Phe Phe His Tyr Asn Gln Lys Asp Asp Pro Lys Met
165 170 175
Arg Ile Val Ala Met Leu Tyr Thr Pro Leu Arg Ser Asn Gly Ser Gly
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Ser Pro
195 200 205
Asp Phe Asp Phe Thr Tyr Leu Val Pro Pro Thr Val Glu Ser Lys Thr
210 215 220
Lys Pro Phe Thr Leu Pro Ile Leu Thr Leu Gly Glu Leu Ser Asn Ser
225 230 235 240
Arg Phe Pro Val Ser Ile Asp Gln Met Tyr Thr Ser Pro Asn Glu Val
245 250 255
Ile Ser Val Gln Cys Gln Asn Gly Arg Cys Thr Leu Asp Gly Glu Leu
260 265 270
Gln Gly Thr Thr Gln Leu Gln Val Ser Gly Ile Cys Ala Phe Lys Gly
275 280 285
Glu Val Thr Ala His Leu His Asp Asn Asp His Leu Tyr Asn Val Thr
290 295 300
Ile Thr Asn Leu Asn Gly Ser Pro Phe Asp Pro Ser Glu Asp Ile Pro
305 310 315 320
Ala Pro Leu Gly Val Pro Asp Phe Gln Gly Arg Val Phe Gly Val Ile
325 330 335
Ser Gln Arg Asp Lys His Asn Ser Pro Gly His Asn Glu Pro Ala Asn
340 345 350
Arg Gly His Asp Ala Val Val Pro Thr Tyr Thr Ser Gln Tyr Thr Pro
355 360 365
Lys Leu Gly Gln Ile Gln Ile Gly Thr Trp Gln Thr Asp Asp Leu Thr
370 375 380
Val Asn Gln Pro Val Lys Phe Thr Pro Val Gly Leu Asn Asp Thr Glu
385 390 395 400
His Phe Asn Gln Trp Val Val Pro Arg Tyr Ala Gly Ala Leu Asn Leu
405 410 415
Asn Thr Asn Leu Ala Pro Ser Val Ala Pro Val Phe Pro Gly Glu Arg
420 425 430
Leu Leu Phe Phe Arg Ser Tyr Ile Pro Leu Lys Gly Gly Tyr Gly Asn
435 440 445
Pro Ala Ile Asp Cys Leu Leu Pro Gln Glu Trp Val Gln His Phe Tyr
450 455 460
Gln Glu Ala Ala Pro Ser Met Ser Glu Val Ala Leu Val Arg Tyr Ile
465 470 475 480
Asn Pro Asp Thr Gly Arg Ala Leu Phe Glu Ala Lys Leu His Arg Ala
485 490 495
Gly Phe Met Thr Val Ser Ser Asn Thr Ser Ala Pro Val Val Val Pro
500 505 510
Ala Asn Gly Tyr Phe Arg Phe Asp Ser Trp Val Asn Gln Phe Tyr Ser
515 520 525
Leu Ala Pro Met Gly Thr Gly Asn Gly Arg Arg Arg Val Gln
530 535 540
<210> 29
<211> 542
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 29
Met Lys Met Ala Ser Asn Asp Ala Ala Pro Ser Asn Asp Gly Ala Ala
1 5 10 15
Gly Leu Val Pro Glu Ile Asn Asn Glu Thr Met Ala Leu Glu Pro Val
20 25 30
Ala Gly Gly Ala Ile Ala Ala Pro Leu Thr Gly Gln Thr Asn Phe Ile
35 40 45
Asp Pro Trp Ile Arg Gly Asn Tyr Val Gln Ala Pro Asn Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ser Pro Gly Glu Ile Leu Leu Asn Leu Glu
65 70 75 80
Leu Gly Pro Glu Leu Asn Pro Phe Leu Ala His Leu Ser Arg Met Tyr
85 90 95
Asn Gly Tyr Ala Gly Gly Ile Asp Val Gln Val Ile Met Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Ile Ile Phe Ala Ala Val Pro Pro His Phe
115 120 125
Pro Val Glu Asn Ile Ser Pro Pro Gln Ile Thr Met Phe Pro His Ile
130 135 140
Ile Val Asp Val Arg Thr Leu Glu Pro Ile Asn Ile Pro Val Pro Asp
145 150 155 160
Val Arg Asn Asn Phe Phe His Tyr Asn Gln Asp Arg Asp Ser Arg Met
165 170 175
Arg Leu Val Ala Met Leu Tyr Thr Pro Leu Arg Ser Asn Gly Ser Thr
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Lys Pro Ser Ala
195 200 205
Asp Phe Glu Phe Asn Tyr Leu Val Pro Pro Thr Val Glu Ser Arg Thr
210 215 220
Lys Pro Phe Ser Ile Pro Ile Leu Thr Ile Gly Glu Met Thr Asn Ser
225 230 235 240
Arg Phe Pro Leu Pro Ile Asp Met Leu Tyr Thr Ser Pro Thr Glu Asn
245 250 255
Leu Val Val Gln Pro Gln Asn Gly Arg Cys Thr Thr Glu Gly Glu Leu
260 265 270
Leu Gly Thr Thr Gln Leu Val Thr Pro Ser Ile Cys Ser Leu Arg Gly
275 280 285
Ala Ile Thr Gly His Glu Gly Asn Asp Asp Asp His Lys Trp His Met
290 295 300
Thr Val Thr Ser Pro Asn Gly Ala Ala Phe Asp Pro Thr Glu Asp Val
305 310 315 320
Pro Ala Pro Leu Gly Thr Pro Asp Phe Thr Gly Asp Ile Tyr Gly Val
325 330 335
Leu Ser Gln Arg Asp Arg Asn Ile Asn Pro Gly Gln Thr Ala Pro Ala
340 345 350
Asn Arg Ala His Glu Ala Val Val Ser Thr Arg Ser Asn Lys Phe Thr
355 360 365
Pro Lys Leu Gly Ser Val Met Ile Ala Thr Trp Glu Thr Thr Asp Val
370 375 380
Leu Gln Gln Pro Thr Lys Phe Thr Pro Val Gly Leu Glu Ser Pro Asn
385 390 395 400
His Tyr Asn Gln Trp Gln Leu Pro Asn Tyr Ser Gly Ala Leu Thr Leu
405 410 415
Asn Met Gly Leu Ala Pro Ser Val Phe Pro Thr Tyr Pro Gly Glu Gln
420 425 430
Ile Leu Phe Phe Arg Ser Phe Ile Pro Leu Lys Gly Gly Tyr Gly Asn
435 440 445
Ser Ala Ile Asp Cys Leu Val Pro Gln Glu Trp Ile Gln His Phe Tyr
450 455 460
Gln Glu Ser Ala Pro Ser Gln Thr Asp Val Ala Leu Ile Arg Tyr Val
465 470 475 480
Asn Pro Glu Thr Gly Arg Val Leu Phe Glu Ala Lys Leu His Arg Gln
485 490 495
Gly Phe Ile Thr Val Ala Lys Thr Gly Asp Ser Pro Ile Asn Val Pro
500 505 510
Ala Asn Gly Tyr Phe Arg Phe Asp Ser Trp Val Asn Pro Phe Tyr Ser
515 520 525
Leu Ala Pro Met Gly Thr Gly Asn Gly Arg Arg Arg Asn Gln
530 535 540
<210> 30
<211> 548
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 30
Met Lys Met Ala Ser Asn Asp Ala Ala Pro Ser Asn Asp Gly Ala Ala
1 5 10 15
Gly Leu Val Pro Glu Ile Asn Asn Glu Ala Met Ala Leu Glu Pro Val
20 25 30
Ala Gly Ala Ala Ile Ala Ala Pro Leu Thr Gly Gln Gln Asn Ile Ile
35 40 45
Asp Pro Trp Ile Met Asn Asn Phe Val Gln Ala Pro Gly Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ser Pro Gly Glu Val Leu Leu Asn Leu Glu
65 70 75 80
Leu Gly Pro Glu Ile Asn Pro Tyr Leu Ala His Leu Ala Arg Met Tyr
85 90 95
Asn Gly Tyr Ala Gly Gly Phe Glu Val Gln Val Val Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Ile Ile Phe Ala Ala Ile Pro Pro Asn Phe
115 120 125
Pro Ile Asp Asn Leu Ser Ala Ala Gln Ile Thr Met Cys Pro His Val
130 135 140
Ile Val Asp Val Arg Gln Leu Glu Pro Val Asn Leu Pro Met Pro Asp
145 150 155 160
Val Arg Asn Asn Phe Phe His Tyr Asn Gln Gly Ser Asp Ser Arg Leu
165 170 175
Arg Leu Val Ala Met Leu Tyr Thr Pro Leu Arg Ala Asn Asn Ser Gly
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Ser Pro
195 200 205
Asp Phe Ser Phe Asn Phe Leu Val Pro Pro Thr Val Glu Ser Lys Thr
210 215 220
Lys Pro Phe Thr Leu Pro Ile Leu Thr Ile Ser Glu Met Ser Asn Ser
225 230 235 240
Arg Phe Pro Val Pro Ile Asp Ser Leu His Thr Ser Pro Thr Glu Asn
245 250 255
Ile Val Val Gln Cys Gln Asn Gly Arg Val Thr Leu Asp Gly Glu Leu
260 265 270
Met Gly Thr Thr Gln Leu Leu Pro Ser Gln Ile Cys Ala Phe Arg Gly
275 280 285
Val Leu Thr Arg Ser Thr Ser Arg Ala Ser Asp Gln Ala Asp Thr Ala
290 295 300
Thr Pro Arg Leu Phe Asn Tyr Tyr Trp His Ile Gln Leu Ala Asn Leu
305 310 315 320
Asn Gly Thr Pro Tyr Asp Pro Ala Glu Asp Ile Pro Gly Pro Leu Gly
325 330 335
Thr Pro Asp Phe Arg Gly Lys Val Phe Gly Val Ala Cys Gln Arg Asn
340 345 350
Pro Asp Cys Thr Thr Arg Ala His Glu Ala Lys Val Asp Thr Thr Ala
355 360 365
Gly Arg Phe Thr Pro Lys Leu Gly Ser Leu Glu Ile Ser Thr Glu Ser
370 375 380
Gly Asp Phe Asp Gln Asn Gln Pro Thr Arg Phe Thr Pro Val Gly Ile
385 390 395 400
Gly Val Asp His Glu Ala Asp Phe Gln Gln Trp Ser Leu Pro Asp Tyr
405 410 415
Ser Gly Gln Phe Thr His Asn Met Asn Leu Ala Pro Ala Val Ala Pro
420 425 430
Asn Phe Pro Gly Glu Gln Leu Leu Phe Phe Arg Ser Gln Leu Pro Ser
435 440 445
Ser Gly Gly Arg Ser Asn Gly Ile Leu Asp Cys Leu Val Pro Gln Glu
450 455 460
Trp Val Gln His Phe Tyr Gln Glu Ser Ala Pro Ala Gln Thr Gln Val
465 470 475 480
Ala Leu Val Arg Tyr Val Asn Pro Asp Thr Gly Arg Val Leu Phe Glu
485 490 495
Ala Lys Leu His Lys Leu Gly Phe Met Thr Ile Ala Lys Asn Gly Asp
500 505 510
Ser Pro Ile Thr Val Pro Pro Asn Gly Tyr Phe Arg Phe Glu Ser Trp
515 520 525
Val Asn Pro Phe Tyr Thr Leu Ala Pro Met Gly Thr Gly Asn Gly Arg
530 535 540
Arg Arg Ile Gln
545
<210> 31
<211> 540
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 31
Met Lys Met Ala Ser Ser Asp Ala Asn Pro Ser Asp Gly Ser Thr Ala
1 5 10 15
Asn Leu Val Pro Glu Val Asn Asn Glu Val Met Ala Leu Glu Pro Val
20 25 30
Val Gly Ala Ala Ile Ala Ala Pro Val Ala Gly Gln Gln Asn Val Ile
35 40 45
Asp Pro Trp Ile Arg Asn Asn Phe Val Gln Ala Pro Gly Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ala Pro Gly Glu Ile Leu Trp Ser Ala Pro
65 70 75 80
Leu Gly Pro Asp Leu Asn Pro Tyr Leu Ser His Leu Ala Arg Met Tyr
85 90 95
Asn Ser Tyr Ala Gly Gly Phe Glu Val Gln Val Ile Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Ile Ile Phe Ala Ala Val Pro Pro Asn Phe
115 120 125
Pro Thr Glu Gly Leu Ser Pro Ser Gln Val Thr Met Phe Pro His Ile
130 135 140
Ile Val Asp Val Arg Gln Leu Glu Pro Val Leu Ile Pro Leu Pro Asp
145 150 155 160
Val Arg Asn Asn Phe Tyr His Tyr Asn Gln Ser Asn Asp Pro Thr Ile
165 170 175
Lys Leu Ile Ala Met Leu Tyr Thr Pro Leu Arg Ala Asn Asn Ala Gly
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Ser Pro
195 200 205
Asp Phe Asp Phe Ile Phe Leu Val Pro Pro Thr Val Glu Ser Arg Thr
210 215 220
Lys Pro Phe Ser Val Pro Ile Leu Thr Val Glu Glu Met Thr Asn Ser
225 230 235 240
Arg Phe Pro Ile Pro Leu Glu Lys Leu Phe Thr Gly Pro Ser Ser Ala
245 250 255
Phe Val Val Gln Pro Gln Asn Gly Arg Cys Thr Thr Asp Gly Val Leu
260 265 270
Leu Gly Thr Thr Gln Leu Ser Pro Val Asn Ile Cys Thr Phe Arg Gly
275 280 285
Asp Val Thr His Ile Ala Gly Thr Gln Glu Tyr Thr Met Asn Leu Ala
290 295 300
Ser Gln Asn Trp Asn Asn Tyr Asp Pro Thr Glu Glu Ile Pro Ala Pro
305 310 315 320
Leu Gly Thr Pro Asp Phe Val Gly Lys Ile Gln Gly Val Leu Thr Gln
325 330 335
Thr Thr Arg Arg Asp Gly Ser Thr Arg Gly His Lys Ala Thr Val Ser
340 345 350
Thr Gly Ser Val His Phe Thr Pro Lys Leu Gly Arg Ile Gln Phe Ser
355 360 365
Thr Asp Thr Ser Asn Asp Phe Glu Thr Gly Gln Asn Thr Arg Phe Thr
370 375 380
Pro Val Gly Val Val Gln Asp Gly Ser Thr Thr His Gln Asn Glu Pro
385 390 395 400
Gln Gln Trp Val Leu Pro Asn Tyr Ser Gly Arg Asp Ser His Asn Val
405 410 415
His Leu Ala Pro Ala Val Ala Pro Ser Phe Pro Gly Glu Gln Leu Leu
420 425 430
Phe Phe Arg Ser Thr Met Pro Gly Cys Ser Gly Tyr Pro Asn Met Asn
435 440 445
Leu Asp Cys Leu Leu Pro Gln Glu Trp Val Gln His Phe Tyr Gln Glu
450 455 460
Ala Ala Pro Ala Gln Ser Asp Val Ala Leu Leu Arg Phe Val Asn Pro
465 470 475 480
Asp Thr Gly Arg Val Leu Phe Glu Cys Lys Leu His Lys Ser Gly Tyr
485 490 495
Val Thr Val Ala His Thr Gly Gln His Asp Leu Val Ile Pro Pro Asn
500 505 510
Gly Tyr Phe Arg Phe Asp Ser Trp Val Asn Gln Phe Tyr Thr Leu Ala
515 520 525
Pro Met Gly Asn Gly Thr Gly Arg Arg Arg Ala Leu
530 535 540
<210> 32
<211> 537
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 32
Met Lys Met Ala Ser Ser Asp Ala Asn Pro Ser Asp Gly Ser Thr Ala
1 5 10 15
Ser Leu Val Pro Glu Val Asn Asn Glu Val Met Ala Leu Glu Pro Val
20 25 30
Val Gly Ala Ala Ile Ala Ala Pro Val Ala Gly Gln Gln Asn Val Ile
35 40 45
Asp Pro Trp Ile Arg Asn Asn Phe Val Gln Ala Pro Gly Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ala Pro Gly Glu Ile Leu Trp Ser Ala Pro
65 70 75 80
Leu Gly Pro Asp Leu Asn Pro Tyr Leu Ser His Leu Ala Arg Met Tyr
85 90 95
Asn Gly Tyr Ala Gly Gly Phe Glu Val Gln Val Ile Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Ile Ile Phe Ala Ala Val Pro Pro Asn Phe
115 120 125
Pro Thr Glu Gly Leu Ser Pro Ser Gln Val Thr Met Phe Pro His Ile
130 135 140
Ile Val Asp Val Arg Gln Leu Glu Pro Val Leu Ile Pro Leu Pro Asp
145 150 155 160
Val Arg Asn Asn Phe Tyr His Tyr Asn Gln Ser Asn Asp Ser Thr Ile
165 170 175
Lys Leu Ile Ala Met Leu Tyr Thr Pro Leu Arg Ala Asn Asn Ala Gly
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Ser Pro
195 200 205
Asp Phe Asp Phe Ile Phe Leu Val Pro Pro Thr Val Glu Ser Arg Thr
210 215 220
Lys Pro Phe Ser Val Pro Ile Leu Thr Val Glu Glu Met Thr Asn Ser
225 230 235 240
Arg Phe Pro Ile Pro Leu Glu Lys Leu Phe Thr Gly Pro Ser Ser Thr
245 250 255
Phe Val Val Gln Pro Gln Asn Gly Arg Cys Thr Thr Asp Gly Val Leu
260 265 270
Leu Gly Thr Thr Gln Leu Ser Pro Val Asn Ile Cys Thr Phe Arg Gly
275 280 285
Gly Ile Thr Arg Ile Gly Gln Ser Glu Ser Tyr Lys Met Asn Leu Ala
290 295 300
Ser Gln Asn Trp Asn Asn Tyr Asp Pro Thr Glu Glu Ile Pro Ala Pro
305 310 315 320
Leu Gly Thr Pro Asp Phe Lys Gly Arg Ile Arg Gly Leu Leu Thr Gln
325 330 335
Thr Thr Lys Gly Ala Gly Ser Thr Arg Gly His Lys Ala Thr Val Leu
340 345 350
Thr Gly Gly Ser Asp Phe Thr Pro Lys Leu Gly Thr Val Arg Phe Asp
355 360 365
Thr Lys Ser Ile Asp Phe Glu Asn Asn Gln Asn Thr Lys Phe Thr Pro
370 375 380
Val Gly Val Val Gln Asp Gly Asn Asn His Asp Glu Pro Thr Gln Trp
385 390 395 400
Val Leu Pro Asn Tyr Ser Gly Pro Asp Thr His Asn Val His Leu Ala
405 410 415
Pro Ala Val Ala Pro Thr Phe Pro Gly Glu Gln Leu Leu Phe Phe Arg
420 425 430
Ser Thr Met Pro Gly Cys Ser Gly Tyr Pro Lys Met Glu Leu Asp Cys
435 440 445
Leu Leu Pro Gln Glu Trp Val Gln His Phe Tyr Gln Glu Ala Ala Pro
450 455 460
Ala Gln Thr Asp Val Ala Leu Leu Arg Phe Val Asn Pro Asp Thr Gly
465 470 475 480
Arg Val Leu Phe Glu Cys Lys Leu His Lys Ser Gly Tyr Val Thr Val
485 490 495
Ala His Thr Gly Asp His Asp Leu Val Ile Pro Pro Asn Gly Tyr Phe
500 505 510
Arg Phe Asp Ser Trp Val Asn Gln Phe Tyr Thr Leu Ala Pro Met Gly
515 520 525
Asn Gly Thr Gly Arg Arg Arg Ala Leu
530 535
<210> 33
<211> 540
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 33
Met Lys Met Ala Ser Asn Asp Ala Asn Pro Ser Asp Gly Ser Ala Ala
1 5 10 15
Asn Leu Val Pro Glu Val Asn Asn Glu Val Met Ala Leu Glu Pro Val
20 25 30
Ala Gly Ala Ala Leu Ala Ala Pro Val Ala Gly Gln Gln Asn Val Ile
35 40 45
Asp Pro Trp Ile Arg Asn Asn Phe Val Gln Ala Pro Gly Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ala Pro Gly Glu Ile Leu Trp Ser Ala Pro
65 70 75 80
Leu Ser Pro Asp Leu Asn Pro Tyr Leu Ser His Leu Ala Arg Met Tyr
85 90 95
Asn Ser Tyr Ala Gly Gly Phe Glu Val Gln Val Ile Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Ile Ile Phe Ala Ala Val Pro Pro Asn Phe
115 120 125
Pro Ile Glu Gly Leu Ser Pro Ser Gln Val Thr Met Phe Pro His Ile
130 135 140
Ile Val Asp Val Arg Gln Leu Glu Pro Val Leu Ile Pro Leu Pro Asp
145 150 155 160
Val Arg Asn Asn Phe Tyr His Tyr Asn Gln Thr Asn Glu Pro Thr Ile
165 170 175
Lys Leu Ile Ala Met Leu Tyr Thr Pro Leu Arg Ala Asn Asn Ala Gly
180 185 190
Glu Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Ser Pro
195 200 205
Asp Phe Asp Phe Ile Phe Leu Val Pro Pro Thr Val Glu Ser Arg Thr
210 215 220
Lys Pro Phe Thr Val Pro Ile Leu Thr Val Glu Glu Met Thr Asn Ser
225 230 235 240
Arg Phe Pro Ile Pro Leu Glu Lys Leu Phe Thr Gly Pro Ser Ser Ser
245 250 255
Phe Val Val Gln Pro Gln Asn Gly Arg Cys Thr Thr Asp Gly Val Leu
260 265 270
Leu Gly Thr Thr Gln Leu Ser Pro Val Asn Ile Cys Thr Phe Arg Gly
275 280 285
Asp Val Thr His Ile Ala Gly Ser Arg Asn Tyr Thr Met Asn Leu Ala
290 295 300
Ser Ile Asn Trp Asn Asn Tyr Asp Pro Thr Glu Glu Ile Pro Ala Pro
305 310 315 320
Leu Gly Thr Pro Asp Phe Val Gly Lys Ile Gln Gly Met Leu Thr Gln
325 330 335
Thr Thr Arg Gly Glu Gly Ser Thr Arg Ala His Arg Ala Thr Val Tyr
340 345 350
Thr Gly Ser Ala Pro Phe Thr Pro Lys Leu Gly Ser Val Gln Phe Thr
355 360 365
Thr Asp Thr Asp Asn Asp Phe Asp Ala Asn Gln Asn Thr Lys Phe Thr
370 375 380
Pro Val Gly Val Ile Gln Asp Gly Asp Thr Ala His Arg Asn Glu Pro
385 390 395 400
Gln Gln Trp Val Leu Pro Ser Tyr Ser Gly Arg Asn Val Gln Asn Val
405 410 415
His Leu Ala Pro Ala Val Ala Pro Thr Phe Pro Gly Glu Gln Leu Leu
420 425 430
Phe Phe Arg Ser Thr Met Pro Gly Cys Ser Gly Tyr Pro Asn Met Asp
435 440 445
Leu Asp Cys Leu Leu Pro Gln Glu Trp Val Gln His Phe Tyr Gln Glu
450 455 460
Ala Ala Pro Ala Gln Ser Asp Val Ala Leu Leu Arg Phe Val Asn Pro
465 470 475 480
Asp Thr Gly Arg Val Leu Phe Glu Cys Lys Leu His Lys Ser Gly Tyr
485 490 495
Val Thr Val Ala His Thr Gly Gln His Asp Leu Val Ile Pro Pro Asn
500 505 510
Gly Tyr Phe Arg Phe Asp Ser Trp Val Asn Gln Phe Tyr Thr Leu Ala
515 520 525
Pro Met Gly Asn Gly Ala Gly Arg Arg Arg Ala Leu
530 535 540
<210> 34
<211> 540
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 34
Met Lys Met Ala Ser Asn Asp Ala Asn Pro Ser Asp Gly Ser Ala Ala
1 5 10 15
Asn Leu Val Pro Glu Val Asn Asn Glu Val Met Ala Leu Glu Pro Val
20 25 30
Val Gly Ala Ala Ile Ala Ala Pro Val Ala Gly Gln Gln Asn Val Ile
35 40 45
Asp Pro Trp Ile Arg Asn Asn Phe Val Gln Ala Pro Gly Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ala Pro Gly Glu Ile Leu Trp Ser Ala Pro
65 70 75 80
Leu Gly Pro Asp Leu Asn Pro Tyr Leu Ser His Leu Ala Arg Met Tyr
85 90 95
Asn Gly Tyr Ala Gly Gly Phe Glu Val Gln Val Ile Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Ile Ile Phe Ala Ala Val Pro Pro Asn Phe
115 120 125
Pro Thr Glu Gly Leu Ser Pro Ser Gln Val Thr Met Phe Pro His Ile
130 135 140
Ile Val Asp Val Arg Gln Leu Glu Pro Val Leu Ile Pro Leu Pro Asp
145 150 155 160
Val Arg Asn Asn Phe Tyr His Tyr Asn Gln Ser Asn Asp Ser Thr Ile
165 170 175
Lys Leu Ile Ala Met Leu Tyr Thr Pro Leu Arg Ala Asn Asn Ala Gly
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Ser Pro
195 200 205
Asp Phe Asp Phe Ile Phe Leu Val Pro Pro Thr Val Glu Ser Arg Ser
210 215 220
Lys Pro Phe Ser Val Pro Val Leu Thr Val Glu Glu Met Thr Asn Ser
225 230 235 240
Arg Phe Pro Ala Thr Leu Asp Lys Leu Phe Thr Gly Pro Ser Ser Thr
245 250 255
Phe Val Val Gln Pro Gln Asn Gly Arg Cys Met Ile Asp Gly Val Leu
260 265 270
Leu Gly Thr Thr Gln Leu Ser Pro Val Asn Ile Cys Thr Phe Arg Gly
275 280 285
Asp Val Thr His Leu Arg Asp Ser Pro Ile Tyr Thr Met Asn Leu Ala
290 295 300
Ser Pro Asn Trp Asn Asn Tyr Asp Ser Thr Glu Glu Ile Pro Ala Pro
305 310 315 320
Leu Gly Thr Pro Asp Phe Val Gly Lys Ile Gln Gly Val Leu Thr Gln
325 330 335
Thr Thr Lys Gly Glu Gly Ser Thr Arg Gly His Arg Ala Thr Val Tyr
340 345 350
Val Gly Ser Ala Asn Tyr Thr Pro Lys Leu Gly Lys Val Gln Phe Glu
355 360 365
Thr Asn Thr Thr Asn Asp Leu Tyr Ala His Gln Asn Thr Lys Phe Thr
370 375 380
Pro Val Gly Val Val Gln Gly Gly Glu Ser Ala His Arg Ser Glu Pro
385 390 395 400
Gln Gln Trp Val Leu Pro Gly Tyr Ser Gly Arg Asp Thr Pro Asn Val
405 410 415
His Leu Ala Pro Ala Val Ala Pro Thr Phe Pro Gly Glu Gln Leu Leu
420 425 430
Phe Phe Arg Ser Thr Ile Pro Gly Cys Gly Gly His Pro Asn Met Asp
435 440 445
Leu Asp Cys Leu Leu Pro Gln Glu Trp Val Gln His Phe Tyr Gln Glu
450 455 460
Ala Ala Pro Ala Gln Ser Asp Val Ala Leu Leu Arg Phe Val Asn Pro
465 470 475 480
Asp Thr Ser Arg Val Leu Phe Glu Cys Lys Leu His Lys Ser Gly Tyr
485 490 495
Val Thr Val Ala His Thr Gly Gln His Asp Leu Val Ile Pro Pro Asn
500 505 510
Gly Tyr Phe Arg Phe Asp Ser Trp Val Asn Gln Phe Tyr Thr Leu Ala
515 520 525
Pro Met Gly Asn Gly Thr Gly Arg Lys Arg Ala Ile
530 535 540
<210> 35
<211> 539
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 35
Met Lys Met Ala Ser Ser Asp Ala Asn Pro Ser Asp Gly Ser Ala Ala
1 5 10 15
Asn Leu Val Pro Glu Val Asn Asn Glu Val Met Ala Leu Glu Pro Val
20 25 30
Val Gly Ala Ala Ile Ala Ala Pro Val Ala Gly Gln Gln Asn Val Ile
35 40 45
Asp Pro Trp Ile Arg Asn Asn Phe Val Gln Ala Pro Gly Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ala Pro Gly Glu Ile Leu Trp Ser Ala Pro
65 70 75 80
Leu Gly Pro Asp Leu Asn Pro Tyr Leu Ser His Leu Ala Arg Met Tyr
85 90 95
Asn Gly Tyr Ala Gly Gly Phe Glu Val Gln Val Ile Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Ile Ile Phe Ala Ala Val Pro Pro Thr Phe
115 120 125
Pro Thr Glu Gly Leu Ser Pro Ser Gln Val Thr Met Phe Pro His Ile
130 135 140
Ile Val Asp Val Arg Gln Leu Glu Pro Val Leu Ile Pro Leu Pro Asp
145 150 155 160
Val Arg Asn Asn Phe Tyr His Tyr Asn Gln Ser Asn Asp Ser Thr Ile
165 170 175
Lys Leu Ile Ala Met Leu Tyr Thr Pro Leu Arg Ala Asn Asn Pro Gly
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Ser Pro
195 200 205
Asp Phe Asp Phe Ile Phe Leu Val Pro Pro Thr Val Glu Ser Arg Thr
210 215 220
Lys Pro Phe Ser Val Pro Ile Leu Thr Val Gly Glu Met Thr Asn Ser
225 230 235 240
Arg Phe Pro Ile Asn Leu Glu Arg Leu Phe Thr Gly Pro Ser Ser Ala
245 250 255
Asn Val Val Gln Pro Gln Asn Gly Arg Cys Thr Ile Asp Gly Glu Leu
260 265 270
Leu Gly Thr Thr Gln Leu Ser Ser Val Asn Ile Cys Thr Phe Arg Gly
275 280 285
Asp Val Thr His Ile Gly Ser Thr His His Trp Thr Met Asn Leu Ala
290 295 300
Ser Pro Asn Trp Asn Asn Tyr Asp Pro Thr Glu Glu Thr Pro Ala Pro
305 310 315 320
Leu Gly Thr Pro Asp Phe Val Gly Lys Ile His Gly Met Leu Thr Gln
325 330 335
Thr Thr Gln Gly Asn Gly Ser Thr Arg Gly His Arg Ala Thr Val Tyr
340 345 350
Val Gly Ser Ala Glu Phe Thr Pro Lys Leu Gly Lys Val Gln Phe Lys
355 360 365
Thr Glu Thr Asp His Asp Leu Ala Ile Arg Gln Asn Thr Lys Phe Thr
370 375 380
Pro Val Gly Val Ile Gln Glu Ser Asp His His Arg Asp Glu Pro Gln
385 390 395 400
Gln Trp Arg Leu Pro Asn Tyr Ser Gly Ala Asn Thr Phe Asn Val His
405 410 415
Leu Ala Pro Ala Val Ala Pro Asn Phe Pro Gly Glu Gln Leu Leu Phe
420 425 430
Phe Arg Ser Thr Leu Pro Gly Cys Gly Gly His Pro Asn Met Asp Leu
435 440 445
Asp Cys Leu Leu Pro Gln Glu Trp Val Gln His Phe Tyr Gln Glu Ala
450 455 460
Ala Pro Ala Gln Ser Asp Val Ala Leu Leu Arg Phe Val Asn Pro Asp
465 470 475 480
Thr Ser Arg Val Leu Phe Glu Cys Lys Leu His Lys Ser Gly Tyr Val
485 490 495
Thr Val Ala His Thr Gly Gln Tyr Asp Leu Val Leu Pro Ser Asn Gly
500 505 510
Tyr Phe Arg Phe Asp Ser Trp Val Asn Gln Phe Tyr Thr Leu Ala Pro
515 520 525
Met Gly Asn Gly Thr Gly Arg Arg Arg Ala Leu
530 535
<210> 36
<211> 539
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 36
Met Lys Met Ala Ser Asn Asp Ala Ser Pro Ser Asp Gly Ser Ala Ala
1 5 10 15
Asn Leu Val Pro Glu Val Asn Asn Glu Val Met Ala Leu Glu Pro Val
20 25 30
Val Gly Ala Ala Ile Ala Ala Pro Val Ala Gly Gln Gln Asn Val Ile
35 40 45
Asp Pro Trp Ile Arg Asn Asn Phe Val Gln Ala Pro Gly Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ala Pro Gly Glu Ile Leu Trp Ser Ala Pro
65 70 75 80
Leu Gly Pro Asp Leu Asn Pro Tyr Leu Ser His Leu Ala Arg Met Tyr
85 90 95
Asn Gly Tyr Ala Gly Gly Phe Glu Val Gln Val Ile Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Ile Ile Phe Ala Ala Val Pro Pro Asn Phe
115 120 125
Pro Thr Glu Gly Leu Ser Pro Ser Gln Val Thr Met Phe Pro His Ile
130 135 140
Val Val Asp Val Arg Gln Leu Glu Pro Val Leu Ile Pro Leu Pro Asp
145 150 155 160
Val Arg Asn Asn Phe Tyr His Tyr Asn Gln Ser Lys Asp Pro Thr Ile
165 170 175
Lys Leu Ile Ala Met Leu Tyr Thr Pro Leu Arg Ala Asn Asn Ala Gly
180 185 190
Glu Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Ser Pro
195 200 205
Asp Phe Asp Phe Ile Phe Leu Val Pro Pro Thr Val Glu Ser Arg Ser
210 215 220
Lys Pro Phe Thr Val Pro Ile Leu Thr Val Glu Glu Met Thr Asn Ser
225 230 235 240
Arg Phe Pro Ile Pro Leu Glu Lys Leu Phe Thr Gly Pro Ser Gly Ala
245 250 255
Phe Val Val Gln Pro Gln Asn Gly Arg Cys Thr Thr Asp Gly Val Leu
260 265 270
Leu Gly Thr Thr Gln Leu Ser Pro Val Asn Ile Cys Thr Phe Arg Gly
275 280 285
Asp Leu Thr His Phe Thr Gly Thr Ser Glu Tyr Ala Met Asn Leu Ala
290 295 300
Ser Gln Asn Trp Asp Asn Tyr Asp Pro Thr Glu Glu Ile Pro Ala Pro
305 310 315 320
Leu Gly Ala Pro Asp Phe Val Gly Lys Ile Arg Gly Met Leu Thr Gln
325 330 335
Thr Thr Arg Arg Asp Gly Ser Thr Arg Gly His Arg Ala Thr Leu Ser
340 345 350
Thr Gly Ser Ala His Phe Thr Pro Lys Leu Gly Asn Ile Arg Phe Ser
355 360 365
Thr Asp Thr Asn Asn Asp Phe Glu Ala Gly Gln Asn Thr Lys Phe Thr
370 375 380
Pro Val Gly Val Phe Gln Glu Gly Asp Asn His Gln Asn Glu Pro Gln
385 390 395 400
Gln Trp Val Leu Pro Asn Tyr Ser Gly Ala Thr Ala His Asn Val His
405 410 415
Leu Ala Pro Ala Val Ala Pro Ala Phe Pro Gly Glu Gln Leu Leu Phe
420 425 430
Phe Arg Ser Thr Met Pro Gly Cys Gly Gly Tyr Pro Asn Met Asn Leu
435 440 445
Asp Cys Leu Leu Pro Gln Glu Trp Val Gln His Phe Tyr Gln Glu Ala
450 455 460
Ala Pro Ala Gln Ser Asp Val Ala Leu Leu Arg Phe Val Asn Pro Asp
465 470 475 480
Thr Ser Arg Val Leu Phe Glu Cys Lys Leu His Lys Ser Gly Tyr Val
485 490 495
Thr Val Ala His Thr Gly Gln His Asp Leu Val Ile Pro Pro Asn Gly
500 505 510
Tyr Phe Arg Phe Asp Ser Trp Val Asn Gln Phe Tyr Thr Leu Ala Pro
515 520 525
Met Gly Asn Gly Thr Gly Arg Arg Arg Ala Leu
530 535
<210> 37
<211> 539
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 37
Met Lys Met Ala Ser Ser Asp Ala Asn Pro Ser Asp Gly Ser Thr Ala
1 5 10 15
Asn Leu Val Pro Glu Ala Asn Asn Glu Val Met Ala Leu Glu Pro Val
20 25 30
Val Gly Ala Ala Ile Ala Ala Pro Val Ala Gly Gln Gln Asn Val Ile
35 40 45
Asp Pro Trp Ile Arg Asn Asn Phe Val Gln Ala Pro Gly Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ala Pro Gly Glu Ile Leu Trp Ser Ala Pro
65 70 75 80
Leu Gly Pro Asp Leu Asn Pro Tyr Leu Ser His Leu Ser Arg Met Tyr
85 90 95
Asn Gly Tyr Ala Gly Gly Phe Glu Val Gln Val Ile Leu Ala Gly Asn
100 105 110
Ala Phe Ala Ala Gly Lys Ile Ile Phe Ala Ala Val Pro Pro Asn Phe
115 120 125
Pro Thr Glu Gly Leu Ser Pro Ser Gln Val Thr Met Phe Pro His Leu
130 135 140
Ile Val Asp Val Arg Gln Leu Glu Pro Val Met Ile Pro Leu Pro Asp
145 150 155 160
Ile Arg Asn Asn Phe Tyr His Tyr Asn Gln Ser Asn Asp Pro Thr Ile
165 170 175
Lys Leu Ile Ala Met Leu Tyr Thr Pro Leu Arg Ala Asn Asn Val Gly
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Ser Pro
195 200 205
Asp Phe Asp Phe Ile Phe Leu Val Pro Pro Thr Val Glu Ser Lys Thr
210 215 220
Asn Pro Phe Ser Val Pro Ile Leu Thr Ile Glu Glu Met Thr Asn Ser
225 230 235 240
Arg Phe Pro Ile Pro Leu Glu Lys Leu Phe Thr Gly Pro Ser Ser Ala
245 250 255
Leu Val Val Gln Pro Gln Asn Gly Arg Cys Thr Thr Asp Gly Val Leu
260 265 270
Leu Gly Thr Thr Gln Leu Ser Pro Val Asn Ile Cys Thr Phe Arg Gly
275 280 285
Asp Val Thr His Thr Thr Lys Thr His Thr Tyr Gln Met Asn Leu Ala
290 295 300
Ala Gln Asn Trp Asn Ser Tyr Asp Pro Thr Glu Glu Ile Pro Ala Pro
305 310 315 320
Leu Gly Thr Pro Asp Phe Val Gly Lys Ile Gln Gly Val Leu Thr Gln
325 330 335
Thr Thr Lys Gly Asn Gly Ser Thr Arg Ala His Lys Ala Thr Val Tyr
340 345 350
Thr Gly Ser Ala Glu Phe Thr Pro Lys Leu Gly Arg Ile Gln Leu Phe
355 360 365
Thr Asp Thr Asp Asn Asp Leu Glu Ala Asn Gln Asn Thr Lys Phe Thr
370 375 380
Pro Val Gly Val Ile Gln Asp Gly Asp Thr His Gln Asn Glu Pro Gln
385 390 395 400
Gln Trp Val Leu Pro Ser Tyr Ser Gly Arg Asn Asn His Asn Val His
405 410 415
Leu Ala Pro Ala Val Ala Pro Thr Phe Pro Gly Glu Gln Leu Leu Phe
420 425 430
Phe Arg Ser Thr Met Pro Gly Cys Ser Gly Tyr Pro Asn Met Asn Leu
435 440 445
Asp Cys Leu Leu Pro Gln Glu Trp Val Gln Tyr Phe Tyr Gln Glu Ala
450 455 460
Ala Pro Ala Gln Ser Asp Val Ala Leu Leu Arg Phe Val Asn Pro Asp
465 470 475 480
Thr Gly Arg Val Leu Phe Glu Cys Lys Leu His Lys Ser Gly Tyr Val
485 490 495
Thr Val Ala His Thr Gly His His Asp Leu Phe Ile Pro Pro Asn Gly
500 505 510
Tyr Phe Arg Phe Asp Ser Trp Val Ser Pro Phe Tyr Thr Leu Ala Pro
515 520 525
Met Gly Asn Gly Thr Gly Arg Arg Arg Ala Leu
530 535
<210> 38
<211> 538
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 38
Met Lys Met Ala Ser Ser Asp Ala Asn Pro Ser Asp Gly Ser Ala Ala
1 5 10 15
Asn Leu Val Pro Glu Val Asn Asn Glu Val Met Ala Leu Glu Pro Val
20 25 30
Val Gly Ala Ala Ile Ala Ala Pro Val Ala Gly Gln Gln Asn Val Ile
35 40 45
Asp Pro Trp Ile Arg Asn Asn Phe Val Gln Ala Pro Gly Gly Glu Phe
50 55 60
Thr Ile Ser Pro Arg Asn Ala Pro Gly Glu Ile Leu Trp Ser Ala Pro
65 70 75 80
Leu Gly Pro Asp Leu Asn Pro Tyr Leu Ser His Leu Ala Arg Met Tyr
85 90 95
Asn Gly Tyr Ala Gly Gly Phe Glu Val Gln Val Val Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Ile Ile Phe Ala Ala Val Pro Pro Asn Phe
115 120 125
Pro Thr Glu Gly Leu Ser Pro Ser Gln Val Thr Met Phe Pro His Ile
130 135 140
Ile Val Asp Val Arg Gln Leu Glu Pro Val Leu Ile Pro Leu Pro Asp
145 150 155 160
Val Arg Asn Asn Phe Tyr His Tyr Asn Gln Ser Lys Asp Ser Thr Ile
165 170 175
Lys Leu Ile Ala Met Leu Tyr Thr Pro Leu Arg Ala Asn Asn Ala Gly
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Ser Pro
195 200 205
Asp Phe Asp Phe Ile Phe Leu Val Pro Pro Thr Val Glu Ser Arg Thr
210 215 220
Lys Pro Phe Ser Val Pro Val Leu Thr Val Glu Glu Met Thr Asn Ser
225 230 235 240
Arg Phe Pro Ile Pro Leu Glu Lys Leu Phe Thr Gly Pro Ser Ser Ala
245 250 255
Phe Val Val Gln Pro Gln Asn Gly Arg Cys Thr Thr Asp Gly Val Leu
260 265 270
Leu Gly Thr Thr Gln Leu Ser Ala Val Asn Ile Cys Thr Phe Arg Gly
275 280 285
Asp Val Thr His Val Ala Gly Asp Thr Phe Ala Met Asn Leu Ala Ser
290 295 300
Leu Asn Trp Asn Asn Tyr Asp Pro Thr Glu Glu Thr Pro Ala Pro Leu
305 310 315 320
Gly Thr Pro Asp Phe Val Gly Arg Ile His Gly Met Leu Thr Gln Thr
325 330 335
Thr Arg Ser Asp Gly Ala Thr Arg Ala His Lys Ala Thr Val Ser Thr
340 345 350
Gly Gly Ala Asp Phe Thr Pro Lys Leu Gly Ser Val Arg Tyr Ser Thr
355 360 365
Asp Thr Ser Ser Asp Leu Glu Val Arg Glu Asn Thr Lys Phe Thr Pro
370 375 380
Ile Gly Val Leu His Ser Ser Gly Gly His Arg Ala Glu Pro Asp Gln
385 390 395 400
Trp Arg Leu Pro Glu Tyr Ser Gly Arg Asn Val His Asn Val His Leu
405 410 415
Ala Pro Ala Val Ala Pro Thr Phe Pro Gly Glu Gln Leu Leu Phe Phe
420 425 430
Arg Ser Thr Met Pro Gly Cys Gly Gly Tyr Pro Asn Met Asp Leu Asp
435 440 445
Cys Leu Leu Pro Gln Glu Trp Val Gln His Phe Tyr Gln Glu Ala Ala
450 455 460
Pro Ala Gln Ser Asp Val Ala Leu Leu Arg Phe Val Asn Pro Asp Thr
465 470 475 480
Gly Arg Val Leu Phe Glu Cys Lys Leu His Lys Ser Gly Tyr Val Thr
485 490 495
Val Ala His Thr Gly Pro His Asp Leu Val Ile Pro Pro Asn Gly Tyr
500 505 510
Phe Arg Phe Asp Ser Trp Val Asn Gln Phe Tyr Thr Leu Ala Pro Met
515 520 525
Gly Asn Gly Thr Gly Arg Arg Arg Ala Leu
530 535
<210> 39
<211> 539
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 39
Met Lys Met Ala Ser Ser Asp Ala Asn Pro Ser Asp Gly Ser Ala Ala
1 5 10 15
Asn Leu Val Pro Glu Val Asn Asn Glu Val Met Ala Leu Glu Pro Val
20 25 30
Val Gly Ala Ala Ile Ala Ala Pro Val Ala Gly Gln Gln Asn Ile Ile
35 40 45
Asp Pro Trp Ile Arg Asn Asn Phe Val Gln Ala Pro Gly Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ala Pro Gly Glu Ile Leu Trp Ser Ala Pro
65 70 75 80
Leu Gly Pro Asp Leu Asn Pro Tyr Leu Ser His Leu Ser Arg Met Tyr
85 90 95
Asn Gly Tyr Ala Gly Gly Phe Glu Val Gln Val Ile Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Val Ile Phe Ala Ala Val Pro Pro Asn Phe
115 120 125
Pro Thr Glu Gly Leu Ser Pro Ser Gln Val Thr Met Phe Pro His Ile
130 135 140
Ile Val Asp Val Arg Gln Leu Glu Pro Val Leu Ile Pro Leu Pro Asp
145 150 155 160
Val Arg Asn Asn Phe Tyr His Tyr Asn Gln Ser His Asp Ser Thr Leu
165 170 175
Lys Leu Ile Ala Val Leu Tyr Thr Pro Leu Arg Thr Asn Asn Ala Gly
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Ser Pro
195 200 205
Asp Phe Asp Phe Ile Phe Leu Val Pro Pro Thr Val Glu Ser Arg Thr
210 215 220
Lys Pro Phe Thr Val Pro Ile Leu Thr Val Glu Glu Met Ser Asn Ser
225 230 235 240
Arg Phe Pro Ile Pro Leu Glu Lys Leu Tyr Thr Gly Pro Ser Ser Ala
245 250 255
Phe Val Val Gln Pro Gln Asn Gly Arg Cys Thr Thr Asp Gly Val Leu
260 265 270
Leu Gly Thr Thr Gln Leu Ser Ala Val Asn Ile Cys Asn Phe Arg Gly
275 280 285
Asp Val Thr His Ile Val Gly Ser His Glu Thr Thr Met Asn Leu Ala
290 295 300
Ser Gln Asn Trp Ser Asn Tyr Asp Pro Thr Gln Lys Ile Pro Ala Pro
305 310 315 320
Leu Gly Thr Pro His Phe Val Gly Lys Ile Gln Gly Leu Leu Thr Gln
325 330 335
Thr Thr Arg Ala His Gly Ser Thr Arg Ala His Lys Ala Thr Val Ser
340 345 350
Thr Gly Ser Val His Phe Thr Pro Lys Leu Gly Ser Val Gln Phe Thr
355 360 365
Thr Asp Thr Asn Asn Asp Phe Gln Thr Gly Gln Asn Thr Lys Phe Thr
370 375 380
Pro Val Gly Val Ile Gln Asp Gly Asp His His Gln Asn Glu Pro Gln
385 390 395 400
Gln Trp Val Leu Pro Asn Tyr Ser Gly Arg Thr Gly His Asn Val His
405 410 415
Leu Ala Pro Ala Val Ala Pro Thr Phe Pro Gly Glu Gln Leu Leu Phe
420 425 430
Phe Arg Ser Thr Met Pro Gly Cys Ser Gly Tyr Pro Asn Met Asn Leu
435 440 445
Asp Cys Leu Leu Pro His Glu Trp Val Leu His Phe Tyr Gln Glu Ala
450 455 460
Ala Pro Ala Gln Ser Asp Val Ala Leu Leu Arg Phe Val Asn Pro Asp
465 470 475 480
Thr Gly Arg Val Leu Phe Glu Cys Lys Leu His Lys Ser Gly Tyr Ile
485 490 495
Thr Val Ala His Thr Gly Pro Phe Asp Leu Gly Ile Pro Pro Asn Gly
500 505 510
Tyr Phe Arg Phe Asp Ser Trp Val Asn Gln Phe Tyr Thr Leu Ala Pro
515 520 525
Met Gly Asn Gly Thr Gly Arg Arg Arg Ala Leu
530 535
<210> 40
<211> 539
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 40
Met Lys Met Ala Ser Asn Asp Ala Ser Pro Ser Asp Gly Ser Thr Ala
1 5 10 15
Asn Leu Val Pro Glu Val Asn Asn Glu Val Met Ala Leu Glu Pro Val
20 25 30
Val Gly Ala Ala Ile Ala Ala Pro Val Ala Gly Gln Gln Asn Val Ile
35 40 45
Asp Pro Trp Ile Arg Asn Ser Ser Val Gln Ala Pro Gly Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asp Ala Pro Gly Glu Ile Leu Trp Ser Ala Pro
65 70 75 80
Leu Gly Pro Asp Leu Asn Pro Tyr Leu Ser His Leu Ala Arg Met Tyr
85 90 95
Asn Gly Tyr Ala Gly Gly Phe Glu Val Gln Val Ile Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Ile Ile Phe Ala Ala Ala Pro Pro Asn Phe
115 120 125
Pro Thr Glu Gly Leu Ser Pro Ser Gln Val Thr Met Phe Pro His Ile
130 135 140
Ile Val Gly Val Arg Gln Leu Glu Pro Val Leu Ile Pro Leu Pro Asp
145 150 155 160
Val Arg Asn Asn Phe Tyr His Tyr Asn Gln Ser Asn Asp Ser Thr Ile
165 170 175
Lys Leu Ile Ala Met Leu Tyr Thr Pro Leu Arg Ala Asn Asn Ala Gly
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Ser Pro
195 200 205
Asp Phe Asp Phe Ile Phe Leu Val Pro Pro Thr Val Glu Ser Arg Thr
210 215 220
Lys Pro Phe Thr Val Pro Ile Leu Thr Val Glu Glu Met Thr Asn Ser
225 230 235 240
Arg Phe Pro Ile Pro Leu Glu Asn Cys Ser Arg Val Pro Ala Val Pro
245 250 255
Leu Ser Ser Asn His Lys Met Gln Cys Thr Thr Asp Gly Val Leu Leu
260 265 270
Gly Thr Thr Gln Leu Ser Pro Val Asn Ile Cys Thr Phe Arg Gly Asp
275 280 285
Val Thr His Ile Pro Gly Thr Arg Thr Tyr Arg Met Asn Leu Ala Ser
290 295 300
Gln Asn Trp Asn Asn Tyr Asp Pro Thr Glu Glu Ile Pro Ala Pro Leu
305 310 315 320
Gly Thr Pro Asp Phe Val Gly Lys Ile Gln Gly Met Leu Thr Gln Thr
325 330 335
Thr Lys Gly Asp Gly Ser Thr Arg Gly His Lys Ala Thr Val Ser Thr
340 345 350
Gly Ser Val Asp Phe Thr Pro Lys Leu Gly Ser Val Gln Phe Ala Thr
355 360 365
Asp Thr Asp Asn Asp Phe Glu Thr Gly Gln Asn Thr Arg Phe Thr Pro
370 375 380
Val Gly Val Ile Gln Asp Gly Ser Ser Thr His Arg Asn Glu Pro Gln
385 390 395 400
Gln Trp Val Leu Pro Asp Tyr Ser Gly Arg Thr Val His Asn Val His
405 410 415
Leu Ala Pro Ala Val Ala Pro Thr Phe Pro Gly Glu Gln Leu Leu Phe
420 425 430
Phe Arg Ser Thr Met Pro Gly Cys Ser Gly Tyr Pro Asn Met Asp Leu
435 440 445
Asp Cys Leu Leu Pro Gln Glu Trp Val Gln His Phe Tyr Gln Glu Ala
450 455 460
Ala Pro Ser Gln Ser Asp Val Ala Leu Leu Arg Phe Val Asn Pro Asp
465 470 475 480
Thr Gly Arg Val Leu Phe Glu Cys Lys Leu His Lys Ala Gly Tyr Val
485 490 495
Thr Val Ala His Thr Gly Gln His Asp Leu Val Ile Pro Pro Asn Gly
500 505 510
Tyr Phe Arg Phe Asp Ser Trp Val Asn Gln Phe Tyr Thr Leu Ala Pro
515 520 525
Met Gly Asn Gly Ala Gly Arg Arg Arg Ala Leu
530 535
<210> 41
<211> 539
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 41
Met Lys Met Ala Ser Ser Asp Ala Asn Pro Ser Asp Gly Ser Ser Ala
1 5 10 15
Asn Leu Val Pro Glu Val Asn Asn Glu Val Met Ala Leu Glu Pro Val
20 25 30
Val Gly Ala Ala Ile Ala Ala Pro Val Ala Gly Gln Gln Asn Ile Ile
35 40 45
Asp Pro Trp Ile Arg Asn Asn Phe Val Gln Ala Pro Gly Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ala Pro Gly Glu Ile Leu Trp Ser Ala Pro
65 70 75 80
Leu Ser Pro Asp Leu Asn Pro Tyr Leu Ser His Leu Ser Arg Met Tyr
85 90 95
Asn Gly Tyr Ala Gly Gly Phe Glu Val Gln Val Ile Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Ile Val Phe Ala Ala Val Pro Pro Asn Phe
115 120 125
Pro Thr Glu Gly Leu Ser Pro Ser Gln Val Thr Met Phe Pro His Ile
130 135 140
Ile Val Asp Val Arg Gln Leu Glu Pro Val Leu Ile Pro Leu Pro Asp
145 150 155 160
Val Arg Asn Asn Phe Tyr His Tyr Asn Gln Ala Asn Asp Ser Thr Leu
165 170 175
Lys Leu Ile Ala Met Leu Tyr Thr Pro Leu Arg Ala Asn Asn Ala Gly
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Ser Pro
195 200 205
Asp Phe Asp Phe Ile Phe Leu Val Pro Pro Thr Val Glu Ser Arg Thr
210 215 220
Lys Pro Phe Thr Val Pro Val Leu Thr Val Glu Glu Met Thr Asn Ser
225 230 235 240
Arg Phe Pro Ile Pro Leu Glu Arg Leu Phe Thr Gly Pro Ser Thr Ala
245 250 255
Phe Val Val Gln Pro Gln Asn Gly Arg Cys Thr Thr Asp Gly Val Leu
260 265 270
Leu Gly Thr Thr Gln Leu Ser Ala Val Asn Ile Cys Asn Phe Arg Gly
275 280 285
Glu Val Asn His Ile Ala Gly Thr His Asp Tyr Thr Met Arg Leu Thr
290 295 300
Ser Gln Asn Trp Asn Asn Tyr Asp Pro Thr Glu Glu Ile Pro Ala Pro
305 310 315 320
Leu Gly Thr Pro Asp Phe Val Gly Arg Ile Gln Gly Val Leu Thr Gln
325 330 335
Thr Thr Arg Ser Asp Gly Ser Thr Arg Ser His Lys Ala Thr Val Ser
340 345 350
Thr Gly Ser Val His Phe Thr Pro Lys Leu Gly Ser Val Gln Phe Thr
355 360 365
Thr Asp Thr Thr Asn Asp Leu Asn Ala Gly Gln Asn Thr Lys Phe Thr
370 375 380
Pro Val Gly Val Glu Gln Thr Ser Gly Asp His Gln Ser Glu Pro Gln
385 390 395 400
Gln Trp Thr Leu Pro Asn Tyr Ser Gly Thr Pro Asn His Asn Val His
405 410 415
Leu Ala Pro Ala Val Ala Pro Thr Phe Pro Gly Glu Gln Leu Leu Phe
420 425 430
Phe Arg Ser Thr Leu Pro Gly Cys Gly Gly Tyr Pro Asn Met Asn Leu
435 440 445
Asp Cys Leu Leu Pro Gln Glu Trp Val Leu His Phe Tyr Gln Glu Ala
450 455 460
Ala Pro Ala Gln Ser Asp Val Ala Leu Leu Arg Phe Val Asn Pro Asp
465 470 475 480
Thr Gly Arg Val Leu Phe Glu Cys Lys Leu His Arg Ser Gly Phe Ile
485 490 495
Thr Val Ala His Ser Gly Ser His Asp Leu Val Ile Pro Pro Asn Gly
500 505 510
Tyr Phe Arg Phe Asp Ser Trp Val Asn Gln Phe Tyr Thr Leu Ala Pro
515 520 525
Met Gly Asn Gly Ser Gly Arg Arg Arg Val Val
530 535
<210> 42
<211> 540
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 42
Met Lys Met Ala Ser Asn Asp Ala Thr Pro Ser Asn Asp Gly Ala Ala
1 5 10 15
Gly Leu Val Pro Glu Ser Asn Asn Glu Ala Met Ala Leu Glu Pro Val
20 25 30
Val Gly Ala Ser Leu Ala Ala Pro Val Thr Gly Gln Thr Asn Ile Ile
35 40 45
Asp Pro Trp Ile Arg Thr Asn Phe Val Gln Ala Pro Asn Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ser Pro Gly Glu Ile Leu Val Asn Leu Glu
65 70 75 80
Leu Gly Pro Glu Leu Asn Pro Tyr Leu Ala His Leu Ala Arg Met Tyr
85 90 95
Asn Gly Tyr Ala Gly Gly Met Glu Val Gln Val Met Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Ile Ile Phe Ala Ala Val Pro Pro Tyr Phe
115 120 125
Pro Val Glu Asn Leu Ser Pro Ser Gln Ile Thr Met Phe Pro His Val
130 135 140
Ile Ile Asp Val Arg Thr Leu Glu Pro Val Leu Leu Pro Met Pro Asp
145 150 155 160
Val Arg Ser Thr Leu Phe His Phe Asn Gln Lys Asp Glu Pro Lys Met
165 170 175
Arg Leu Val Ala Met Leu Tyr Thr Pro Leu Arg Ser Asn Gly Ser Gly
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Ile Leu Thr Arg Pro Ser Pro
195 200 205
Glu Phe Asp Phe Thr Tyr Leu Val Pro Pro Thr Val Glu Ser Lys Thr
210 215 220
Lys Pro Phe Thr Leu Pro Val Leu Thr Leu Gly Glu Leu Ser Asn Ser
225 230 235 240
Arg Phe Pro Leu Ser Ile Asp Glu Met Val Thr Ser Pro Asn Glu Ser
245 250 255
Ile Val Val Gln Pro Gln Asn Gly Arg Val Thr Leu Asp Gly Glu Leu
260 265 270
Leu Gly Thr Thr Gln Leu Gln Ala Cys Asn Ile Cys Ser Ile Arg Gly
275 280 285
Lys Val Thr Gly Gln Val Pro Asn Glu Gln His Met Trp Asn Leu Gln
290 295 300
Ile Thr Asn Leu Asn Gly Thr Gln Phe Asp Pro Thr Asp Asp Val Pro
305 310 315 320
Ala Pro Leu Gly Val Pro Asp Phe Ala Gly Glu Val Phe Gly Val Leu
325 330 335
Ser Gln Arg Asn Arg Gly Glu Ser Asn Pro Ala Asn Arg Ala His Asp
340 345 350
Ala Val Val Ala Thr Tyr Ser Asp Lys Tyr Thr Pro Lys Leu Gly Leu
355 360 365
Val Gln Ile Gly Thr Trp Asn Thr Asn Asp Val Glu Asn Gln Pro Thr
370 375 380
Lys Phe Thr Pro Ile Gly Leu Asn Glu Val Ala Asn Gly His Arg Phe
385 390 395 400
Glu Gln Trp Thr Leu Pro Arg Tyr Ser Gly Ala Leu Thr Leu Asn Met
405 410 415
Asn Leu Ala Pro Ala Val Ala Pro Leu Phe Pro Gly Glu Arg Leu Leu
420 425 430
Phe Phe Arg Ser Tyr Val Pro Leu Lys Gly Gly Phe Gly Asn Pro Ala
435 440 445
Ile Asp Cys Leu Val Pro Gln Glu Trp Val Gln His Phe Tyr Gln Glu
450 455 460
Ser Ala Pro Ser Leu Gly Asp Val Ala Leu Val Arg Tyr Val Asn Pro
465 470 475 480
Asp Thr Gly Arg Val Leu Phe Glu Ala Lys Leu His Lys Gly Gly Phe
485 490 495
Leu Thr Val Ser Ser Thr Ser Thr Gly Pro Val Val Val Pro Ala Asn
500 505 510
Gly Tyr Phe Arg Phe Asp Ser Trp Val Asn Gln Phe Tyr Ser Leu Ala
515 520 525
Pro Met Gly Thr Gly Asn Gly Arg Arg Arg Phe Gln
530 535 540
<210> 43
<211> 547
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 43
Met Lys Met Ala Ser Asn Asp Ala Ala Pro Ser Asn Asp Gly Ala Ala
1 5 10 15
Asn Leu Val Pro Glu Ala Asn Asn Glu Val Met Ala Leu Glu Pro Val
20 25 30
Ala Gly Ala Ser Ile Ala Ala Pro Val Val Gly Gln Gln Asn Ile Ile
35 40 45
Asp Pro Trp Ile Arg Glu Asn Phe Val Gln Ala Pro Gln Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ser Pro Gly Glu Met Leu Leu Asn Leu Glu
65 70 75 80
Leu Gly Pro Glu Leu Asn Pro Tyr Leu Ser His Leu Ser Arg Met Tyr
85 90 95
Asn Gly Tyr Ala Gly Gly Met Gln Val Gln Val Val Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Ile Ile Phe Ala Ala Val Pro Pro His Phe
115 120 125
Pro Val Lys Asn Ile Ser Ala Ala Gln Ile Thr Met Cys Pro His Val
130 135 140
Ile Val Asp Val Arg Gln Leu Glu Pro Val Leu Leu Pro Leu Pro Asp
145 150 155 160
Ile Arg Asn Arg Phe Phe His Tyr Asn Gln Glu Asn Thr Pro Arg Met
165 170 175
Arg Leu Val Ala Met Leu Tyr Thr Pro Leu Arg Ala Asn Ser Gly Glu
180 185 190
Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Ala Pro Asp
195 200 205
Phe Glu Phe Thr Phe Leu Val Pro Pro Thr Val Glu Ser Lys Thr Lys
210 215 220
Pro Phe Thr Leu Pro Ile Leu Thr Leu Gly Glu Leu Ser Asn Ser Arg
225 230 235 240
Phe Pro Ala Pro Ile Asp Met Leu Tyr Thr Asp Pro Asn Glu Gly Ile
245 250 255
Val Val Gln Pro Gln Asn Gly Arg Cys Thr Leu Asp Gly Thr Leu Gln
260 265 270
Gly Thr Thr Gln Leu Val Pro Thr Gln Ile Cys Ala Phe Arg Gly Thr
275 280 285
Leu Ile Gly Gln Thr Ser Arg Ser Ser Asp Ser Thr Asp Ser Ala Pro
290 295 300
Arg Arg Arg Asp His Pro Leu His Val Gln Leu Lys Asn Leu Asp Gly
305 310 315 320
Thr Gln Tyr Asp Pro Thr Asp Glu Val Pro Ala Val Leu Gly Ala Ile
325 330 335
Asp Phe Lys Gly Thr Val Phe Gly Val Ala Ser Gln Arg Asp Val Ser
340 345 350
Gly Gln Gln Val Gly Ala Thr Arg Ala His Glu Val His Ile Asn Thr
355 360 365
Thr Asp Pro Arg Tyr Thr Pro Lys Leu Gly Ser Ile Leu Ile His Ser
370 375 380
Glu Ser Asp Asp Phe Val Thr Gly Gln Pro Val Arg Phe Thr Pro Ile
385 390 395 400
Gly Met Gly Asp Asn Asp Trp His Gln Trp Glu Leu Pro Asp Tyr Ser
405 410 415
Gly His Leu Thr Leu Asn Met Asn Leu Ala Pro Ala Val Ala Pro Ala
420 425 430
Phe Pro Gly Glu Arg Ile Leu Phe Phe Arg Ser Met Val Pro Ser Ala
435 440 445
Gly Gly Tyr Gly Ser Gly Gln Ile Asp Cys Leu Ile Pro Gln Glu Trp
450 455 460
Val Gln His Phe Tyr Gln Glu Ala Ala Pro Ser Gln Ser Ala Val Ala
465 470 475 480
Leu Ile Arg Tyr Val Asn Pro Asp Thr Gly Arg Asn Ile Phe Glu Ala
485 490 495
Lys Leu His Arg Glu Gly Phe Ile Thr Val Ala Asn Ser Gly Asn Asn
500 505 510
Pro Ile Val Val Pro His Asn Gly Tyr Phe Arg Phe Glu Ala Trp Val
515 520 525
Asn Gln Phe Tyr Thr Leu Thr Pro Met Gly Thr Gly Gln Gly Arg Arg
530 535 540
Arg Asn Gln
545
<210> 44
<211> 540
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 44
Met Lys Met Ala Ser Asn Asp Ala Ala Pro Ser Asn Asp Gly Ala Ala
1 5 10 15
Gly Leu Val Pro Glu Ile Asn Asn Glu Val Met Pro Leu Glu Pro Val
20 25 30
Ala Gly Ala Ser Leu Ala Thr Pro Val Val Gly Gln Gln Asn Ile Ile
35 40 45
Asp Pro Trp Ile Arg Asn Asn Phe Val Gln Ala Pro Ala Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ser Pro Gly Glu Ile Leu Leu Asp Leu Glu
65 70 75 80
Leu Gly Pro Glu Leu Asn Pro Tyr Leu Ala His Leu Ala Arg Met Tyr
85 90 95
Asn Gly His Ala Gly Gly Met Glu Val Gln Ile Val Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Ile Ile Phe Ala Ala Ile Pro Pro Gly Phe
115 120 125
Pro Tyr Glu Asn Leu Ser Pro Ser Gln Ile Thr Met Cys Pro His Val
130 135 140
Ile Ile Asp Val Arg Gln Leu Glu Pro Val Leu Leu Pro Met Pro Asp
145 150 155 160
Ile Arg Asn Asn Phe Phe His Tyr Asn Gln Gly Asn Asp Pro Lys Leu
165 170 175
Arg Leu Ile Ala Met Leu Tyr Thr Pro Leu Arg Ala Asn Asn Ser Gly
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Lys Pro Ser Pro
195 200 205
Asp Phe Glu Phe Thr Phe Leu Val Pro Pro Thr Val Glu Ser Lys Thr
210 215 220
Lys Gln Phe Thr Leu Pro Ile Leu Lys Ile Ser Glu Met Thr Asn Ser
225 230 235 240
Arg Phe Pro Val Pro Val Glu Met Met Tyr Thr Ala Arg Asn Glu Asn
245 250 255
Gln Val Val Gln Pro Gln Asn Gly Arg Val Thr Leu Asp Gly Glu Leu
260 265 270
Leu Gly Thr Thr Pro Leu Leu Ala Val Asn Ile Cys Lys Phe Lys Gly
275 280 285
Glu Val Ile Ala Lys Asn Gly Asp Val Arg Ser Tyr Arg Met Asp Met
290 295 300
Glu Ile Thr Asn Thr Asp Gly Thr Pro Ile Asp Pro Thr Glu Asp Thr
305 310 315 320
Pro Gly Pro Ile Gly Ser Pro Asp Phe Gln Gly Ile Leu Phe Gly Val
325 330 335
Ala Ser Gln Arg Asn Lys Asn Glu Gln Asn Pro Ala Thr Arg Ala His
340 345 350
Glu Ala Asn Ile Asn Thr Gly Gly Asp Gln Tyr Ala Pro Lys Leu Ala
355 360 365
Gln Val Lys Phe Phe Ser Glu Ser Gln Asp Phe Glu Val His Gln Pro
370 375 380
Thr Val Phe Thr Pro Val Gly Val Ala Gly Asp Thr Ser His Pro Phe
385 390 395 400
Arg Gln Trp Val Leu Pro Arg Tyr Gly Gly His Leu Thr Asn Asn Thr
405 410 415
His Leu Ala Pro Ala Val Ala Pro Leu Phe Pro Gly Glu Gln Ile Leu
420 425 430
Phe Phe Arg Ser Gln Ile Pro Ser Ser Gly Gly His Glu Leu Gly Tyr
435 440 445
Met Asp Cys Leu Val Pro Gln Glu Trp Val Gln His Phe Tyr Gln Glu
450 455 460
Ala Ala Thr Ala Gln Ser Glu Val Ala Leu Ile Arg Phe Ile Asn Pro
465 470 475 480
Asp Thr Gly Arg Val Leu Phe Glu Ala Lys Leu His Lys Gln Gly Phe
485 490 495
Ile Thr Val Ala His Thr Gly Asp Asn Pro Ile Val Met Pro Pro Asn
500 505 510
Gly Tyr Phe Arg Phe Glu Ala Trp Val Asn Gln Phe Tyr Ser Leu Ala
515 520 525
Pro Val Gly Thr Gly Asn Gly Arg Arg Arg Ile Gln
530 535 540
<210> 45
<211> 537
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 45
Met Lys Met Ala Ser Asn Asp Ala Ala Pro Ser Asn Asp Gly Ala Ala
1 5 10 15
Gly Leu Val Pro Glu Ile Asn His Glu Val Met Ala Ile Glu Pro Val
20 25 30
Ala Gly Ala Ser Leu Ala Ala Pro Val Val Gly Gln Leu Asn Ile Ile
35 40 45
Asp Pro Trp Ile Arg Asn Asn Phe Val Gln Ala Pro Ala Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ala Pro Gly Glu Phe Leu Leu Asp Leu Glu
65 70 75 80
Leu Gly Pro Glu Leu Asn Pro Tyr Leu Ala His Leu Ala Arg Met Tyr
85 90 95
Asn Gly His Ala Gly Gly Met Glu Val Gln Ile Val Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Ile Leu Phe Ala Val Ile Pro Pro Gly Phe
115 120 125
Pro Tyr Glu Asn Leu Ser Pro Ala Gln Leu Thr Met Cys Pro His Val
130 135 140
Val Val Asp Val Arg Gln Leu Glu Pro Ile Leu Leu Pro Met Pro Asp
145 150 155 160
Ile Arg Asn Thr Phe Phe His Tyr Asn Gln Ser Asn Gly Pro Lys Leu
165 170 175
Arg Leu Val Ala Met Leu Tyr Thr Pro Leu Arg Ala Asn Asn Ala Gly
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Ser Pro
195 200 205
Asp Phe Glu Phe Asn Phe Leu Val Pro Pro Ser Val Glu Ser Lys Thr
210 215 220
Lys Ala Phe Thr Leu Pro Ile Leu Lys Ile Ser Glu Met Thr Asn Ser
225 230 235 240
Arg Phe Pro Ile Pro Val Asp Gln Met Tyr Thr Ser Arg Asn Glu Asn
245 250 255
Val Val Val Gln Pro Gln Asn Gly Arg Val Thr Leu Asp Gly Glu Leu
260 265 270
Gln Gly Thr Thr Thr Leu Gln Pro Val Ser Ile Cys Gly Phe Arg Gly
275 280 285
Thr Leu Gln Thr Arg Leu Ala Asp Gln Pro Asn Tyr Thr Tyr Gln Val
290 295 300
His Leu Glu Asn Leu Asp Gly Ser Pro Val Asp Pro Thr Asp Glu Val
305 310 315 320
Pro Ala Pro Leu Gly Thr Pro Asp Phe Gln Ala Gln Leu Phe Gly Val
325 330 335
Val Ser Gln Arg Ser Ser Asp Asn Ala Thr Arg Ala His Glu Ala Arg
340 345 350
Val Asn Thr Asn Asp Pro Thr Phe Ala Pro Gln Ile Ala Gln Val Arg
355 360 365
Phe Lys Ser Pro Ser His Asp Phe Phe Asp Asn Glu Pro Ile Lys Phe
370 375 380
Thr Pro Val Gly Ile Ser Val Asp Ser Glu Asn Ser Tyr Asn Gln Trp
385 390 395 400
Leu Leu Pro Arg Tyr Gly Gly His Leu Thr Asn Asn Thr His Leu Ala
405 410 415
Pro Ser Val Ser Pro Met Phe Pro Gly Glu Gln Ile Leu Phe Phe Arg
420 425 430
Ser Phe Met Pro Gly Ala Ser Gly His Thr Asp Gly Ala Ile Asp Cys
435 440 445
Leu Leu Pro Gln Glu Trp Val Ala His Phe Tyr Gln Glu Ala Ala Thr
450 455 460
Ala Gln Thr Asp Val Ala Leu Ile Arg Phe Val Asn Pro Asp Thr Gly
465 470 475 480
Arg Val Leu Phe Glu Gly Lys Leu His Lys Gln Gly Phe Ile Thr Ile
485 490 495
Ser Asn Ser Gly Asp His Pro Ile Val Met Pro Ala Asn Gly Tyr Phe
500 505 510
Arg Phe Glu Ala Trp Val Asn Gln Phe Tyr Ser Leu Ala Pro Val Gly
515 520 525
Thr Gly Ser Gly Arg Arg Arg Ile Gln
530 535
<210> 46
<211> 535
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 46
Met Lys Met Ala Ser Asn Asp Ala Ala Pro Ser Asn Asp Gly Ala Ala
1 5 10 15
Gly Leu Val Pro Glu Val Asn Asn Glu Thr Met Ala Leu Glu Pro Val
20 25 30
Ala Gly Ala Ser Ile Ala Ala Pro Leu Thr Gly Gln Asn Asn Val Ile
35 40 45
Asp Pro Trp Ile Arg Leu Asn Phe Val Gln Ala Pro Asn Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ser Pro Gly Glu Val Leu Leu Asn Leu Glu
65 70 75 80
Leu Gly Pro Glu Leu Asn Pro Tyr Leu Ala His Leu Ser Arg Met Tyr
85 90 95
Asn Gly Tyr Ala Gly Gly Val Glu Val Gln Val Leu Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Leu Val Phe Ala Ala Val Pro Pro His Phe
115 120 125
Pro Leu Glu Asn Ile Ser Pro Gly Gln Ile Thr Met Phe Pro His Val
130 135 140
Ile Ile Asp Val Arg Thr Leu Glu Pro Val Leu Leu Pro Leu Pro Asp
145 150 155 160
Val Arg Asn Asn Phe Phe His Tyr Asn Gln Gln Asn Glu Pro Arg Met
165 170 175
Arg Leu Val Ala Met Leu Tyr Thr Pro Leu Arg Ser Asn Gly Ser Gly
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Ser Pro
195 200 205
Asp Phe Asp Phe Asn Tyr Leu Val Pro Pro Thr Val Glu Ser Lys Thr
210 215 220
Lys Pro Phe Thr Leu Pro Ile Leu Thr Ile Gly Glu Leu Thr Asn Ser
225 230 235 240
Arg Phe Pro Val Pro Ile Asp Glu Leu Tyr Thr Ser Pro Asn Glu Ser
245 250 255
Leu Val Val Gln Pro Gln Asn Gly Arg Cys Ala Leu Asp Gly Glu Leu
260 265 270
Gln Gly Thr Thr Gln Leu Leu Pro Thr Ala Ile Cys Ser Phe Arg Gly
275 280 285
Arg Ile Asn Gln Lys Val Ser Gly Glu Asn His Val Trp Asn Met Gln
290 295 300
Ile Thr Asn Ile Asn Gly Thr Pro Phe Asp Pro Thr Glu Asp Val Pro
305 310 315 320
Ala Pro Leu Gly Thr Pro Asp Phe Ser Gly Lys Leu Phe Gly Val Leu
325 330 335
Ser Gln Arg Asp His Asp Asn Ala Cys Arg Ser His Asp Ala Val Ile
340 345 350
Ala Thr Asn Ser Ala Lys Phe Thr Pro Lys Leu Gly Ala Ile Gln Ile
355 360 365
Gly Thr Trp Glu Gln Asp Asp Val His Ile Asn Gln Pro Thr Lys Phe
370 375 380
Thr Pro Val Gly Leu Phe Glu Ser Glu Gly Phe Asn Gln Trp Thr Leu
385 390 395 400
Pro Asn Tyr Ser Gly Ala Leu Thr Leu Asn Met Gly Leu Ala Pro Pro
405 410 415
Val Ala Pro Thr Phe Pro Gly Glu Gln Ile Leu Phe Phe Arg Ser His
420 425 430
Ile Pro Leu Lys Gly Gly Val Ala Asp Pro Val Ile Asp Cys Leu Leu
435 440 445
Pro Gln Glu Trp Ile Gln His Leu Tyr Gln Glu Ser Ala Pro Ser Gln
450 455 460
Thr Asp Val Ala Leu Ile Arg Phe Thr Asn Pro Asp Thr Gly Arg Val
465 470 475 480
Leu Phe Glu Ala Lys Leu His Arg Ser Gly Tyr Ile Thr Val Ala Asn
485 490 495
Thr Gly Ser Arg Pro Ile Val Val Pro Ala Asn Gly Tyr Phe Arg Phe
500 505 510
Asp Ser Trp Val Asn Gln Phe Tyr Ser Leu Ala Pro Met Gly Thr Gly
515 520 525
Asn Gly Arg Arg Arg Val Gln
530 535
<210> 47
<211> 528
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 47
Met Lys Met Ala Ser Asn Asp Ala Ala Pro Ser Asn Asp Gly Ala Ala
1 5 10 15
Ser Leu Val Pro Glu Ala Ile Asn Glu Thr Met Pro Leu Glu Pro Val
20 25 30
Ala Gly Ala Ser Ile Ala Ala Pro Val Ala Gly Gln Thr Asn Ile Ile
35 40 45
Asp Pro Trp Ile Arg Thr Asn Phe Val Gln Ala Pro Asn Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ser Pro Gly Glu Ile Leu Leu Asn Leu Glu
65 70 75 80
Leu Gly Pro Asp Leu Asn Pro Tyr Leu Ala His Leu Ser Arg Met Tyr
85 90 95
Asn Gly Tyr Ala Gly Gly Val Glu Val Gln Val Leu Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Ile Leu Phe Ala Ala Ile Pro Pro Asn Phe
115 120 125
Pro Val Asp Met Ile Ser Pro Ala Gln Ile Thr Met Leu Pro His Leu
130 135 140
Ile Val Asp Val Arg Thr Leu Glu Pro Ile Met Ile Pro Leu Pro Asp
145 150 155 160
Val Arg Asn Val Phe Tyr His Phe Asn Asn Gln Pro Gln Pro Arg Met
165 170 175
Arg Leu Val Ala Met Leu Tyr Thr Pro Leu Arg Ser Asn Gly Ser Gly
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Thr Pro
195 200 205
Asp Phe Glu Phe Ile Tyr Leu Val Pro Pro Ser Val Glu Ser Lys Thr
210 215 220
Lys Pro Phe Thr Leu Pro Ile Leu Thr Ile Ser Glu Leu Thr Asn Ser
225 230 235 240
Arg Phe Pro Ile Pro Ile Glu Gln Leu Tyr Thr Ala Pro Asn Glu Asn
245 250 255
Asn Val Val Gln Cys Gln Asn Gly Arg Cys Thr Leu Asp Gly Glu Leu
260 265 270
Gln Gly Thr Thr Gln Leu Leu Ser Ser Ala Val Cys Ser Tyr Arg Gly
275 280 285
Arg Thr Val Ala Asn Arg Gly Asp Asn Trp Asp Gln Asn Leu Leu Gln
290 295 300
Leu Thr Tyr Pro Ser Gly Ala Ser Tyr Asp Pro Thr Asp Glu Val Pro
305 310 315 320
Ala Pro Leu Gly Thr Gln Asp Phe Ser Gly Ile Leu Tyr Gly Val Leu
325 330 335
Thr Gln Asp Asn Val Ser Glu Gly Thr Gly Glu Ala Lys Asn Ala Lys
340 345 350
Gly Val Tyr Ile Ser Thr Thr Ser Gly Lys Phe Thr Pro Lys Ile Gly
355 360 365
Ser Ile Gly Leu His Ser Ile Thr Glu Asn Val His Pro Asn Gln Gln
370 375 380
Ser Arg Phe Thr Pro Val Gly Val Ala Gln Asn Glu Asn Thr Pro Phe
385 390 395 400
Gln Gln Trp Val Leu Pro His Tyr Ala Gly Ala Leu Ala Leu Asn Thr
405 410 415
Asn Leu Ala Pro Ala Val Ala Pro Thr Phe Pro Gly Glu Gln Leu Leu
420 425 430
Phe Phe Arg Ser Arg Val Pro Cys Val Gln Gly Leu Arg Gly Gln Asp
435 440 445
Ala Phe Ile Asp Cys Leu Leu Pro Gln Glu Trp Val Asn His Phe Tyr
450 455 460
Gln Glu Ala Ala Pro Ser Gln Ala Asp Val Ala Leu Ile Arg Tyr Val
465 470 475 480
Asn Pro Asp Thr Gly Arg Thr Leu Phe Glu Ala Lys Leu His Arg Ser
485 490 495
Gly Phe Ile Thr Val Ser His Thr Gly Ala Tyr Pro Leu Val Val Pro
500 505 510
Pro Asn Gly His Phe Arg Phe Asp Ser Trp Val Asn Gln Phe Tyr Ser
515 520 525
<210> 48
<211> 536
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 48
Met Lys Met Ala Ser Asn Asp Ala Thr Pro Ser Asp Asp Gly Ala Ala
1 5 10 15
Gly Leu Val Pro Glu Ile Asn Asn Glu Val Met Ala Leu Glu Pro Val
20 25 30
Ala Gly Ala Ser Ile Ala Ala Pro Val Val Gly Gln Gln Asn Ile Ile
35 40 45
Asp Pro Trp Ile Arg Asn Asn Phe Val Gln Ala Pro Ala Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ser Pro Gly Glu Leu Leu Leu Asp Leu Glu
65 70 75 80
Leu Gly Pro Glu Leu Asn Pro Tyr Leu Ala His Leu Ala Arg Met Tyr
85 90 95
Asn Gly His Ala Gly Gly Met Glu Val Gln Ile Val Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Ile Leu Phe Ala Ala Ile Pro Pro Ser Phe
115 120 125
Pro Tyr Glu Asn Leu Ser Pro Ala Gln Leu Thr Met Cys Pro His Val
130 135 140
Ile Val Asp Val Arg Gln Leu Glu Pro Val Leu Leu Pro Met Pro Asp
145 150 155 160
Ile Arg Asn Val Phe Tyr His Tyr Asn Gln Asn Asn Ser Pro Lys Leu
165 170 175
Arg Leu Val Ala Met Leu Tyr Thr Pro Leu Arg Ala Asn Asn Ser Gly
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Ser Pro
195 200 205
Asp Phe Gln Phe Thr Phe Leu Val Pro Pro Thr Val Glu Ser Lys Thr
210 215 220
Lys Asn Phe Thr Leu Pro Val Leu Arg Val Ser Glu Met Thr Asn Ser
225 230 235 240
Arg Phe Pro Val Val Leu Asp Gln Met Tyr Thr Ser Arg Asn Glu Asn
245 250 255
Ile Ile Val Gln Pro Gln Asn Gly Arg Cys Thr Thr Asp Gly Glu Leu
260 265 270
Leu Gly Thr Thr Thr Leu Gln Ser Val Ser Ile Cys Asn Phe Arg Gly
275 280 285
Thr Met Gln Ala Lys Leu Asn Glu Gln Pro Arg Tyr Gln Leu Gln Leu
290 295 300
Thr Asn Leu Asp Gly Ser Pro Ile Asp Pro Thr Asp Asp Met Pro Ala
305 310 315 320
Pro Leu Gly Thr Pro Asp Phe Gln Ala Met Leu Tyr Gly Val Ala Ser
325 330 335
Gln Arg Ser Ser Arg Asp Asn Ala Thr Arg Ala His Asp Ala Gln Ile
340 345 350
Asp Thr Ala Gly Asp Thr Phe Ala Pro Lys Ile Gly Gln Val Arg Phe
355 360 365
Lys Ser Ser Ser Asp Asp Phe Asp Leu His Asp Pro Thr Lys Phe Thr
370 375 380
Pro Ile Gly Val Asn Val Asp Asp Gln His Pro Phe Arg Gln Trp Ser
385 390 395 400
Leu Pro Asn Tyr Gly Gly His Leu Ala Leu Asn Asn His Leu Ala Pro
405 410 415
Ala Val Thr Pro Leu Phe Pro Gly Glu Gln Ile Leu Phe Phe Arg Ser
420 425 430
His Ile Pro Ser Ala Gly Gly His Thr Asp Gly Ala Ile Asp Cys Leu
435 440 445
Leu Pro Gln Glu Trp Ile Glu His Phe Tyr Gln Glu Ala Ala Pro Ser
450 455 460
Gln Ser Asp Ile Ala Leu Val Arg Phe Ile Asn Pro Asp Thr Gly Arg
465 470 475 480
Val Leu Leu Glu Ala Lys Leu His Lys Gln Gly Phe Leu Thr Val Ala
485 490 495
Ala Ser Gly Asp His Pro Ile Val Met Pro Thr Asn Gly Tyr Phe Arg
500 505 510
Phe Glu Ala Trp Val Asn Pro Phe Tyr Thr Leu Ala Pro Val Gly Thr
515 520 525
Gly Ser Gly Arg Arg Arg Ile Gln
530 535
<210> 49
<211> 538
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 49
Met Lys Met Ala Ser Asn Asp Ala Ala Pro Ser Asn Asp Gly Ala Ala
1 5 10 15
Gly Leu Val Pro Glu Gly Asn Asn Glu Thr Leu Pro Leu Glu Pro Val
20 25 30
Ala Gly Ala Ala Ile Ala Ala Pro Val Thr Gly Gln Asn Asn Ile Ile
35 40 45
Asp Pro Trp Ile Arg Thr Asn Phe Val Gln Ala Pro Asn Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ser Pro Gly Glu Ile Leu Leu Asn Leu Glu
65 70 75 80
Leu Gly Pro Asp Leu Asn Pro Tyr Leu Ala His Leu Ser Arg Met Tyr
85 90 95
Asn Gly Tyr Ala Gly Gly Val Glu Val Gln Val Leu Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Ile Leu Phe Ala Ala Val Pro Pro Asn Phe
115 120 125
Pro Val Glu Phe Leu Ser Pro Ala Gln Ile Thr Met Leu Pro His Ile
130 135 140
Ile Val Asp Val Arg Thr Leu Glu Pro Ile Met Ile Pro Leu Pro Asp
145 150 155 160
Val Arg Asn Thr Phe Phe His Tyr Asn Asn Gln Pro Asn Ser Arg Met
165 170 175
Arg Leu Val Ala Met Leu Tyr Thr Pro Leu Arg Ser Asn Gly Ser Gly
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Thr Pro
195 200 205
Asp Phe Glu Phe Thr Tyr Leu Val Pro Pro Ser Val Glu Ser Lys Thr
210 215 220
Lys Pro Phe Ser Leu Pro Ile Leu Thr Leu Ser Glu Leu Thr Asn Ser
225 230 235 240
Arg Phe Pro Val Pro Ile Asp Ser Leu Phe Thr Ala Gln Asn Asn Val
245 250 255
Leu Gln Val Gln Cys Gln Asn Gly Arg Cys Thr Leu Asp Gly Glu Leu
260 265 270
Gln Gly Thr Thr Gln Leu Leu Pro Ser Gly Ile Cys Ala Phe Arg Gly
275 280 285
Arg Val Thr Ala Glu Thr Asp Asn Pro Asp Lys Trp His Met Gln Leu
290 295 300
Gln Asn Leu Asn Gly Thr Thr Tyr Asp Pro Thr Asp Asp Val Pro Ala
305 310 315 320
Pro Leu Gly Thr Pro Asp Phe Lys Gly Val Val Phe Gly Val Ala Ser
325 330 335
Gln Arg Asn Val Gly Asn Asp Ala Pro Gly Ser Thr Arg Ala His Glu
340 345 350
Ala Val Ile Ser Thr Tyr Ser Pro Lys Phe Val Pro Lys Leu Gly Ser
355 360 365
Val Asn Phe Arg Ser Asn Asp Asp Asp Phe Gln Leu Gln Pro Thr Arg
370 375 380
Phe Thr Pro Val Gly Ile Asn Asp Asp Gly Asn His Pro Phe Arg Gln
385 390 395 400
Trp Glu Leu Pro Asp Tyr Ser Gly Val Leu Thr Leu Asn Met Asn Leu
405 410 415
Ala Pro Pro Val Ala Pro Asn Phe Pro Gly Glu Gln Leu Leu Leu Phe
420 425 430
Arg Ser Phe Val Pro Cys Ser Gly Gly Tyr Asn Gln Gly Ile Ile Asp
435 440 445
Cys Leu Ile Pro Gln Glu Trp Ile Gln His Phe Tyr Gln Glu Ser Ala
450 455 460
Pro Ser Gln Ser Asp Val Ala Leu Ile Arg Tyr Val Asn Pro Asp Thr
465 470 475 480
Gly Arg Thr Leu Phe Glu Ala Lys Leu His Arg Ser Gly Tyr Ile Thr
485 490 495
Val Ala His Ser Gly Asp Tyr Pro Leu Val Val Pro Ala Asn Gly Tyr
500 505 510
Phe Arg Phe Asp Ser Trp Val Asn Gln Phe Tyr Ser Leu Ala Pro Met
515 520 525
Gly Thr Gly Asn Gly Arg Arg Arg Ala Gln
530 535
<210> 50
<211> 540
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 50
Met Lys Met Ala Ser Asn Asp Ala Ala Pro Ser Asn Asp Gly Ala Thr
1 5 10 15
Gly Leu Val Pro Glu Ile Asn Asn Glu Thr Leu Pro Leu Glu Pro Val
20 25 30
Ala Gly Ala Ala Ile Ala Ala Pro Val Thr Gly Gln Asn Asn Ile Ile
35 40 45
Asp Pro Trp Ile Arg Thr Asn Phe Val Gln Ala Pro Asn Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ser Pro Gly Glu Ile Leu Leu Asn Leu Glu
65 70 75 80
Leu Gly Pro Asp Leu Asn Pro Tyr Leu Ala His Leu Ser Arg Met Tyr
85 90 95
Asn Gly Tyr Ala Gly Gly Val Glu Val Gln Val Leu Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Ile Leu Phe Ala Ala Val Pro Pro Asn Phe
115 120 125
Pro Val Glu Phe Leu Ser Pro Ala Gln Ile Thr Met Leu Pro His Leu
130 135 140
Ile Val Asp Val Arg Thr Leu Glu Pro Ile Met Ile Pro Leu Pro Asp
145 150 155 160
Val Arg Asn Thr Phe Phe His Tyr Asn Asn Gln Pro Ala Asn Arg Met
165 170 175
Arg Leu Val Ala Met Leu Tyr Thr Pro Leu Arg Ser Asn Gly Ser Gly
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Thr Pro
195 200 205
Asp Phe Glu Phe Thr Tyr Leu Val Pro Pro Ser Val Glu Ser Lys Thr
210 215 220
Lys Pro Phe Ser Leu Pro Ile Leu Thr Ile Ser Glu Leu Thr Asn Ser
225 230 235 240
Arg Phe Pro Ala Pro Ile Asp Ser Leu Phe Thr Ala Gln Asn Asn Asn
245 250 255
Leu Asn Val Gln Cys Gln Asn Gly Arg Cys Thr Leu Asp Gly Glu Leu
260 265 270
Gln Gly Thr Thr Gln Leu Leu Pro Ser Gly Ile Cys Ala Phe Arg Gly
275 280 285
Arg Leu Thr Ala Asp Val Asp Gly Ser His Asp Asp Arg Trp His Met
290 295 300
Gln Leu Thr Asn Leu Asn Gly Thr Pro Phe Asp Pro Thr Glu Asp Val
305 310 315 320
Pro Ala Pro Leu Gly Thr Pro Asp Phe Thr Gly Leu Leu Phe Gly Val
325 330 335
Ala Ser Gln Arg Asn Val Gly Ser Asn Pro Asn Thr Thr Arg Ala His
340 345 350
Glu Ala Val Ile Ser Thr Thr Ser Ser Gln Phe Val Pro Lys Leu Gly
355 360 365
Ser Val Asn Phe Gly Ser Thr Ser Thr Asp Phe Gln Leu Gln Gln Pro
370 375 380
Thr Lys Phe Thr Pro Val Gly Ile Lys Ile Glu Ser Gly His Glu Phe
385 390 395 400
Asp Gln Trp Ala Leu Pro Arg Tyr Ser Gly His Leu Thr Leu Asn Met
405 410 415
Asn Leu Ala Pro Pro Ile Ala Pro Asn Phe Pro Gly Glu Gln Leu Leu
420 425 430
Phe Phe Arg Ser Asn Val Pro Cys Ala Gly Gly Val Ser Asp Gly Val
435 440 445
Ile Asp Cys Leu Leu Pro Gln Glu Trp Ile Gln His Phe Tyr Gln Glu
450 455 460
Ser Ala Pro Ser Gln Ser Asp Val Ala Leu Ile Arg Tyr Val Asn Pro
465 470 475 480
Asp Thr Gly Arg Thr Leu Phe Glu Ala Lys Leu His Arg Thr Gly Tyr
485 490 495
Ile Thr Val Ala His Ser Gly Asp Tyr Pro Leu Val Val Pro Ser Asn
500 505 510
Gly Tyr Phe Arg Phe Asp Ser Trp Val Asn Gln Phe Tyr Ser Leu Ala
515 520 525
Pro Met Gly Thr Gly Asn Gly Arg Arg Arg Val Gln
530 535 540
<210> 51
<211> 540
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 51
Met Lys Met Ala Ser Asn Asp Ala Ala Pro Ser Asn Asp Gly Ala Ala
1 5 10 15
Gly Leu Val Pro Glu Ile Asn Thr Glu Thr Leu Pro Leu Glu Pro Val
20 25 30
Ala Gly Ala Ala Ile Ala Ala Pro Val Thr Gly Gln Asn Asn Ile Ile
35 40 45
Asp Pro Trp Ile Arg Asn Asn Phe Val Gln Ala Pro Asn Gly Glu Phe
50 55 60
Thr Val Ser Pro Arg Asn Ser Pro Gly Glu Ile Leu Met Asn Leu Glu
65 70 75 80
Leu Gly Pro Asp Leu Asn Pro Tyr Leu Ala His Leu Ser Arg Met Tyr
85 90 95
Asn Gly Tyr Ala Gly Gly Val Glu Val Gln Val Leu Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Ile Leu Phe Ala Ala Val Pro Pro Asn Phe
115 120 125
Pro Val Asp Met Leu Ser Pro Ala Gln Ile Thr Met Leu Pro His Leu
130 135 140
Ile Val Asp Val Arg Thr Leu Glu Pro Ile Met Ile Pro Leu Pro Asp
145 150 155 160
Val Arg Asn Val Phe Tyr His Phe Asn Asn Gln Pro Ala Pro Arg Met
165 170 175
Arg Leu Val Ala Met Leu Tyr Thr Pro Leu Arg Ser Asn Gly Ser Gly
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Thr Pro
195 200 205
Asp Phe Glu Phe Thr Tyr Leu Val Pro Pro Ser Val Glu Ser Lys Thr
210 215 220
Lys Pro Phe Thr Leu Pro Ile Leu Thr Ile Gly Glu Leu Thr Asn Ser
225 230 235 240
Arg Phe Pro Ala Pro Ile Asp Gln Leu Tyr Thr Ser Pro Asn Ala Asp
245 250 255
Val Val Val Gln Pro Gln Asn Gly Arg Cys Thr Leu Asp Gly Glu Leu
260 265 270
Gln Gly Thr Thr Gln Leu Leu Thr Thr Ala Ile Cys Ser Tyr Arg Gly
275 280 285
Thr Thr Ser Asn Pro Thr Ser Asp Tyr Trp Asp Asp His Leu Leu His
290 295 300
Leu Val His Pro Asn Gly Ala Thr Tyr Asp Pro Thr Glu Asp Val Pro
305 310 315 320
Ala Pro Phe Gly Thr Gln Asp Phe Arg Gly Ile Leu Tyr Gly Val Leu
325 330 335
Thr Gln Asn Thr Gln Asn Pro Arg Asp Glu Val Ser Asn Ser Arg Gly
340 345 350
Ile Tyr Ile Ser Ser Thr Ser Asp Lys Phe Thr Pro Lys Leu Gly Thr
355 360 365
Ile Gly Leu His Gln Val Gln Gly Asp Thr Ala Ser Asn Gln Gln Ser
370 375 380
Lys Phe Thr Pro Val Gly Ile Ala Val Asn Gln Asn Thr Pro Phe Lys
385 390 395 400
Gln Trp Glu Leu Pro Asn Tyr Ser Gly Ala Leu Thr Leu Asn Thr Asn
405 410 415
Leu Ala Pro Ala Val Gly Pro Asn Phe Pro Gly Glu Gln Ile Leu Phe
420 425 430
Phe Arg Ser Asn Val Pro Ser Val Gln Gly Asn His Pro Thr Gln Glu
435 440 445
Ile Asp Cys Leu Ile Pro Gln Glu Trp Ile Ser His Phe Tyr Gln Glu
450 455 460
Ser Ala Pro Ser Gln Ser Asp Val Ala Leu Val Arg Tyr Val Asn Pro
465 470 475 480
Asp Thr Gly Arg Thr Ile Phe Glu Ala Lys Leu His Arg Gln Gly Phe
485 490 495
Ile Thr Ile Ala Ala Thr Gly Ser Asn Pro Val Val Val Pro Pro Asn
500 505 510
Gly Tyr Phe Arg Phe Asp Ser Trp Val Asn Gln Phe Tyr Ala Leu Ala
515 520 525
Pro Met Gly Thr Gly Asn Gly Arg Arg Arg Ala Gln
530 535 540
<210> 52
<211> 541
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 52
Met Lys Met Ala Ser Asn Asp Ala Ala Pro Ser Asn Asp Gly Ala Ala
1 5 10 15
Gly Leu Val Pro Glu Ile Asn Thr Glu Val Met Ala Leu Glu Pro Val
20 25 30
Ala Gly Gly Ala Ile Ala Ala Pro Leu Thr Gly Gln Thr Asn Ile Ile
35 40 45
Asp Pro Trp Ile Arg Asn Asn Phe Val Gln Ala Pro Asn Gly Glu Phe
50 55 60
Thr Ile Ser Pro Arg Asn Ser Pro Gly Glu Ile Leu Leu Asn Met Glu
65 70 75 80
Leu Gly Pro Glu Leu Asn Pro Phe Leu Ala His Leu Ser Arg Met Tyr
85 90 95
Asn Gly Phe Ala Gly Gly Met Glu Val Gln Val Leu Met Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Val Ile Phe Ala Ala Ile Pro Pro His Phe
115 120 125
Pro Val Glu Asn Leu Ser Pro Pro Gln Ile Thr Met Phe Pro His Ile
130 135 140
Ile Ile Asp Val Arg Thr Leu Glu Pro Val Leu Leu Pro Met Pro Asp
145 150 155 160
Val Arg Asn Gln Phe Phe His Tyr Asn Gln Val Asn Glu Pro Arg Met
165 170 175
Arg Leu Val Ala Met Leu Tyr Thr Pro Leu Arg Ser Asn Gly Ser Thr
180 185 190
Glu Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Ser Pro
195 200 205
Asp Phe Glu Phe Asn Tyr Leu Val Pro Pro Thr Val Glu Ser Arg Thr
210 215 220
Lys Pro Phe Thr Leu Pro Ile Leu Thr Ile Gly Glu Met Thr Asn Ser
225 230 235 240
Arg Phe Pro Ala Pro Ile Asp Met Leu Tyr Thr Ser Pro Asn Asp Asn
245 250 255
Val Val Val Gln Pro Gln Asn Gly Arg Cys Thr Leu Asp Gly Glu Leu
260 265 270
Gln Gly Ser Thr Gln Leu Val Pro Ala Asn Val Cys Ala Phe Lys Gly
275 280 285
Lys Ile Thr Ala Arg Ile Val Asp Gln Ala Ala His Gln Trp His Met
290 295 300
Gln Ile Asp Asn Pro Asn Gly Thr Leu Phe Asp Pro Thr Glu Asp Val
305 310 315 320
Pro Ala Pro Leu Gly Thr Pro Asp Phe Lys Ala Lys Ile Phe Gly Val
325 330 335
Ile Ser Gln Arg Asn Asp Tyr Asn Asp Gly Ser Gln Gly Pro Ala Asn
340 345 350
Arg Ala His Asp Ala Val Val Pro Thr Thr Ser Ala Lys Phe Thr Pro
355 360 365
Lys Leu Gly Ser Ile Leu Val Gly Thr Trp Glu Asn Asn Asp Ile Glu
370 375 380
Thr Gln Pro Ser Lys Phe Thr Pro Val Gly Leu Leu Glu Met Asn Asp
385 390 395 400
Phe Asn Gln Trp Ser Leu Pro Asn Tyr Ser Gly Ala Leu Thr Leu Asn
405 410 415
Met Gly Leu Ala Pro Ala Val Phe Pro Thr Phe Pro Gly Glu Gln Ile
420 425 430
Leu Phe Phe Arg Ser Phe Ile Pro Leu Lys Gly Gly His Gly Asn Pro
435 440 445
Ala Ile Asp Cys Leu Leu Pro Gln Glu Trp Ile Gln His Phe Tyr Gln
450 455 460
Glu Ser Ala Pro Ser Gln Thr Ser Val Ala Leu Ile Arg Tyr Val Asn
465 470 475 480
Pro Asp Thr Gly Arg Val Leu Phe Glu Gly Lys Leu His Arg Gln Gly
485 490 495
Phe Ile Thr Ile Ala Lys Ser Gly Asp Gly Pro Ile Val Val Pro Pro
500 505 510
Asn Gly Tyr Phe Arg Phe Asp Ser Trp Val Asn Gln Phe Tyr Ser Leu
515 520 525
Ala Pro Met Gly Asn Gly Asn Gly Arg Arg Arg Ile Gln
530 535 540
<210> 53
<211> 542
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 53
Met Lys Met Ala Ser Asn Asp Ala Ala Pro Ser Asn Asp Gly Ala Ala
1 5 10 15
Asn Leu Val Pro Glu Ala Asn Lys Glu Val Met Ala Leu Glu Pro Val
20 25 30
Ala Gly Gly Ala Ile Ala Ala Pro Leu Thr Gly Gln Thr Asn Ile Ile
35 40 45
Asp Pro Trp Ile Met Asn Asn Phe Val Gln Ala Pro Asn Gly Glu Phe
50 55 60
Thr Ile Ser Pro Arg Asn Ser Pro Gly Glu Val Leu Leu Asn Leu Glu
65 70 75 80
Leu Gly Pro Asp Leu Asn Pro Phe Leu Ala His Leu Ser Arg Met Tyr
85 90 95
Asn Gly Tyr Ala Gly Gly Val Glu Val Gln Val Ile Met Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Val Ile Phe Ala Ala Val Pro Pro His Phe
115 120 125
Pro Val Asp Asn Leu Ser Pro Pro Gln Val Thr Met Phe Pro His Val
130 135 140
Ile Val Asp Val Arg Thr Phe Glu Pro Ile Leu Leu Pro Leu Pro Asp
145 150 155 160
Val Arg Asn Ser Phe Tyr His Tyr Asn Gln Val Asn Asp Ser Arg Met
165 170 175
Arg Leu Ile Ala Met Leu Tyr Thr Pro Leu Arg Ser Asn Gly Ser Ser
180 185 190
Asp Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Thr Pro
195 200 205
Asp Phe Glu Phe Asn Tyr Leu Val Pro Pro Thr Val Glu Ser Arg Thr
210 215 220
Lys Pro Phe Ser Val Pro Ile Leu Thr Ile Gly Glu Met Thr Asn Ser
225 230 235 240
Arg Phe Pro Leu Pro Ile Asp Met Leu Tyr Thr Ser Pro Thr Glu Asn
245 250 255
Ile Val Val Gln Pro Gln Asn Gly Arg Cys Thr Leu Glu Gly Glu Leu
260 265 270
Leu Gly Thr Thr Gln Leu Val Thr Pro Asn Ile Cys Ala Leu Arg Gly
275 280 285
Glu Ile Arg Gly His Glu Gly Ser Gly Asp Asn His Lys Trp His Phe
290 295 300
Met Val Arg Ser Pro Asn Gly Ala Ala Phe Asp Pro Thr Glu Asp Val
305 310 315 320
Pro Ala Pro Leu Gly Thr Pro Asp Phe Ile Gly Asp Val Phe Gly Val
325 330 335
Leu Ser Gln Arg Asn Arg Asn Thr Asp Ser Gly Gln Ser Gly Pro Ala
340 345 350
Asn Arg Ser His Asp Ala Val Val Ser Thr Arg Asp Ser Arg Phe Thr
355 360 365
Pro Lys Leu Gly Ser Val Met Ile Ala Thr Trp Glu Thr Ser Asp Ile
370 375 380
Gln Asp Gln Pro Thr Arg Phe Thr Pro Val Gly Leu Glu Asn Pro Asp
385 390 395 400
His Tyr Asn Gln Trp Gln Leu Pro Asn Tyr Ser Gly Ala Leu Thr Leu
405 410 415
Asn Met Gly Leu Ala Pro Ser Val Phe Pro Thr Tyr Pro Gly Glu Gln
420 425 430
Ile Leu Phe Phe Arg Ser Tyr Ile Pro Leu Lys Gly Gly Tyr Gly Asp
435 440 445
Ser His Ile Asp Cys Leu Val Pro Gln Glu Trp Ile Gln His Phe Tyr
450 455 460
Gln Glu Ser Ala Pro Ser Gln Thr Asp Val Ala Leu Ile Arg Tyr Val
465 470 475 480
Asn Pro Glu Thr Gly Arg Val Leu Phe Glu Ala Lys Leu His Arg Gln
485 490 495
Gly Tyr Ile Thr Val Ala Arg Ser Gly Ser Ser Pro Ile Asn Val Pro
500 505 510
Ala Asn Gly Tyr Phe Arg Phe Asp Ser Trp Val Asn Gln Phe Tyr Ser
515 520 525
Leu Ala Pro Met Gly Thr Gly Asn Gly Arg Arg Arg Ile Gln
530 535 540
<210> 54
<211> 541
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 54
Met Lys Met Ala Ser Asn Asp Ala Ala Pro Ser Asn Asp Gly Ala Ala
1 5 10 15
Gly Leu Val Pro Glu Ile Asn Asn Glu Val Met Ala Leu Glu Pro Val
20 25 30
Ala Gly Gly Ala Ile Ala Ala Pro Leu Thr Gly Gln Thr Asn Val Ile
35 40 45
Asp Pro Trp Ile Arg Thr Asn Phe Val Gln Ala Pro Asn Gly Glu Phe
50 55 60
Thr Ile Ser Pro Arg Asn Ser Pro Gly Glu Val Leu Leu Asn Met Glu
65 70 75 80
Leu Gly Pro Glu Leu Asn Pro Phe Leu Gly His Leu Ser Arg Met Tyr
85 90 95
Asn Gly Tyr Ala Gly Gly Ile Glu Val Gln Val Leu Met Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Val Ile Phe Ala Ala Val Pro Pro His Phe
115 120 125
Pro Val Glu Asn Leu Ser Pro Pro Gln Val Thr Met Phe Pro His Ile
130 135 140
Ile Val Asp Val Arg Thr Leu Glu Pro Ile Leu Leu Pro Leu Pro Asp
145 150 155 160
Val Arg Asn Gln Phe Phe His Tyr Ser Gln Val Asp Glu Pro Lys Met
165 170 175
Arg Leu Val Ala Met Leu Tyr Thr Pro Leu Arg Ser Asn Gly Ser Ala
180 185 190
Glu Asp Val Phe Thr Val Ser Cys Arg Val Leu Thr Arg Pro Ser Pro
195 200 205
Asp Phe Glu Phe Asn Tyr Leu Val Pro Pro Thr Val Glu Ser Arg Thr
210 215 220
Lys Pro Phe Thr Val Pro Ile Leu Thr Ile Gly Glu Met Ser Asn Ser
225 230 235 240
Arg Phe Pro Ala Pro Ile Asp Met Leu Tyr Thr Ser Pro Asn Asp Asn
245 250 255
Gln Asn Val Gln Pro Gln Asn Gly Arg Cys Thr Leu Asp Gly Glu Leu
260 265 270
Gln Gly Thr Thr Gln Leu Val Pro Ser Gly Val Cys Ala Phe Arg Gly
275 280 285
Arg Ile Thr Gly His Glu Gly Ser Glu Gln Asn Gln Trp His Met Gln
290 295 300
Leu Thr Asn Leu Asn Gly Thr Pro Phe Asp Pro Thr Glu Asp Ile Pro
305 310 315 320
Ala Pro Leu Gly Thr Pro Asp Phe Lys Gly Glu Ile Phe Gly Phe Ile
325 330 335
Ser Gln Arg Asn Ala Gln Asn Asp Pro Gly Gln Ser Gln Pro Ala Asn
340 345 350
Arg Ala His Asp Ala Val Val Ser Thr Arg Ala Pro Lys Phe Thr Pro
355 360 365
Lys Leu Gly Ser Val Met Ile Gly Thr Trp Val Asn Ser Asp Ile Glu
370 375 380
Asn Gln Pro Ser Lys Phe Thr Pro Val Gly Leu Asn Ser Asn Glu Asn
385 390 395 400
Phe Arg Gln Trp Glu Leu Pro Asp Tyr Ser Gly Val Leu Thr Leu Asn
405 410 415
Met Gly Leu Ala Pro Val Val His Pro Thr Tyr Pro Gly Glu Gln Ile
420 425 430
Leu Phe Phe Arg Ser Tyr Ile Pro Leu Lys Gly Gly His Gly Asn Pro
435 440 445
Ala Ile Asp Cys Leu Leu Pro Gln Glu Trp Ile Gln His Phe Tyr Gln
450 455 460
Glu Ser Ala Pro Ser Gln Thr Asp Val Ala Leu Leu Arg Tyr Val Asn
465 470 475 480
Pro Asp Thr Gly Arg Val Leu Phe Glu Ala Lys Leu His Arg Gln Gly
485 490 495
Tyr Ile Thr Ile Ala Lys Ser Gly Asp Gly Pro Ile Val Val Pro Pro
500 505 510
Asn Gly Tyr Phe Arg Phe Asp Ser Trp Val Asn Gln Phe Tyr Ser Leu
515 520 525
Ala Pro Met Gly Asn Gly Asn Gly Arg Arg Arg Val Gln
530 535 540
<210> 55
<211> 556
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 55
Met Lys Met Ala Ser Ser Asp Ala Ala Pro Ser Thr Asp Gly Ala Gly
1 5 10 15
Asn Leu Val Pro Glu Ser Gln Gln Glu Val Leu Pro Leu Ala Pro Val
20 25 30
Ala Gly Ala Ala Leu Ala Ala Pro Val Val Gly Gln Thr Asn Ile Ile
35 40 45
Asp Pro Trp Ile Lys Glu Asn Phe Val Gln Ala Pro Gln Gly Glu Phe
50 55 60
Thr Val Ser Pro Lys Asn Ser Pro Gly Glu Ile Leu Val Asn Leu Glu
65 70 75 80
Leu Gly Pro Lys Leu Asn Pro Tyr Leu Asp His Leu Ser Arg Met Tyr
85 90 95
Asn Ser Tyr Ala Gly Gly Ile Asp Val Met Val Val Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Val Leu Ile Ala Ala Ile Pro Pro Asn Phe
115 120 125
Pro Val Glu Gly Val Ser Ala Ser Gln Ala Thr Gln Phe Pro His Val
130 135 140
Ile Ile Asp Val Arg Thr Leu Asp Pro Val Arg Leu Pro Leu Pro Asp
145 150 155 160
Val Arg Ser Thr Phe Phe His Tyr Thr Asn Asp Thr Glu Pro Lys Met
165 170 175
Arg Leu Val Ile Trp Leu Tyr Thr Pro Leu Arg Thr Asn Gly Ser Gly
180 185 190
Asp Asp Ser Phe Thr Val Ser Gly Arg Ile Leu Thr Arg Pro Ser Gln
195 200 205
Asp Phe Glu Phe Ala Phe Leu Ile Pro Pro Thr Val Glu Thr Lys Thr
210 215 220
Thr Pro Phe Ser Val Pro Gly Phe Ser Val Gln Glu Met Ser Asn Ser
225 230 235 240
Arg Trp Pro Ala Ala Ile Ser Ala Met Val Val Arg Gly Asn Glu Pro
245 250 255
Gln Val Val Gln Phe Gln Asn Gly Arg Ala His Leu Asp Gly Met Leu
260 265 270
Leu Gly Thr Thr Pro Val Ser Pro Asn Tyr Ile Ala Ser Tyr Arg Gly
275 280 285
Ile Ser Thr Gly Asn Ser Arg Ser Ala Ser Ser Glu Ala Asp Glu Arg
290 295 300
Ala Val Gly Ser Phe Asp Val Trp Val Arg Leu Gln Glu Pro Asp Gly
305 310 315 320
Gln Pro Tyr Asp Ile Phe Gly Lys Gln Pro Ala Pro Ile Gly Thr Pro
325 330 335
Asp Phe Lys Ala Val Ile Val Gly Phe Ala Ala Arg Pro Leu Thr Ser
340 345 350
Gly Ser Tyr Ala Asn Glu Ala Tyr Val Asn Thr Thr Ala Ser Asp Tyr
355 360 365
Ala Pro Ala Thr Gly Asn Met Arg Phe Thr Val Arg Asn Gly Gly Thr
370 375 380
Gly His Ile Ser Ala Asn Lys Tyr Trp Glu Phe Lys Ser Phe Gly Val
385 390 395 400
Glu Gly Glu Arg His Thr Asp Ile Gln Tyr Gln Glu Tyr Glu Leu Pro
405 410 415
Asp Tyr Ser Gly Gln Val Ala Ser Asn His Asn Leu Ala Pro Pro Val
420 425 430
Ala Pro Arg Met Pro Gly Glu Ser Leu Leu Leu Phe Gln Ser Asn Met
435 440 445
Pro Val Trp Asp Asp Gly His Gly Glu Ser Thr Pro Lys Lys Ile His
450 455 460
Cys Leu Leu Pro Gln Glu Phe Ile Gly His Phe Phe Asp Arg Gln Ala
465 470 475 480
Pro Ser Leu Gly Asp Ala Ala Leu Leu Arg Tyr Val Asn Gln Glu Thr
485 490 495
Asn Arg Val Leu Phe Glu Cys Lys Leu Tyr Arg Asp Gly Tyr Ile Thr
500 505 510
Val Ala Ala Ser Ser Gly Leu Leu Asp Phe Pro Leu Asp Gly Phe Phe
515 520 525
Arg Phe Asp Ser Trp Val Ser Ser Phe Tyr Ile Leu Ser Pro Val Gly
530 535 540
Ser Gly Gln Gly Arg Arg Gly Arg Val Arg Phe Gln
545 550 555
<210> 56
<211> 554
<212> PRT
<213> 诺如病毒（Norovirus）
<400> 56
Met Lys Met Ala Ser Asn Asp Ala Pro Pro Ser Ser Asp Gly Ala Gly
1 5 10 15
Asn Leu Val Pro Glu Ser His Gln Glu Val Leu Pro Leu Ala Pro Val
20 25 30
Ala Gly Ala Glu Leu Ala Ala Pro Val Val Gly Gln Thr Asn Ile Ile
35 40 45
Asp Pro Trp Ile Lys Glu Asn Phe Val Gln Ala Pro Gln Gly Glu Phe
50 55 60
Thr Val Ser Pro Lys Asn Ala Pro Gly Glu Ile Leu Val Asn Leu Glu
65 70 75 80
Leu Gly Pro Asn Leu Asn Pro Tyr Leu Glu His Leu Ser Arg Met Tyr
85 90 95
Asn Ala Tyr Ala Gly Gly Ile Glu Val Glu Ile Ile Leu Ala Gly Asn
100 105 110
Ala Phe Thr Ala Gly Lys Ile Leu Ile Ala Ala Val Pro Pro Asn Phe
115 120 125
Pro Val Glu Ser Val Ser Ala Ser Gln Ala Thr Gln Phe Pro His Ala
130 135 140
Ile Val Asp Val Arg Thr Leu Glu Pro Val Arg Leu Pro Leu Pro Asp
145 150 155 160
Val Arg Ser Asn Phe Phe His Tyr Thr Thr Lys Asp Glu Pro Lys Met
165 170 175
Arg Leu Val Ile Trp Leu Tyr Thr Pro Leu Arg Thr Asn Gly Ser Gly
180 185 190
Asp Asp Ser Phe Thr Val Ser Gly Arg Leu Leu Thr Arg Pro Ser Met
195 200 205
Asp Phe Gln Phe Ser Phe Leu Val Pro Pro Thr Val Glu Thr Lys Thr
210 215 220
Val Leu Phe Thr Val Pro Gly Leu Thr Pro Gln Glu Met Ser Asn Ser
225 230 235 240
Arg Trp Pro Ala Gln Ile Ser Gly Met Val Val Arg Gly Asn Glu Pro
245 250 255
Gln Val Val Gln Phe Gln Asn Gly Arg Cys His Thr Asp Gly Thr Leu
260 265 270
Leu Gly Thr Thr Thr Val Ser Glu Gln Cys Ile Ala Gly Phe Val Gly
275 280 285
Thr Ser Thr Asn Thr Arg Ser Ala Thr Gly Ser Thr Thr Glu Thr Arg
290 295 300
Thr Gly Asp Thr Asp Leu Trp Leu Arg Leu Glu Glu Pro Asn Gly Gln
305 310 315 320
Pro Tyr Asp Ile Phe Gly Asp Gln Pro Ala Pro Leu Gly Thr Pro Asp
325 330 335
Phe Arg Ala Val Ile Val Gly Phe Ala Ser Arg Pro Gln Thr Gln Gly
340 345 350
Ser Tyr Met Asn Glu Ala Tyr Val Asn Thr Val Asp Ser His Phe Ala
355 360 365
Pro Ala Thr Gly Asn Thr Lys Ile Ile Leu Arg Arg Gly Gly Thr Gly
370 375 380
His Val Gly Gly Gly His Leu Trp Lys Phe Arg Pro Phe Gly Val Glu
385 390 395 400
Gly Gly Glu Gly Arg Val Ser Tyr Gln Glu Tyr Val Leu Pro Asn Tyr
405 410 415
Ser Gly Ala Thr Ala Ser Asn His Asn Leu Ala Pro Pro Val Ala Pro
420 425 430
Arg Met Pro Gly Glu Leu Leu Leu Leu Phe Glu Ser Asp Met Pro Val
435 440 445
Trp Asp Asp Gly His Gly Ala Ala Pro Ala Gln Lys Ile His Cys Leu
450 455 460
Leu Pro Gln Gln Phe Ile Thr His Phe Phe Asp Ser Gln Ala Pro Ala
465 470 475 480
Leu Ala Glu Ala Ala Leu Leu Arg Tyr Val His Pro Asp Ser Ser Arg
485 490 495
Val Leu Phe Glu Thr Lys Leu Tyr Arg Glu Gly Phe Met Val Val Ser
500 505 510
Ala Pro Thr Gly Arg Phe Asp Phe Pro Leu Asp Gly Tyr Phe Arg Phe
515 520 525
Asp Ser Trp Val Asn Ser Phe Tyr Val Leu Ser Pro Val Gly Ser Gly
530 535 540
Gln Gly Arg Arg Gly Arg Ser Lys Val Val
545 550
<210> 57
<211> 6
<212> PRT
<213> 人工序列（artificial）
<220>
<223> 具有变体氨基酸残基的序列区段
<220>
<221> 变体（VARIANT）
<222> (4)..(4)
<223> Leu或Val
<400> 57
Ala Ala Leu Xaa His Tyr
1 5
<210> 58
<211> 6
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> 具有变体氨基酸残基的序列区段
<220>
<221> VARIANT
<222> (4)..(4)
<223> Leu或Val
<220>
<221> 变体（VARIANT）
<222> (5)..(5)
<223> Arg或Lys
<400> 58
Ala Ala Leu Xaa Xaa Tyr
1 5
<210> 59
<211> 8
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> 具有变体氨基酸残基的序列区段
<220>
<221> 变体（variant）
<222> (4)..(4)
<223> Leu或Val
<220>
<221> 变体（variant）
<222> (7)..(7)
<223> Val、Leu或Ile
<400> 59
Ala Ala Leu Xaa His Tyr Xaa Asp
1 5
<210> 60
<211> 8
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> 具有变体氨基酸残基的序列区段
<220>
<221> 变体（variant）
<222> (4)..(4)
<223> Leu或Val
<220>
<221> 变体（variant）
<222> (5)..(5)
<223> Arg或Lys
<220>
<221> 变体（variant）
<222> (7)..(7)
<223> Val或Leu或Ile
<400> 60
Ala Ala Leu Xaa Xaa Tyr Xaa Asp
1 5
<210> 61
<211> 5
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> 具有变体氨基酸残基的序列区段
<220>
<221> 变体（VARIANT）
<222> (4)..(4)
<223> Leu或Val
<400> 61
Ala Ala Leu Xaa His
1 5

Claims (17)

1.一种诺如病毒基因组IVP1衣壳蛋白，其中所述蛋白的氨基酸序列在对应于SEQ IDNO：3中Arg472的位置处具有Arg或Lys残基。
2.一种诺如病毒基因组IVP1衣壳蛋白，其具有P结构域中的氨基酸序列区段Ala-Ala-Leu-Leu/Val-His-Tyr被修饰为Ala-Ala-Leu-Leu/Val-Arg/Lys-Tyr的氨基酸序列，其中Leu/Val意指Leu或Val之一，并且Arg/Lys意指Arg或Lys。
3.如权利要求2所述的衣壳蛋白，其中P结构域中的氨基酸序列区段Ala-Ala-Leu-Leu/Val-His-Tyr-Val/Leu/Ile-Asp被修饰为Ala-Ala-Leu-Leu/Val-Arg/Lys-Tyr-Val/Leu/Ile-Asp，其中Val/Leu/Ile意指Val或Leu或Ile之一。
4.如权利要求1至3中任一项所述的衣壳蛋白，其中所述衣壳蛋白属于诺如病毒基因组I的以下任一基因型：GI.1、GI.2、GI.3、GI.4、GI.5、GI.6、GI.7、GI.8或GI.9。
5.如权利要求1至4中任一项所述的衣壳蛋白，其中所述蛋白具有如SEQ ID NO：6至21中任一项所定义的氨基酸序列，只不过对应于SEQ ID NO：3中Arg472位置处的氨基酸残基是Arg或Lys；或所述蛋白具有如SEQ ID NO：3至5中任一项所定义的氨基酸序列。
6.如权利要求1至5中任一项所述的衣壳蛋白，其中
(i)所述蛋白的氨基酸序列包含SEQ ID NO：6至21中任一项的氨基酸序列的至少500个连续氨基酸残基或由其组成，只不过对应于SEQ ID NO：3中Arg472位置处的氨基酸残基是Arg或Lys；或
(ii)所述蛋白的氨基酸序列包含至少500个氨基酸残基或由其组成，并且在这个长度上与SEQ ID NO：6至21中任一项的氨基酸序列的至少500个连续氨基酸残基的序列区段具有至少80％，优选至少85％，更优选至少90％的序列同一性；或
(iii)所述蛋白的氨基酸序列与SEQ ID NO：6至21中任一项的氨基酸序列的至少500个连续氨基酸残基的序列区段相比具有1至50个，优选1至40个，更优选1至30个缺失、取代、添加或插入；
其中在第(ii)或(iii)项中，对应于SEQ ID NO：3中Arg472位置处的氨基酸残基是Arg或Lys。
7.如权利要求1至6中任一项所述的衣壳蛋白，其中
(i')所述蛋白的氨基酸序列包含来自SEQ ID NO：3、4或5的残基43至残基540的氨基酸序列或由其组成；或
(ii')所述蛋白的氨基酸序列与来自SEQ ID NO：3、4或5的残基43至残基540的氨基酸序列具有至少80％，优选至少85％，更优选至少90％的序列同一性；或
(iii')所述蛋白的氨基酸序列与SEQ ID NO：3、4或5的残基43至残基540的氨基酸序列相比具有1至50个，优选1至40个，更优选1至30个缺失、取代、添加或插入；
其中在第(ii')或(iii')项中，对应于SEQ ID NO：3中Arg472位置处的氨基酸残基是Arg或Lys。
8.一种编码权利要求1至7中任一项所述的衣壳蛋白的核酸分子。
9.一种包含权利要求1至7中任一项所述的衣壳蛋白或由其组成的病毒样颗粒(VLP)。
10.一种包含权利要求1至7中任一项所述的衣壳蛋白或权利要求9所述的VLP以及任选的药学上可接受的载体的免疫原性组合物。
11.如权利要求10所述的免疫原性组合物，其进一步包含诺如病毒基因组II VP1衣壳蛋白，或进一步包含含有基因组IIVP1衣壳蛋白或由其组成的VLP。
12.一种抗诺如病毒感染的疫苗，其包含权利要求10或11所述的免疫原性组合物，或包含权利要求1至7中任一项所述的衣壳蛋白，或包含权利要求9所述的VLP。
13.如权利要求12所述的疫苗，其包含诺如病毒基因组II VP1衣壳蛋白或含有基因组II VP1衣壳蛋白或由其组成的VLP。
14.如权利要求1至7中任一项所述的衣壳蛋白，或如权利要求9所述的VLP，或如权利要求12或13中任一项所述的疫苗，其用于预防或治疗受试者中，优选人类受试者中的诺如病毒感染。
15.一种提高诺如病毒基因组IVLP稳定性的方法，包括将基因组IVP1衣壳蛋白的P结构域中的序列区段Ala-Ala-Leu-Leu/Val-His-Tyr中的His残基替换为Arg或Lys，优选Arg。
16.一种预防或治疗有此需要的受试者中的诺如病毒感染的方法，包括向所述受试者施用权利要求1至7中任一项所述的衣壳蛋白、或权利要求9所述的VLP、或权利要求12或13所述的疫苗一次或多次。
17.如权利要求16所述的方法，其中所述受试者是人类受试者。
CN202080020212.XA 2019-03-12 2020-03-11 具有提高的稳定性的诺如病毒样颗粒 Pending CN113557240A (zh)

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