CN112867505A - 经修饰的pedv刺突蛋白 - Google Patents
经修饰的pedv刺突蛋白 Download PDFInfo
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- CN112867505A CN112867505A CN201980060531.0A CN201980060531A CN112867505A CN 112867505 A CN112867505 A CN 112867505A CN 201980060531 A CN201980060531 A CN 201980060531A CN 112867505 A CN112867505 A CN 112867505A
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Abstract
本发明是关于经修饰的猪流行性腹泻病毒刺突蛋白。此外，本发明是关于包含该经修饰的PEDV刺突蛋白的免疫原性组合物及对个体实施免疫的方法，该方法包含向个体施用该免疫原性组合物。
Description
序列表
本申请案含有符合37C.F.R.1.821-1.825的序列表。本申请案随附的序列表特此以全文引用的方式并入。
技术领域
本发明是关于经修饰的PEDV(猪流行性腹泻病毒)刺突(S)蛋白。该等修饰会产生经改良的PEDV疫苗生产方法。此外，包含该等经修饰的刺突蛋白的疫苗作为疫苗是有效的，且提供抵抗PEDV感染或攻击的保护。由于不到10日龄仔猪的死亡率较高(高达100％)，因此该疾病影响经济，例如对于美国养猪业而言。
背景技术
猪流行性腹泻病毒是包膜正义单链RNA病毒，会造成猪只急性腹泻、呕吐及脱水。在三周龄及更小的猪只中，经PEDV感染后24小时即可观察到临床征象(包括急性水泻、腹泻、呕吐及脱水)，此导致高达100％的死亡率。此外，感染PEDV的动物肠中的严重变化及组织学变化会引起小肠中严重的病理性病灶。
PEDV最初是在欧洲发现，但在包括韩国、中国、日本、菲律宾及泰国在内的许多亚洲国家已变得越来越成问题。自2013年以来，PEDV在美国出现且PEDV感染的经济影响已然显著。因此，业内持续需要开发能够保护猪抵抗与PEDV相关的疾病的疫苗。就此而言，尤其需要有效抵抗新出现的PEDV品系且可经由黏膜途径(经口或鼻内)施用的疫苗。
尽管仅报导PEDV的一种血清型，但对S基因的系统发生研究显示可在遗传上将PEDV分成2个群组：基因群1(G1；经典)及基因群2(G2；现场流行或大流行的)。该等基因群中的每一者可进一步分成亚群(1a及1b；2a及2b)。G1a包括原型PEDV品系CV777、疫苗品系及其他细胞培养适应品系，而G1b包含首先在中国且随后在美国、韩国及欧洲鉴别出的新变体。G2包含全球现场分离株，其进一步聚集成分别造成先前亚洲的局部流行性爆发及最近北美洲及亚洲的大流行爆发的2a及2b亚群(G2a及G2b)。
PEDV是α冠状病毒属(Alphacoronavirus)冠状病毒亚科(Coronavirinae)的成员。PEDV是具有大约28kb的正义单链RNA基因组的包膜病毒，其具有5’帽及3’多腺苷酸化尾。(Pensaert及De Bouck P.1978)。该基因组包含5’非转译区(UTR)、3’UTR及至少七个编码四种结构蛋白质(刺突(S)、包膜(E)、膜(M)及核衣壳(N))及三种非结构蛋白质(复制酶1a及1b及ORF3)的开放阅读框(ORF)；该等区在基因组上是以5’-复制酶(1a/1b)-S-ORF3-E-M-N-3’的顺序排列(Oldham J.1972；及Bridgen等人1993)。
PEDV S蛋白是I型糖蛋白，其中(G2b PEDV的)S蛋白是由1,383个氨基酸(aa)构成。基于其与其他冠状病毒的S蛋白的同源性，可将该S蛋白分为S1(例如1-789个aa)及S2(例如790-1,383个aa)结构域。冠状病毒中的S蛋白是表面抗原，在此其在调控与宿主细胞受体糖蛋白的相互作用以介导病毒进入及刺激天然宿主中中和性抗体的诱导中起作用。因此，S糖蛋白是开发有效抵抗PEDV的疫苗的主要靶标。
Madu等人2009(J.Virol.；83(15)，第7411-7421页)阐述SARS(严重急性呼吸症候群)的刺突蛋白中的两种单突变(L803A或L804A)，且显示该等单突变中的每一者对膜融合活性具有影响。此外，Ujike及Taguchi 2015(Viruses；7,1700-1725)阐述酪氨酸依赖性YXXI信号的突变展现细胞表面表达增强。Shirato等人2011(Virus Res.；161(2):188-93)阐述PEDV的KxHxx基序中的突变H1381R使得刺突蛋白转运至质膜。然而，该等文件中均未揭示在刺突蛋白内的任何修饰可改良PEDV疫苗的生产方法且此等利用刺突蛋白内的修饰所产生的疫苗仍将适宜作为疫苗并提供抵抗PEDV感染或攻击的保护。
针对上述技术问题的解决方案是通过说明及申请专利范围中所表征的实施例来达成。
因此，本发明在其不同方面中是根据申请专利范围来实施的。
附图说明
图1.RK13细胞中靶蛋白(PEDV-S2b-wt及PEDV-S2b-mut)的细胞定位。上部三个图展现，自EHV1-PEDV-S2b-wt重组载体启动的刺突蛋白的表达主要位于细胞质中，而如下部三个图中所显示，自EHV1-PEDV-S2b-mut表达的PEDV-S主要位于细胞膜内。
图2.实例3中所阐述载体(CDV-PEDV-刺突-MUT(＝CDV-PEDV-刺突mut)及CDV-PEDV-刺突-WT(＝CDV-PEDV-刺突WT))在Vero细胞中的生长的比较，其中上部曲线是关于CDV-PEDV-刺突mut，且下部曲线是关于CDV-PEDV-刺突WT。
具体实施方式
在阐述本发明的方面之前，必须注意，如本文中且如在随附申请专利范围中所使用，除非上下文另外明确地指示，否则单数形式“一(a、an)”及“该(the)”包括复数个指示物。因此，举例而言，对“抗原”的提及包括复数个抗原，对“病毒”的提及是对本领域技术人员已知的一或多种病毒及其等效物等等的提及。除非另外定义，否则本文所使用的所有技术及科学术语均具有与熟习本发明所属领域技术者通常所理解相同的含义。尽管任何类似或等效于本文所阐述那些的方法及材料可用于本发明的实践或测试中，但现在阐述优选的方法、装置及材料。出于阐述及揭示如结合本发明所使用的出版物中所报导的细胞系、载体及方法的目的，本文所提及的所有出版物均是以引用方式并入本文中。本文中的内容均不应解释为承认本发明无权先于凭借先前发明所作的此揭示内容。
本发明是基于以下令人惊讶的发现：PEDV刺突蛋白的氨基酸序列中的突变足以提高基于载体的PEDV疫苗的生产程度。此外，动物研究已显示，具有此一经修饰的刺突蛋白的基于PEDV载体的疫苗是有效的，且提供或实现抵抗PEDV感染或攻击的保护。因此，本发明解决了先前技术中所固有的问题且在现有技术中提供了明显的进步。
就此而言，本发明提供编码包含以下氨基酸序列的猪流行性腹泻病毒(PEDV)刺突(S)蛋白的核酸分子
RSX1IEDX2X3(SEQ ID NO:1)，其中
(I)X2是除亮氨酸残基以外的氨基酸残基且X3是亮氨酸残基，或
(II)X2是亮氨酸残基且X3是除亮氨酸残基以外的氨基酸残基，或
(III)X2是除亮氨酸残基以外的氨基酸残基且X3是除亮氨酸残基以外的氨基酸残基。
特定而言，序列RSX1IEDX2X3(SEQ ID NO:1)以及序列SEQ ID NO:4、5、21-25及31-35中的任一者的R是位于S1/S2裂解位点的C末端方向上的保守精氨酸残基。在下文中，该R亦称为“该PEDV S蛋白的S1/S2裂解位点的保守精氨酸残基”。更特定而言，该R是在N末端侧接该PEDV S蛋白的融合肽的精氨酸残基。该融合肽的序列通常以序列SXIED开始。特定而言，该融合肽是在PEDV S蛋白的S2亚单元内。
因此，序列RSX1IEDX2X3(SEQ ID NO:1)亦特别理解为该PEDV S蛋白的融合结构域的序列。
更具体而言，在序列RSX1 IEDX2X3(SEQ ID NO:1)以及序列SEQ ID NO:4、5、21-25及31-35中的任一者的情形中，若PEDV S蛋白是基因型2a(G2a)PEDV S蛋白，则R是指在氨基酸位置894处的保守精氨酸残基或若PEDV S蛋白是基因型2b(G2b)PEDV S蛋白，则R是指在氨基酸位置891处的保守精氨酸残基。因此，关于氨基酸位置，陈述“R是该PEDV S蛋白的S1/S2裂解位点的保守精氨酸残基”应理解为等同于“若PEDV S蛋白是基因型2a(G2a)PEDV S蛋白，则R是在氨基酸位置894处的精氨酸残基，且其中氨基酸位置的编号参考野生型G2aPEDV S蛋白、优选地SEQ ID NO:2或SEQ ID NO:39的氨基酸序列，或若PEDV S蛋白是基因型2b(G2b)PEDV S蛋白，则R是在氨基酸位置891处的精氨酸残基，且其中氨基酸位置的编号参考野生型G2a PEDV S蛋白、优选地SEQ ID NO:3的氨基酸序列”。
通常，本发明提供编码包含以下氨基酸序列的猪流行性腹泻病毒(PEDV)刺突(S)蛋白的核酸分子
RSX1IEDX2X3(SEQ ID NO:1)，
其中R是该PEDV S蛋白的S1/S2裂解位点的保守精氨酸残基，X1可为任一氨基酸残基，且其中
(I)X2是除亮氨酸残基以外的氨基酸残基且X3是亮氨酸残基，或
(II)X2是亮氨酸残基且X3是除亮氨酸残基以外的氨基酸残基，或
(III)X2是除亮氨酸残基以外的氨基酸残基且X3是除亮氨酸残基以外的氨基酸残基。
术语“核酸分子”是指包括DNA分子、RNA分子、cDNA分子或衍生物的多核苷酸。该术语涵盖单链以及双链多核苷酸。优选地，该术语是指单链RNA或双链cDNA。本发明的核酸涵盖经分离多核苷酸(即自其天然环境分离)及遗传修饰形式。此外，亦包含经化学修饰的多核苷酸，包括经天然修饰的多核苷酸(例如糖基化或甲基化多核苷酸)或经人工修饰者(例如生物素化多核苷酸)。此外，应理解，由于遗传密码的简并性，因此如上文所提及的刺突蛋白可由大量多核苷酸编码。此外，术语“核酸”及“多核苷酸”可互换使用且是指任一核酸。术语“核酸”及“多核苷酸”亦明确地包括由除5个生物碱基(腺嘌呤、鸟嘌呤、胸腺嘧啶、胞嘧啶及尿嘧啶)以外的碱基构成的核酸。
术语“PEDV”为本领域技术人员所熟知。PEDV代表猪流行性腹泻病毒且是α冠状病毒属(Alphacoronavirus)冠状病毒亚科(Coronavirinae)的成员。
术语“刺突”是指本领域技术人员所熟知的PEDV的特定蛋白质。刺突蛋白是抗体及保护性免疫反应的主要诱导物。此外，刺突蛋白通过结合宿主细胞的细胞受体以及通过介导与宿主细胞的病毒-细胞膜融合而在PEDV的细胞进入程序中起主要作用。此外，应理解，术语“PEDV S蛋白”等同于缩写术语“PEDV S”，其在PEDV的情形中经常使用。
术语“蛋白质”、“氨基酸”及“多肽”可互换使用。术语“蛋白质”是指由天然氨基酸以及其衍生物构成的氨基酸(aa)序列。天然氨基酸或以遗传方式编码的氨基酸残基分别为业内所熟知，且阐述于生物化学的标准教科书中。在氨基酸序列内，氨基酸是由肽键连结。此外，氨基酸序列的两端称为羧基末端(C末端)及氨基末端(N末端)。术语“蛋白质”涵盖基本上经纯化的蛋白质或另外包含其他蛋白质的蛋白质制剂。此外，该术语亦是指蛋白质片段。此外，其包括经化学修饰的蛋白质。此等修饰可为人工修饰或天然修饰，例如磷酸化、糖基化、肉豆蔻酰基化及诸如此类。
在本发明的上下文中，措辞“R是该PEDV S蛋白的S1/S2裂解位点的保守精氨酸残基”应理解为分别等同于“R是位于该PEDV S蛋白的S1/S2裂解位点的C末端方向上的保守精氨酸残基”或等同于“R是在N末端侧接该PEDV S蛋白的融合肽的保守精氨酸残基”。措辞“在N末端侧接融合肽”应理解为等同于“在N末端侧接融合肽序列”。
序列RSX1IEDX2X3(SEQ ID NO:1)应理解为如下：
-R是该PEDV S蛋白的S1/S2裂解位点的保守精氨酸残基，
-S是氨基酸残基丝氨酸，
-X1是20种经遗传编码的氨基酸残基中的任一者，
-I是异亮氨酸残基，
-E是谷氨酸盐残基，
-D是天冬氨酸盐残基，
-X2是变量。X2具有两种情况。X2可为除亮氨酸以外的氨基酸残基(情况1)，此意味着X2可为除亮氨酸残基以外的经遗传编码的氨基酸残基中的任一者。或者，X2可为亮氨酸残基(情况2)，
-X3是变量。X3具有两种情况。X3可为除亮氨酸残基以外的氨基酸残基(情况1)，此意味着X3可为除亮氨酸以外的经遗传编码的氨基酸残基中的任一者。或者，X3可为亮氨酸残基(情况2)。
因此，本发明提供编码包含以下各项的猪流行性腹泻病毒(PEDV)刺突(S)蛋白的核酸分子：
a)氨基酸序列RSX1IEDLX2(SEQ ID NO:21)，且其中R是该PEDV S蛋白的S1/S2裂解位点的保守精氨酸残基，X1可为任一氨基酸残基，X2是除亮氨酸残基以外的氨基酸残基，或
b)氨基酸序列RSX1IEDX2L(SEQ ID NO:22)，且其中R是该PEDV S蛋白的S1/S2裂解位点的保守精氨酸残基，X1可为任一氨基酸残基，X2是除亮氨酸残基以外的氨基酸残基，或
c)氨基酸序列RSX1IEDX2X3(SEQ ID NO:1)，且其中R是该PEDV S蛋白的S1/S2裂解位点的保守精氨酸残基，X1可为任一氨基酸残基，X2及X3是除亮氨酸残基以外的氨基酸残基。
优选地，本发明提供编码包含以下各项的猪流行性腹泻病毒(PEDV)刺突(S)蛋白的核酸分子：
a)氨基酸序列RSXIEDLA(SEQ ID NO:23)，且其中R是该PEDV S蛋白的S1/S2裂解位点的保守精氨酸残基且X可为任一氨基酸残基，或
b)氨基酸序列RSXIEDAL(SEQ ID NO:24)，且其中R是该PEDV S蛋白的S1/S2裂解位点的保守精氨酸残基且X可为任一氨基酸残基，或
c)氨基酸序列RSXIEDAA(SEQ ID NO:25)，且其中R是该PEDV S蛋白的S1/S2裂解位点的保守精氨酸残基且X可为任一氨基酸残基。
如本发明的上下文中所阐述，术语“经遗传编码的氨基酸残基”尤其是指选自由以下组成的组的氨基酸残基(括号中的单字母代码)：丙氨酸残基(A)、半胱氨酸残基(C)、天冬氨酸盐残基(D)、谷氨酸盐残基(E)、苯丙氨酸残基(F)、甘氨酸残基(G)、组氨酸残基(H)、异亮氨酸残基(I)、赖氨酸残基(K)、亮氨酸残基(L)、甲硫氨酸残基(M)、天冬酰胺残基(N)、脯氨酸残基(P)、谷氨酰氨残基(Q)、精氨酸残基(R)、丝氨酸残基(S)、苏氨酸残基(T)、缬氨酸残基(V)、色氨酸残基(W)及酪氨酸残基(Y)。
此外，本发明提供编码选自由以下(a)及(b)组成的组的猪流行性腹泻病毒(PEDV)刺突(S)蛋白的核酸分子：
(a)具有至少一个突变的基因型2a(G2a)PEDV S蛋白，其中
-氨基酸位置900处的亮氨酸残基由除亮氨酸残基以外的氨基酸残基取代，和/或
-氨基酸位置901处的亮氨酸残基由除亮氨酸残基以外的氨基酸残基取代，
其中氨基酸位置的编号参考SEQ ID NO:2或SEQ ID NO:39的野生型G2a PEDV S蛋白的氨基酸序列。
(b)具有至少一个突变的基因型2b(G2b)PEDV S，其中
-氨基酸位置897处的亮氨酸残基由除亮氨酸残基以外的氨基酸残基取代，和/或
-氨基酸位置898处的亮氨酸残基由除亮氨酸残基以外的氨基酸残基取代，
其中氨基酸位置的编号参考SEQ ID NO:3的野生型G2b PEDV S蛋白的氨基酸序列。
因此，本发明提供编码选自由以下(a)及(b)组成的组的猪流行性腹泻病毒(PEDV)刺突(S)蛋白的核酸分子：
(a)具有至少一个突变的基因型2a(G2a)PEDV S蛋白，其中
-氨基酸位置900处的亮氨酸残基由除亮氨酸残基以外的氨基酸残基取代且氨基酸位置901处的残基是亮氨酸残基，或
-氨基酸位置900处的残基是亮氨酸残基且氨基酸位置901处的残基由除亮氨酸残基以外的氨基酸残基取代，或
-氨基酸位置900及901处的残基由除亮氨酸残基以外的氨基酸残基取代，
其中氨基酸位置的编号参考SEQ ID NO:2或SEQ ID NO:39的野生型G2a PEDV S蛋白的氨基酸序列；
(b)具有至少一个突变的基因型2b(G2b)PEDV S，其中
-氨基酸位置897处的亮氨酸残基由除亮氨酸残基以外的氨基酸残基取代且氨基酸位置898处的残基是亮氨酸残基，或
-氨基酸位置897处的残基是亮氨酸残基且氨基酸位置898处的亮氨酸残基由除亮氨酸残基以外的氨基酸残基取代，或
-氨基酸位置897及898处的残基由除亮氨酸残基以外的氨基酸残基取代，
其中氨基酸位置的编号参考SEQ ID NO:3的野生型G2b PEDV S蛋白的氨基酸序列。
如本文所阐述，分别地，措辞“氨基酸位置900及901处的残基由除亮氨酸残基以外的氨基酸残基取代”等同于“氨基酸位置900及901处的残基各自由除亮氨酸残基以外的氨基酸残基取代”，且措辞“氨基酸位置897及898处的残基由除亮氨酸残基以外的氨基酸残基取代”等同于“氨基酸位置897及898处的残基各自由除亮氨酸残基以外的氨基酸残基取代”。
应进一步理解，在PEDV的情形中，术语“基因群”等同于如在文献中经常使用的术语“基因型”。术语“基因型2a(G2a)”及“基因型2b(G2b)”为本领域技术人员所熟知。通过对S基因的系统发生研究，可在遗传上将PEDV分成2个群组：基因群1(G1；经典)及基因群2(G2；现场流行或大流行的)。该等基因群中的每一者可进一步分成亚群(1a及1b；2a及2b)。G2包含全球现场分离株，其进一步聚集成分别造成先前亚洲的局部流行性爆发及最近北美洲及亚洲的大流行爆发的2a及2b亚群。
术语“其中氨基酸位置的编号参考SEQ ID NO:2或SEQ ID NO:39的野生型G2aPEDV S蛋白的氨基酸序列”及“其中氨基酸位置的编号参考SEQ ID NO:3的野生型G2b PEDVS蛋白的氨基酸序列”必须理解为氨基酸位置的编号分别参考全长野生型G2a PEDV S蛋白(SEQ ID NO:2或SEQ ID NO:39)及野生型G2b PEDV S蛋白(SEQ ID NO:3)的氨基酸序列。因此，本文所提及氨基酸位置的编号是关于野生型G2a PEDV S蛋白及野生型G2b PEDV S蛋白序列，其分别具有1388或1386个或1383个氨基酸残基，包括(N末端)氨基酸位置1处的甲硫氨酸残基。因此，如本发明的上下文中所使用的编号是关于天然G2a PEDV S蛋白及野生型G2b PEDV S蛋白的序列，分别如SEQ ID NO:2或SEQ ID NO:39及SEQ ID NO:3中所示。换言之，若例示性地参照位置900处的氨基酸或残基，则氨基酸残基意指分别对应于SEQ ID NO:2或SEQ ID NO:39的氨基酸900的氨基酸残基。然而，此并不意味着本发明的刺突蛋白具有分别与SEQ ID NO:2或SEQ ID NO:39相同的氨基酸序列。其仅是说，如明确所提及，本发明的刺突蛋白的相应氨基酸编码氨基酸残基。
在本发明的核酸分子的另一具体方面中，除亮氨酸残基以外的该氨基酸残基选自以下组成：丙氨酸残基、甘氨酸残基、异亮氨酸残基、甲硫氨酸残基及缬氨酸残基。
在本发明的核酸分子的另一具体方面中，除亮氨酸残基以外的该氨基酸残基是选自由丙氨酸残基或甘氨酸残基组成的组。因此，本发明尤其提供编码包含以下各项的猪流行性腹泻病毒(PEDV)刺突(S)蛋白的核酸分子：
a)氨基酸序列RSXIEDLA(SEQ ID NO:23)，或
b)氨基酸序列RSXIEDAL(SEQ ID NO:24)，或
c)氨基酸序列RSXIEDAA(SEQ ID NO:25)，或
d)氨基酸序列RSXIEDLG(SEQ ID NO:31)，或
e)氨基酸序列RSXIEDGL(SEQ ID NO:32)，或
f)氨基酸序列RSXIEDGG(SEQ ID NO:33)，或
g)氨基酸序列RSXIEDGA(SEQ ID NO:34)，或
h)氨基酸序列RSXIEDAG(SEQ ID NO:35)，
且其中R是该PEDV S蛋白的S1/S2裂解位点的保守精氨酸残基且X可为任一氨基酸残基。
在本发明的核酸分子的另一具体方面中，除亮氨酸残基以外的该氨基酸残基是丙氨酸残基。
在本发明的核酸分子的另一具体方面中，氨基酸位置的编号参考野生型G PEDV S蛋白的氨基酸序列RSXIEDLLF(SEQ ID NO:4)，其中R是S1/S2裂解位点的保守精氨酸残基且LL是在基因型2a(G2a)PEDV S内的氨基酸位置900及901或LL是在基因型2b(G2b)PEDV S内的氨基酸位置897及898。
在本发明的核酸分子的另一具体方面中，该PEDV S蛋白包含氨基酸序列RSXIEDAAF(SEQ ID NO:5)，其中R是该PEDV S蛋白的S1/S2裂解位点的保守精氨酸残基且AA是在基因型2a(G2a)PEDV S内的氨基酸位置900及901或AA是在基因型2b(G2b)PEDV S内的氨基酸位置897及898。
在本发明的核酸分子的另一具体方面中，该PEDV S蛋白进一步包含氨基酸序列
X1X2X3FX4KX5X6X7X8(SEQ ID NO:6)，
其中X8是该PEDV S蛋白的C末端氨基酸残基或是相对于该PEDV S蛋白的C末端氨基酸位置在-2位置处的氨基酸残基，
X2至X5、X7及X8可为任一氨基酸残基，
且其中
(i)X1是除酪氨酸残基以外的氨基酸残基且X6是组氨酸残基，或
(ii)X1是酪氨酸残基且X6是除组氨酸残基以外的氨基酸残基，或
(iii)X1是除酪氨酸残基以外的氨基酸残基且X6是除组氨酸残基以外的氨基酸残基。
优选地，在本发明的上下文中，若该PEDV S蛋白是基因型2b(G2b)PEDV S蛋白，则X8是该PEDV S蛋白的C末端氨基酸残基，或若该PEDV S蛋白是基因型2a(G2a)PEDV S蛋白，则X8是相对于该PEDV S蛋白的C末端氨基酸位置在-2位置处的氨基酸残基。术语“相对于该PEDV S蛋白的C末端氨基酸位置在-2位置处的氨基酸残基”应理解为尤其等同于“在氨基酸位置n-2处的氨基酸残基，其中n是该PEDV S蛋白的C末端氨基酸残基的氨基酸位置”。因此，举例而言，若PEDV蛋白(例如作为基因型2a(G2a)PEDV S蛋白)具有长度为1388个氨基酸残基的氨基酸序列，则相对于该PEDV S蛋白的C末端氨基酸位置在-2位置处的氨基酸残基是分别在该PEDV蛋白或该基因型2a(G2a)PEDV S蛋白的氨基酸位置1386处的氨基酸残基。此外，如本文所阐述，应尤其理解，措辞“X2至X5、X7及X8可为任一氨基酸残基”等同于“X2至X5、X7及X8中的每一者可为任一氨基酸残基”。同样，应尤其理解，分别地，措辞“X2、X3、X4、X5、X6、X7可为任一氨基酸残基”等同于“X2、X3、X4、X5、X6及X7中的每一者可为任一氨基酸残基”、“X1、X2、X3、X4、X6、X7可为任一氨基酸残基”等同于“X1、X2、X3、X4、X6及X7中的每一者可为任一氨基酸残基”，且“X2、X3、X4、X5、X7、X8可为任一氨基酸残基”等同于“X2、X3、X4、X5、X7及X8中的每一者可为任一氨基酸残基”。
有利地，刺突蛋白的保留信号内针对X1X2X3FX4KX5X6X7X8(SEQ ID NO:6)的该修饰使得刺突蛋白定位至质膜中。
此外，该等修饰改良PEDV疫苗的生产方法。此具体而言是指重组载体的稳定性，且另外由于经由所阐述突变防止PEDV刺突蛋白的生物活性，因此可容许重组载体以更高的效价在生产细胞系中生长。
此外，本发明提供编码包含以下氨基酸序列的猪流行性腹泻病毒(PEDV)刺突(S)蛋白的核酸分子
X1X2X3FX4KX5X6X7X8(SEQ ID NO:6)，
其中X8是该PEDV S蛋白的C末端氨基酸残基或是相对于该PEDV S蛋白的C末端氨基酸位置在-2位置处的氨基酸残基，
X2至X5、X7及X8可为任一氨基酸残基，且其中
(i)X1是除酪氨酸残基以外的氨基酸残基且X6是组氨酸残基，或
(ii)X1是酪氨酸残基且X6是除组氨酸残基以外的氨基酸残基，或
(iii)X1是除酪氨酸残基以外的氨基酸残基且X6是除组氨酸残基以外的氨基酸残基，
且其中
-若该PEDV S蛋白是基因型2b(G2b)PEDV S蛋白，则X7优选为该PEDV S蛋白的C末端氨基酸残基，或
-若该PEDV S蛋白是基因型2a(G2a)PEDV S蛋白，则X7优选为相对于该PEDV S蛋白的C末端氨基酸位置在-2位置处的氨基酸残基。
在本发明的核酸分子的另一具体方面中，该PEDV S蛋白进一步包含：
a)氨基酸序列X1X2X3FX4KX5HX6X7(SEQ ID NO:26)，其中X7是该PEDV S蛋白的C末端氨基酸残基或是相对于该PEDV S蛋白的C末端氨基酸位置在-2位置处的氨基酸残基，X1是除酪氨酸残基以外的氨基酸残基且X2、X3、X4、X5、X6、X7可为任一氨基酸残基，
且其中
-若该PEDV S蛋白是基因型2b(G2b)PEDV S蛋白，则X7优选为该PEDV S蛋白的C末端氨基酸残基，或
-若该PEDV S蛋白是基因型2a(G2a)PEDV S蛋白，则X7优选为相对于该PEDV S蛋白的C末端氨基酸位置在-2位置处的氨基酸残基；
或
b)氨基酸序列YX1X2FX3KX4X5X6X7(SEQ ID NO:27)，其中X7是该PEDV S蛋白的C末端氨基酸残基或是相对于该PEDV S蛋白的C末端氨基酸位置在-2位置处的氨基酸残基，X5是除组氨酸残基以外的氨基酸残基且X1、X2、X3、X4、X6、X7可为任一氨基酸残基，
且其中
-若该PEDV S蛋白是基因型2b(G2b)PEDV S蛋白，则X7优选为该PEDV S蛋白的C末端氨基酸残基，或
-若该PEDV S蛋白是基因型2a(G2a)PEDV S蛋白，则X7优选为相对于该PEDV S蛋白的C末端氨基酸位置在-2位置处的氨基酸残基；
或
c)氨基酸序列X1X2X3FX4KX5X6X7X8(SEQ ID NO:6)，其中X8是该PEDV S蛋白的C末端氨基酸残基或是相对于该PEDV S蛋白的C末端氨基酸位置在-2位置处的氨基酸残基，X1是除酪氨酸残基以外的氨基酸残基且X6是除组氨酸残基以外的氨基酸残基且X2、X3、X4、X5、X7、X8可为任一氨基酸残基，
且其中
-若该PEDV S蛋白是基因型2b(G2b)PEDV S蛋白，则X8优选为该PEDV S蛋白的C末端氨基酸残基，或
-若该PEDV S蛋白是基因型2a(G2a)PEDV S蛋白，则X8优选为相对于该PEDV S蛋白的C末端氨基酸位置在-2位置处的氨基酸残基。
在本发明的核酸分子的另一具体方面中，该PEDV S蛋白进一步包含：
a)氨基酸序列AXXFXKXHXX-COOH(SEQ ID NO:28)，或
b)氨基酸序列YXXFXKXRXX-COOH(SEQ ID NO:29)，或
c)氨基酸序列AXXFXKXRXX-COOH(SEQ ID NO:30)，
其中X-COOH是该PEDV S蛋白的C末端氨基酸残基或是相对于该PEDV S蛋白的C末端氨基酸位置在-2位置处的氨基酸残基，且X可为任一氨基酸残基，
且其中
-若该PEDV S蛋白是基因型2b(G2b)PEDV S蛋白，则X-COOH优选为该PEDV S蛋白的C末端氨基酸残基，或
-若该PEDV S蛋白是基因型2a(G2a)PEDV S蛋白，则X-COOH优选为相对于该PEDV S蛋白的C末端氨基酸位置在-2位置处的氨基酸残基。
在本发明的核酸分子的另一具体方面中，
(a)在该G2a PEDV S蛋白中，此外
-氨基酸位置1377处的酪氨酸残基由除酪氨酸残基以外的氨基酸残基取代，和/或
-氨基酸位置1384处的组氨酸残基由除组氨酸残基以外的氨基酸残基取代，
或
(b)在该G2b PEDV S蛋白中，此外
-氨基酸位置1374处的酪氨酸残基由除酪氨酸残基以外的氨基酸残基取代，和/或
-氨基酸位置1381处的组氨酸残基由除组氨酸残基以外的氨基酸残基取代。
如上文所定义，本发明的上下文中所使用的编号是关于天然G2a PEDV S蛋白及野生型G2b PEDV S蛋白的序列，分别如SEQ ID NO:2或SEQ ID NO:39及SEQ ID NO:3中所示。
在本发明的核酸分子的另一具体方面中，
(a)在该G2a PEDV S蛋白中，此外
-氨基酸位置1377处的酪氨酸残基由除酪氨酸残基以外的氨基酸残基取代且氨基酸位置1384处的残基是组氨酸残基，或
-氨基酸位置1377处的氨基酸残基是酪氨酸残基且氨基酸位置1384处的组氨酸残基由除组氨酸残基以外的氨基酸残基取代，或
-氨基酸位置1377处的酪氨酸残基由除酪氨酸残基以外的氨基酸残基取代且氨基酸位置1384处的组氨酸残基由除组氨酸残基以外的氨基酸残基取代，
或
(b)在该G2b PEDV S蛋白中，此外
-氨基酸位置1374处的酪氨酸残基由除酪氨酸残基以外的氨基酸残基取代且氨基酸位置1381处的残基是组氨酸残基，或
-氨基酸位置1374处的残基是酪氨酸残基且氨基酸位置1381处的组氨酸残基由除组氨酸残基以外的氨基酸残基取代，或
-氨基酸位置1374处的酪氨酸残基由除酪氨酸残基以外的氨基酸残基取代且氨基酸位置1381处的组氨酸残基由除组氨酸残基以外的氨基酸残基取代。
在本发明的核酸分子的另一具体方面中，
-除酪氨酸残基以外的该氨基酸残基选自以下组成：丙氨酸残基、甘氨酸残基、亮氨酸残基、异亮氨酸残基、甲硫氨酸残基及缬氨酸残基，和/或
-除组氨酸残基以外的该氨基酸残基是精氨酸残基。
在本发明的核酸分子的另一具体方面中，
-除酪氨酸残基以外的该氨基酸残基是丙氨酸残基，和/或
-除组氨酸残基以外的该氨基酸残基是精氨酸残基。
在本发明的核酸分子的另一具体方面中，氨基酸位置的编号参考野生型G PEDV S蛋白的氨基酸序列YXXFXKXH(SEQ ID NO:7)，其中Y及H是在基因型2a(G2a)PEDV S蛋白内的氨基酸位置1377及1384，或Y及H是在基因型2b(G2b)PEDV S蛋白内的氨基酸位置1374及1381。
在本发明的核酸分子的另一具体方面中，核酸分子包含编码氨基酸序列AXXFXKXR(SEQ ID NO:8)的序列，其中A及R是在基因型2a(G2a)PEDV S蛋白内的氨基酸位置1377及1384或A及R是在基因型2b(G2b)PEDV S蛋白内的氨基酸位置1374及1381。
在本发明的核酸分子的另一具体方面中，该PEDV S蛋白：
(i)(a)包含与SEQ ID NO:15、16、17、18、19、20、40中任一者的氨基酸序列具有至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、至少99％、至少99.1％、至少99.2％、至少99.3％、至少99.4％、至少99.5％、至少99.6％、至少99.7％、至少99.8％或至少99.9％序列相同性的氨基酸序列或由其组成，或
(b)包含与SEQ ID NO:9、10、11、12、13、14中任一者的氨基酸序列具有至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、至少99％、至少99.1％、至少99.2％、至少99.3％、至少99.4％、至少99.5％、至少99.6％、至少99.7％、至少99.8％或至少99.9％序列相同性的氨基酸序列或由其组成；和/或
(ii)(a)由编码与SEQ ID NO:15、16、17、18、19、20、40中任一者的氨基酸序列具有至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、至少99％、至少99.1％、至少99.2％、至少99.3％、至少99.4％、至少99.5％、至少99.6％、至少99.7％、至少99.8％或至少99.9％序列相同性的氨基酸序列的核苷酸序列编码，或
(b)由编码与SEQ ID NO:9、10、11、12、13、14中任一者的氨基酸序列具有至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、至少99％、至少99.1％、至少99.2％、至少99.3％、至少99.4％、至少99.5％、至少99.6％、至少99.7％、至少99.8％或至少99.9％序列相同性的氨基酸序列的核苷酸序列编码。
术语“相同性”或“序列相同性”为业内所已知，且是指两个或更多个多肽序列或两个或更多个多核苷酸序列之间的关系，即参考序列与欲与该参考序列进行比较的给定序列之间的关系。通过将序列最优选地比对以产生最高序列相似性程度之后比较给定序列与参考序列来确定序列相同性，如通过此等序列串之间的匹配所确定。在此比对后，在位置对位置(position-by-position)基础上确定序列相同性，例如，若在一特定位置处核苷酸或氨基酸残基是相同的，则序列在该位置是“相同”的。然后将此等位置相同性的总数除以参考序列中的核苷酸或残基的总数以得到序列相同性％。序列相同性可轻易地通过已知方法来计算，该等方法包括(但不限于)阐述于以下文献中的那些：Computational MolecularBiology,Lesk,A.N.编辑，Oxford University Press,New York(1988)；Biocomputing:Informatics and Genome Projects,Smith,D.W.编辑，Academic Press,New York(1993)；Computer Analysis of Sequence Data，第I部分，Griffin,A.M.及Griffin,H.G.编辑，Humana Press,New Jersey(1994)；Sequence Analysis in Molecular Biology,vonHeinge,G.,Academic Press(1987)；Sequence Analysis Primer,Gribskov,M.及Devereux,J.编辑，M.Stockton Press,New York(1991)；以及Carillo,H.及Lipman,D.,SIAM J.Applied Math.,48:1073(1988)，其教示是以引用的方式并入本文中。设计用于确定序列相同性的优选方法以得到所测试序列之间的最大匹配。将确定序列相同性的方法编成确定给定序列之间的序列相同性的可公开获得的计算机程序。此等程序的实例包括(但不限于)GCG程序包(Devereux,J.等人，Nucleic Acids Research,12(1):387(1984))、BLASTP、BLASTN及FASTA(Altschul,S.F.等人，J.Molec.Biol.,215:403-410(1990)。该BLASTX程序可自NCBI及其他来源公开获得(BLAST Manual,Altschul,S.等人，NCVI NLMNIH Bethesda,MD 20894；Altschul,S.F.等人，J.Molec.Biol.,215:403-410(1990)，其教示是以引用的方式并入本文中)。该等程序最优选地使用默认空位权重比对序列以在给定序列与参考序列之间产生最高序列相同性程度。作为说明，对于多核苷酸具有与参考核苷酸序列具有至少(例如)85％、优选地90％、甚至更优选地95％“序列相同性”的核苷酸序列而言，预计给定多核苷酸的核苷酸序列与参考序列相同，除给定多核苷酸序列可包括最多15个、优选地最多10个、甚至更优选地最多5个点突变/参考核苷酸序列的100个核苷酸。换言之，在具有相对于参考核苷酸序列具有至少85％、优选地90％、甚至更优选地95％相同性的核苷酸序列的多核苷酸中，参考序列中最多15％、优选地10％、甚至更优选地5％的核苷酸可缺失或经另一核苷酸取代，或该参考序列中核苷酸总数的最多15％、优选地10％、甚至更优选地5％数量的核苷酸可插入至该参考序列中。参考序列的该等突变可发生在参考核苷酸序列的5’或3’末端位置或在那些末端位置之间的任何位置，其是个别地散布在参考序列中的各核苷酸之间或在参考序列内呈一或多个邻接基团形式。类似地，对于多肽具有与参考氨基酸序列具有至少(例如)85％、优选地90％、甚至更优选地95％序列相同性的给定氨基酸序列而言，预计多肽的给定氨基酸序列与参考序列相同，除给定多肽序列可包含最多15个、优选地最多10个、甚至更优选地最多5个氨基酸改变/参考氨基酸序列的100个氨基酸。换言之，为获得与参考氨基酸序列具有至少85％、优选地90％、甚至更优选地95％序列相同性的给定多肽序列，该参考序列中最多15％、优选地最多10％、甚至更优选地最多5％的氨基酸残基可缺失或经另一氨基酸取代，或该参考序列中氨基酸残基总数的最多15％、优选地最多10％、甚至更优选地最多5％数量的氨基酸可插入至该参考序列中。参考序列的该等改变可发生在参考氨基酸序列的氨基或羧基末端位置或在那些末端位置之间的任何位置，其是个别地散布在参考序列中的各残基之间或在参考序列内呈一或多个邻接基团形式。优选地，不同残基位置因保守氨基酸取代而不同。然而，当确定序列相同性时，保守取代并不作为匹配包括在内。
术语“相同性”、“序列相同性”及“相同性百分比”在本文中可互换使用。出于本发明的目的，本文定义，为确定两个氨基酸序列或两个核酸序列的相同性百分比，出于最优选对比目的对该等序列进行比对(例如，可将空位引入第一氨基酸或核酸的序列中以获得与第二氨基酸或核酸序列的最优选比对)。然后比较相应氨基酸或核苷酸位置处的氨基酸或核苷酸残基。在第一序列中的位置被与第二序列中的相应位置相同的氨基酸或核苷酸残基占据时，则该等分子在该位置相同。两个序列之间的相同性百分比是该等序列所共有的相同位置数的函数(即，相同性％＝相同位置数/总位置数(即重迭位置)×100)。优选地，两个序列具有相同长度。
可在两个所比较序列的整个长度内或在两个序列的片段内实施序列对比。通常，将在两个所比较序列的全长内实施对比。然而，可在(例如)20个、50个、100个或更多个邻接氨基酸残基的区域内实施序列相同性确定。
本领域技术人员应知晓，实际上，可利用不同计算机程序来确定两个序列之间的同源性。举例而言，可使用数学算法来完成两个序列之间的序列对比及相同性百分比的确定。在优选实施例中，使用Needleman及Wunsch(J.Mol.Biol.(48):444-453(1970))算法(其已纳入至Accelrys GCG软件包(可在http://www.accelrys.com/products/gcg/获得)中的GAP程序中)，使用Blosum 62矩阵或PAM250矩阵及16、14、12、10、8、6或4的空位权重以及1、2、3、4、5或6的长度权重)来确定两个氨基酸或核酸序列之间的相同性百分比。本领域技术人员应了解，所有该等不同参数将产生略微不同的结果，但在使用不同算法时两个序列的总体相同性百分比并不显著改变。
本发明的蛋白质序列或核酸序列可进一步用作“询问序列”来实施针对公共数据库的检索，以(例如)鉴别其他家族成员或相关序列。可使用Altschul等人(1990)J.Mol.Biol.215:403-10的BLASTN及BLASTP程序(2.0版)来实施此等检索。可利用BLASTP程序、评分＝50、字长＝3来实施BLAST蛋白质检索以获得与本发明的蛋白质分子同源的氨基酸序列。为获得用于对比目的的空位比对，可如Altschul等人(1997)Nucleic AcidsRes.25(17):3389-3402中所阐述来利用空位BLAST。在利用BLAST及空位BLAST程序时，可使用各别程序(例如BLASTP及BLASTN)的预设参数。参见国家生物技术信息中心(NationalCenter for Biotechnology Information)的主页http://www.ncbi.nlm.nih.gov/。
如本文所使用，应尤其理解，术语“与SEQ ID NO:Y的序列相同”分别等同于术语“在SEQ ID NO:Y的长度内与SEQ ID NO:Y的序列相同”或术语“在SEQ ID NO:Y的全长内与SEQ ID NO:Y的序列相同”。在此情形中，“Y”是选自1至40的任一整数，从而使得“SEQ IDNO:Y”代表本文所提及SEQ ID NO中的任一者。
在本发明的核酸分子的另一具体方面中，该PEDV S蛋白
(a)包含SEQ ID NO:15、16、17、18、19、20、40中任一者的氨基酸序列，或
(b)包含SEQ ID NO:9、10、11、12、13、14中任一者的氨基酸序列。
在例示性及非限制性实例中，本发明的核酸分子包含选自由以下组成的组的核苷酸序列：SEQ ID NO:36、SEQ ID NO:37及SEQ ID NO:38。
此外，本发明提供由如本文所阐述的核酸分子编码的PEDV(S)蛋白。
在本发明的核酸分子或PEDV S蛋白的另一具体方面中，编码PEDV S蛋白的该核酸分子或PEDV S蛋白是重组的。
如本文所使用的术语“重组”是指具有在相应多核苷酸或多肽中不会天然发生的任何修饰的多核苷酸(包括DNA分子、RNA分子、cDNA分子或衍生物)或多肽(或蛋白质)。举例而言，若多核苷酸或多肽含有人工引入(例如通过人为干预)的插入、缺失、倒位、复位位或点突变，则认为其是“重组”的。因此，多核苷酸或多肽不与其在自然界中相关联的序列(多核苷酸或多肽)的全部或一部分相关联。如关于病毒所使用的术语“重组”意指通过人工操纵病毒基因组所产生的病毒。术语“重组病毒”涵盖经遗传修饰的病毒。
优选地，本发明的蛋白质是非天然蛋白质。
优选地，该蛋白质是经分离多肽。
此外，本发明提供包含如本文所阐述核酸分子的多核苷酸。
本文所阐述核酸分子及多核苷酸的产生为本领域技术人员所熟知，且可根据Sambrook等人，2001,Molecular Cloning,A Laboratory Manual,Cold Spring HarborLaboratory Press,Cold Spring Harbor,NY；Amusable等人，2003,Current Protocols InMolecular Biology,Greene Publishing Associates&Wiley Interscience,NY；Innis等人(编辑)，1995,PCR Strategies,Academic Press,Inc.,San Diego；及Erlich(编辑)，1994,PCR Technology,Oxford University Press,New York以及其他地方中所阐述的重组技术来实施，所有该等文献均是以引用的方式并入本文中。
此外，本发明提供包含如本文所阐述的核酸分子或如本文所阐述的多核苷酸的载体。
如业内所已知的术语“载体”是指用于将遗传物质传递至宿主细胞的多核苷酸构建体，通常为质粒或细菌人工染色体。载体可为(例如)细菌、病毒、噬菌体、细菌人工染色体、黏粒或质粒。如本文所使用的载体可由DNA或RNA构成或可含有DNA或RNA。在一些实施例中，载体是由DNA构成。在一些实施例中，载体是感染性病毒。此一病毒载体含有以携带外源基因的方式操纵的病毒基因组，该外源基因在细胞培养物或宿主动物中的病毒载体复制中均无作用。根据本揭示内容的具体方面，载体可用于各个方面，例如仅传递遗传物质、用于转染宿主细胞或生物体、用作疫苗(例如DNA疫苗)或用于基因表达目的。基因表达是阐述如通过称为基因的特定多核苷酸序列所指导在细胞中生物合成蛋白质的术语。在具体方面中，载体可为“表达载体”，其是在存在于适当环境中时能够指导由该载体携带的一或多个基因编码的蛋白质的表达的载体。
载体及制备和/或使用载体(或重组体)进行表达的方法可尤其通过以下各项中所揭示的方法或类似于该等方法来达成：美国专利第4,603,112号、第4,769,330号、第5,174,993号、第5,505,941号、第5,338,683号、第5,494,807号、第4,722,848号、第5,942,235号、第5,364,773号、第5,762,938号、第5,770,212号、第5,942,235号、第382,425号、PCT公开案WO 94/16716、WO 96/39491、WO 95/30018；Paoletti,“Applications of pox virusvectors to vaccination:An update”,PNAS USA 93:11349-11353，1996年10月；Moss,“Genetically engineered poxviruses for recombinant gene expression,vaccination,and safety”,PNAS USA 93:11341-11348，1996年10月；Smith等人，美国专利第4,745,051号(重组杆状病毒)；Richardson,C.D.(编辑)，Methods in MolecularBiology 39,“Baculovirus Expression Protocols”(1995 Humana Press Inc.)；Smith等人，“Production of Human Beta Interferon in Insect Cells Infected with aBaculovirus Expression Vector”,Molecular and Cellular Biology，1983年12月，第3卷，第12期，第2156-2165页；Pennock等人，“Strong and Regulated Expression ofEscherichia coli B-Galactosidase in Infect Cells with a Baculovirus vector”,Molecular and Cellular Biology，1984年3月，第4卷，第3期，第406页；EPA0 370 573；1986年10月16日提出申请的美国申请案第920,197号；欧洲专利公开案第265785号；美国专利第4,769,331号(重组疱疹病毒)；Roizman,“The function of herpes simplex virusgenes:A primer for genetic engineering of novel vectors”,PNAS USA 93:11307-11312，1996年10月；Andreansky等人，“The application of genetically engineeredherpes simplex viruses to the treatment of experimental brain tumors”,PNASUSA 93:11313-11318，1996年10月；Robertson等人，“Epstein-Barr virus vectors forgene delivery to B lymphocytes”,PNAS USA 93:11334-11340，1996年10月；Frolov等人，“Alphavirus-based expression vectors:Strategies and applications”,PNAS USA93:11371-11377，1996年10月；Kitson等人，J.Virol.65,3068-3075,1991；美国专利第5,591,439号、第5,552,143号；WO 98/00166；获准的美国申请案第08/675,556号及第08/675,566号，二者均于1996年7月3日提出申请(重组腺病毒)；Grunhaus等人，1992,“Adenovirusas cloning vectors”,Seminars in Virology(第3卷)，第237-52页，1993；Ballay等人，EMBO Journal，第4卷，第3861-65页；Graham,Tibtech 8,85-87，1990年4月；Prevec等人，J.Gen Virol.70,42434；PCT WO 91/11525；Felgner等人(1994),J.Biol.Chem.269,2550-2561,Science,259:1745-49,1993；及McClements等人，“Immunization with DNAvaccines encoding glycoprotein D or glycoprotein B,alone or in combination,induces protective immunity in animal models of herpes simplex virus-2disease”,PNAS USA 93:11414-11420，1996年10月；及美国专利第5,591,639号、第5,589,466号及第5,580,859号，以及WO 90/11092、WO93/19183、WO94/21797、WO95/11307、WO95/20660；Tang等人，Nature，及Furth等人，Analytical Biochemistry，其是关于DNA表达载体。亦参见WO 98/33510；Ju等人，Diabetologia,41:736-739,1998(慢病毒表达系统)；Sanford等人，美国专利第4,945,050号；Fischbach等人(Intracel)；WO 90/01543；Robinson等人，Seminars in Immunology，第9卷，第271-283页(1997)，(DNA载体系统)；Szoka等人，美国专利第4,394,448号(将DNA插入至活细胞中的方法)；McCormick等人，美国专利第5,677,178号(细胞病变病毒的用途)；及美国专利第5,928,913号(用于基因递送的载体)；以及本文所引用的其他文件。
优选地，该载体是病毒载体。
术语“病毒载体”阐述通过重组DNA技术操纵的经遗传修饰的病毒，该操纵方式使得其进入至宿主细胞中会产生特定生物活性，例如由载体携带的转基因的表达。在具体方面中，转基因是抗原。病毒载体在靶细胞、组织或生物体中可复制胜任或可不复制胜任。尤其应理解，如本文所使用的术语“病毒载体(viral vector)”等同于术语“病毒的载体(virus vector)”。
病毒载体的产生可使用业内所熟知的任何适宜遗传工程技术来完成，包括(但不限于)限制内核酸酶消化、连接、转化、质粒纯化、DNA测序、细胞培养物转染的标准技术，例如如Sambrook等人(Molecular Cloning:A Laboratory Manual.Cold Spring HarborLaboratory Press,N.Y.(1989))或K.Maramorosch及H.Koprowski(Methods in Virology，第VIII卷，Academic Press Inc.London,UK(2014))中所阐述。
病毒载体可纳入来自任何已知生物体的基因组的序列。该等序列可以其天然形式纳入或可以任何方式经修饰以获得期望活性。举例而言，该等序列可包含插入、缺失或取代。
在本发明载体的具体方面中，载体是CDV(犬瘟热病毒)、EHV(马疱疹病毒)或羊口疮(ORF)病毒(副痘病毒)、PRV(假狂犬病病毒)、CAV(犬腺病毒)、PCMV(猪巨细胞病毒)或BoHV-4(牛疱疹病毒-4)。
在本发明载体的具体方面中，载体是CDV或EHV。
此外，本发明提供免疫原性组合物，其包含编码如本文所阐述的PEDV S蛋白的核酸分子和/或如本文所阐述的PEDV S蛋白和/或如本文所阐述的载体。
术语“免疫原性组合物”是指包含至少一种在施用免疫原性组合物的宿主中引发免疫学反应的抗原的组合物。此免疫学反应可为对本发明的免疫原性组合物的细胞和/或抗体调介的免疫反应。优选地，免疫原性组合物诱导免疫反应，且更优选地赋予抵抗PEDV感染的一或多种临床征象的保护性免疫。宿主亦阐述为“个体”。优选地，本文所阐述或提及的任一宿主或个体是仔猪、猪或母猪。
通常，“免疫学反应”包括(但不限于)以下效应中的一或多者：产生或活化特异性地针对本发明的免疫原性组合物中所包括的一或多种抗原的抗体、B细胞、辅助性T细胞、抑制性T细胞和/或细胞毒性T细胞和/或γ-δT细胞。优选地，宿主将显示保护性免疫学反应或治疗性反应。
“保护性免疫学反应”或“保护性免疫”将由以下展现：受感染宿主所通常显示的临床征象减少或缺乏、较快恢复时间和/或感染性的持续时间降低或受感染宿主的组织或体液或排泄物中的病原体效价降低。
倘若宿主显示保护性免疫学反应，使得对新感染的抗性将增强和/或疾病的临床严重程度降低，则将免疫原性组合物阐述为“疫苗”。
在本发明的免疫原性组合物的另一具体方面中，免疫原性组合物进一步包含医药上可接受的载剂。
术语“医药上可接受的载剂”包括任何及全部溶剂、分散介质、包衣剂、稳定剂、稀释剂、防腐剂、抗细菌及抗真菌剂、等渗剂、吸附延迟剂、佐剂、免疫刺激剂及其组合。
“稀释剂”可包括水、盐水、右旋糖、乙醇、甘油及诸如此类。等渗剂可包括氯化钠、右旋糖、甘露醇、山梨醇及乳糖等。稳定剂包括白蛋白及乙二胺四乙酸的碱金属盐等。
在本发明的一个方面中，医药上可接受的载剂是磷酸盐缓冲盐水。
优选地，免疫原性组合物进一步包含蔗糖明胶稳定剂。
在本发明的一个方面中，医药上可接受的载剂是几丁聚糖。
几丁聚糖是来自甲壳类动物(例如虾、螃蟹)、昆虫及其他无脊椎动物中的几丁质的天然去乙酰化多糖。最近，Rauw等人2009(Vet Immunol Immunop 134:249-258)展现，几丁聚糖增强新城疫(Newcastle disease)活疫苗的细胞免疫反应且提升其保护效应。此外，Wang等人，2012(Arch Virol(2012)157:1451-1461)所显示的结果揭示，几丁聚糖可作为佐剂用于流行性感冒减毒活疫苗中。
优选地，免疫原性组合物可进一步包括一或多种其他免疫调节剂，例如白介素、干扰素或其他细胞介素。可用于本发明情形中的佐剂及添加剂的量及浓度可由本领域技术人员容易地确定。
在一些方面中，本发明的免疫原性组合物含有佐剂。如本文所使用的“佐剂”可包括氢氧化铝及磷酸铝；皂苷，例如Quil A、QS-21(Cambridge Biotech Inc.,CambridgeMA)、GPI-0100(Galenica Pharmaceuticals,Inc.,Birmingham,AL)；油包水型乳液；水包油型乳液；水包油包水型乳液。乳液可尤其基于轻质液体石蜡油(欧洲药典类型(EuropeanPharmacopea type))；类异戊二烯油，例如角鲨烷或角鲨烯；源自烯烃(尤其异丁烯或癸烯)的寡聚的油；含有直链烷基的酸或醇的酯，更具体而言植物油、油酸乙酯、丙二醇二-(辛酸酯/癸酸酯)、三-(辛酸/癸酸)甘油基酯或丙二醇二油酸酯；具支链脂肪酸或醇的酯，尤其异硬脂酸酯。油与乳化剂组合使用以形成乳液。乳化剂优选是非离子型表面活性剂，特定而言为去水山梨醇、二缩甘露醇(例如无水甘露醇油酸酯)、二醇、聚甘油、丙二醇与油酸、异硬脂酸、蓖麻油酸或羟基硬脂酸的可选地经乙氧基化的酯，以及聚氧丙烯-聚氧乙烯共聚物嵌段，特定而言Pluronic产品，尤其L121。参见Hunter等人，The Theory and PracticalApplication of Adjuvants(Stewart-Tull,D.E.S.编辑),John Wiley and Sons,NY，第51-94页(1995)及Todd等人，Vaccine 15:564-570(1997)。例示性佐剂是阐述于M.Powell及M.Newman编辑的“Vaccine Design,The Subunit and Adjuvant Approach”,PlenumPress,1995的第147页上的SPT乳液及阐述于该同一本书第183页上的乳液MF59。
佐剂的另一实例是选自丙烯酸或甲基丙烯酸的聚合物及马来酸酐与烯基衍生物的共聚物的化合物。有利的佐剂化合物是丙烯酸或甲基丙烯酸的聚合物，其尤其与糖类或多元醇的聚烯基醚交联。该等化合物以术语卡波姆(carbomer)而为人所知(Pharmeuropa，第8卷，第2期，1996年6月)。本领域技术人员亦可参考美国专利第2,909,462号，其阐述与多羟基化化合物交联的此等丙烯酸是聚合物，该多羟基化化合物具有至少3个(优选不超过8个)羟基，至少3个羟基的氢原子由具有至少2个碳原子的不饱和脂肪族基团替代。优选基团是含有2个至4个碳原子的那些，例如乙烯基、烯丙基及其他烯是不饱和基团。不饱和基团自身可含有诸如甲基等其他取代基。以名称Carbopol(BF Goodrich,Ohio,USA)出售的产品尤其适合。其可与烯丙基蔗糖或与烯丙基异戊四醇交联。在该等中，可提及者是Carbopol974P、934P及971P。最优选使用Cabopol 971P。共聚物EMA(Monsanto)属马来酸酐与烯基衍生物的共聚物，其为马来酸酐与乙烯的共聚物。将该等聚合物溶解于水中会产生酸溶液，优选将其中和至生理pH以得到佐剂溶液，向该佐剂溶液中纳入免疫原性、免疫或疫苗组合物自身。
其他适宜佐剂包括(但不限于)RIBI佐剂系统(Ribi Inc.)、嵌段共聚物(CytRx,Atlanta GA)、SAF-M(Chiron,Emeryville CA)、单磷酰脂质A、阿夫立定(Avridine)脂质-胺佐剂、来自大肠杆菌(E.coli)(重组或其他方式)的不耐热肠毒素、霍乱毒素、IMS 1314或胞壁酰二肽、或天然或重组细胞介素或其类似物或者内源性细胞介素释放的刺激剂等。
预计佐剂可以每剂量约100μg至约10mg的量、优选地以每剂量约100μg至约10mg的量、更优选地以每剂量约500μg至约5mg的量、甚至更优选地以每剂量约750μg至约2.5mg的量且最优选地以每剂量约1mg的量添加。或者，以最终产物的体积计，佐剂的浓度可为约0.01％至50％，优选地浓度为约2％至30％，更优选地浓度为约5％至25％，仍更优选地浓度为约7％至22％，且最优选地浓度为10％至20％。
在本发明的免疫原性组合物的另一具体方面中，免疫原性组合物是疫苗。术语“疫苗”已在本文中别处进行阐述。然而，倘若宿主显示保护性免疫学反应，使得对新感染的抗性将增强和/或疾病的临床严重程度降低，则将免疫原性组合物阐述为“疫苗”。
此外，本发明提供包含如本文所阐述的核酸分子、如本文所阐述的多核苷酸或如本文所阐述的载体的细胞。
此外，本发明提供产生编码如本文所阐述的PEDV S蛋白的核酸分子和/或如本文所阐述的PEDV S蛋白的方法，其包含利用如本文所阐述的载体转染细胞。
此外，本发明提供制备用于治疗和/或预防个体的PEDV感染的免疫原性组合物的方法，其包含：
a.)利用如本文所阐述的载体感染细胞；
b.)获得该载体；及
c.)添加医药上可接受的载剂。
术语“获得”包含抗原的收获、分离、纯化和/或调配(例如修整(finishing)、灭活和/或掺和)。
术语“收获”是指自经转染细胞或细胞系收集或回收该载体。可使用业内已知的任一习用方法来回收该载体，例如任一分离方法。业内所熟知的方法包含离心或过滤，例如使用具有一定孔径的半渗透膜。
术语“分离”包含该载体的分离步骤。自受感染细胞或细胞系分离该载体的方法为本领域技术人员所已知。那些方法包含物理和/或化学方法，包括(但不限于)冷冻解冻循环、利用超音波处理及诸如此类。
用于自分离株“纯化”该载体的方法为本领域技术人员所已知，例如通过Proteinpurification methods-a practical approach(E.L.V.Harris及S.Angel编辑，IRLPress，Oxford University Press)中所阐述的那些方法来实施。那些方法包括(但不限于)通过离心和/或过滤、沉淀、粒径筛析(凝胶过滤)层析、亲和层析、金属螯合层析、离子交换层析、共价层析、疏水相互作用层析及诸如此类进行分离。载体可以经纯化的纯形式获得，或不含或实质上不含其他细胞物质或培养基等。在该分离和/或纯化后，抗原展现至少80％、优选地80％-90％、更优选地90％-97％、最优选地超过97％直至不含任何污染的绝对纯形式的纯度。
根据另一方面，如本文所使用的“获得”亦可包括其他修整步骤作为最终调配制程的一部分，如添加缓冲剂、灭活、中和步骤及诸如此类。
优选地，细胞系来自真核细胞系。
在本发明方法的具体方面中，细胞系Vero细胞、ST细胞或BHK-21、Ma104、MDBK、RK13、MDCK或PK15。
所提及的所有细胞系均为本领域技术人员所熟知且可公开获得。Vero细胞例示性地以登录号ATCC CCL-81保藏在美国组织培养物保藏中心(American Tissue CultureCollection)。ST细胞例示性地以登录号CRL-1746保藏在美国组织培养物保藏中心。BHK-21细胞例示性地以登录号ATCC CCL-10保藏在美国组织培养物保藏中心。MDCK细胞例示性地以登录号ATCC CCL-34或ATCC CRL-2285保藏在美国组织培养物保藏中心。
在本发明的免疫原性组合物或方法的另一具体方面中，该医药上可接受的载剂选自以下组成：溶剂、分散介质、包衣剂、稳定剂、稀释剂、防腐剂、抗细菌及抗真菌剂、等渗剂、吸附延迟剂、佐剂、免疫刺激剂及其组合。
此外，本发明提供对个体实施免疫的方法，其包含向此个体施用如本文所阐述的免疫原性组合物。
有利地，本发明的免疫原性组合物已证明是安全且有效的。
术语“实施免疫”是关于通过以下方式达成的主动免疫：向欲实施免疫的个体施用免疫原性组合物，由此引起针对此免疫原性组合物中所包括抗原的免疫学反应。
优选地，免疫使得畜群中特定PEDV感染的发病率减小或使得由特定PEDV感染引起或与其相关的临床征象的严重程度降低。
此外，利用如本文所提供的免疫原性组合物对有需要的个体实施免疫使得可预防由PEDV感染所致的个体感染。甚至更优选地，免疫产生有效、长效的抵抗PEDV感染的免疫学反应。应理解，该时间段将持续1个月以上、优选地2个月以上、优选地3个月以上、更优选地4个月以上、更优选地5个月以上、更优选地6个月以上。应理解，免疫不可能在实施免疫的所有个体中均有效。然而，该术语需要畜群中的大部分个体得以有效免疫。
优选地，在此上下文中设想通常(即未进行免疫)将发生通常由PEDV感染引起或与其相关的临床征象的个体畜群。本领域技术人员可易于确定畜群的个体是否有效地免疫。优选地，若与未实施免疫或利用可在本发明之前获得的免疫原性组合物实施免疫但随后感染特定PEDV的个体相比，给定畜群中至少33％、至少50％、至少60％、至少70％、至少80％、至少90％、仍更优选地至少95％、且最优选地100％的个体的临床征象的发病率或严重程度减小至少10％、更优选地至少20％、仍更优选地至少30％、甚至更优选地至少40％、仍更优选地至少50％、甚至更优选地至少60％、仍更优选地至少70％、甚至更优选地至少80％、仍更优选地至少90％、仍更优选地至少95％且最优选地100％，则免疫应是有效的。
此外，本发明提供治疗和/或预防有需要的个体中由PEDV感染引起的临床征象的方法，该方法包含向该个体施用治疗有效量的如本文所阐述的免疫原性组合物。
有利地，本发明的免疫原性组合物已证明减少由PEDV感染所引起的临床征象。
术语“治疗和/或预防”是指减小畜群中特定PEDV感染的发病率或降低由特定PEDV感染引起或与其相关的临床征象的严重程度。因此，术语“治疗和/或预防”亦是指与个体尚未接受如本文所提供的免疫原性组合物的一群个体相比，在个体已接受有效量的此免疫原性组合物的一群个体中，降低畜群中感染特定PEDV的个体数量(＝减小特定PEDV感染的发病率)或降低通常与PEDV感染相关或由其引起的临床征象的严重程度或降低感染特定PEDV后的病毒脱落或预防或降低感染特定PEDV后的腹泻。
“治疗和/或预防”通常涉及将有效量的本发明的免疫原性组合物施用给需要此一治疗/预防或可自其受益的个体或个体畜群。术语“治疗”是指在个体或畜群的至少一些个体已感染此PEDV且其中此等个体已显示出一些由此PEDV感染引起或与其相关的临床征象后，施用有效量的免疫原性组合物。术语“预防”是指在此个体经PEDV任何感染之前或至少在此个体未显示或个体群中没有个体显示由此PEDV感染引起或与其相关的任何临床征象之前，施用个体。术语“预防(prophylaxis及preventing)”在本申请案中可互换使用。
如本文所使用的术语“有效量”意指但不限于引发或能够引发个体中的免疫反应的抗原量。此有效量能够减小畜群中特定PEDV感染的发病率或降低特定PEDV感染的临床征象的严重程度。
优选地，与未经治疗或经可在本发明之前获得的免疫原性组合物治疗但随后感染特定PEDV的个体相比，临床征象的发病率或严重程度减小至少10％、更优选地至少20％、仍更优选地至少30％、甚至更优选地至少40％、仍更优选地至少50％、甚至更优选地至少60％、仍更优选地至少70％、甚至更优选地至少80％、仍更优选地至少90％、仍更优选地至少95％、且最优选地100％。
如本文所使用的术语“临床征象”是指个体中来自PEDV的感染征象。此等临床征象的实例包括(但不限于)病毒载量、腹泻、病毒脱落、体温升高、死亡、肠中的严重病理性病灶、抑郁症、体重减轻、生长速率降低及食欲下降。然而，临床征象亦包括(但不限于)可自活动物直接观察到的临床征象。可自活动物直接观察到的临床征象的实例包括体重减轻、生长速率降低、食欲下降、脱水、水泻腹泻、呕吐、跛行、嗜睡、消瘦及生长发育不良及诸如此类。
优选地，与未经未治疗或经可在本发明之前获得的免疫原性组合物治疗但随后感染特定PEDV的个体相比，经治疗个体中临床征象的发病率或严重程度减小是指体重减轻降低、病毒载量降低、腹泻减少、病毒脱落减少、直肠温度降低、死亡率降低、肠中的严重病理性病灶减少或其组合。
如本文所使用的术语“有需要(in need或of need)”意指，施用/治疗与加强或改良健康或临床征象或对于接受本发明的免疫原性组合物的个体的健康的任何其他正性医学效应相关。
此外，本发明提供与相同物种的非免疫对照组的个体相比减少个体腹泻的方法，该方法包含向该个体施用治疗有效量的如本文所阐述的免疫原性组合物。
此外，本发明提供与相同物种的非免疫对照组的个体相比降低个体死亡率的方法，该方法包含向该个体施用治疗有效量的如本文所阐述的免疫原性组合物。
术语“降低死亡率”意指与未经治疗(未实施免疫)但随后感染特定PEDV的个体相比，死亡率降低至少10％、更优选地至少20％、仍更优选地至少30％、甚至更优选地至少40％、仍更优选地至少50％、甚至更优选地至少60％、仍更优选地至少70％、甚至更优选地至少80％、甚至更优选地至少90％、仍更优选地至少95％、最优选地100％。
因此，必须理解，可利用本发明的免疫原性组合物对个体进行疫苗接种以减少或预防该个体中诸如腹泻或死亡等临床征象。优选地，该个体是仔猪、猪或母猪。
此外，本发明提供用于在个体中诱导产生对PEDV具有特异性的抗体的方法，其中该方法包含向该个体施用如本文所阐述的免疫原性组合物。优选地，该个体是仔猪、猪或母猪。
此外，本发明提供用于在母猪中诱导产生对PEDV具有特异性的抗体的方法，其中该方法包含向该母猪施用如本文所阐述的免疫原性组合物。
术语“对PEDV具有特异性的抗体”是指可检测到的抗PEDV抗体。此外，因应于利用本发明的PEDV疫苗进行疫苗接种，已开发出母猪中的抗PEDV抗体。术语“对PEDV具有特异性的抗体”或“母猪中对PEDV具有特异性的抗体”应进一步意指(但不限于)母猪具有优选地至少1:10、更优选地大于1:20、甚至更优选地大于1:40、甚至更优选地大于1:80、甚至更优选地1:160、甚至更优选地大于1:320且、最优选地大于1:640的可检测到的抗PEDV抗体效价。优选地，该抗PEDV抗体效价在特异性抗PEDV免疫分析中可检测到且可量化。
有利地，本发明的免疫原性组合物已显示在母猪中诱导产生对PEDV具有特异性的抗体。
本领域技术人员熟知如何检测对PEDV具有特异性的抗体的产生，例如通过ELISA分析(ELISA可商业购得)。
此外，本发明提供与非免疫对照组的仔猪相比减少仔猪腹泻的方法，该方法包含向该仔猪的母猪施用治疗有效量的如本文所阐述的免疫原性组合物，其中该仔猪是由该母猪进行哺乳。如本文所使用，术语“仔猪的母猪”应尤其理解为分别等同于“仔猪的生育母猪”或“仔猪的照护母猪”。
此外，本发明提供与非免疫对照组的仔猪相比降低仔猪死亡率的方法，该方法包含向该仔猪的母猪施用治疗有效量的如本文所阐述的免疫原性组合物，其中该仔猪是由该母猪进行哺乳。
此外，本发明提供减少或预防仔猪中因感染PEDV所引起的临床征象或疾病的方法，其中该仔猪是由经施用如本文所阐述的免疫原性组合物的母猪进行哺乳。
优选地，所降低的临床征象是死亡率。因此，本发明亦提供降低仔猪中因感染PEDV所引起的死亡率的方法，其中该仔猪是由经施用如本文所阐述的免疫原性组合物的母猪进行哺乳。
此外，本发明提供减少或预防仔猪中因感染PEDV所引起的临床征象或疾病的方法，其中该方法包含
-向母猪施用如本文所阐述的免疫原性组合物，及
-容许该仔猪由该母猪进行哺乳或分别地，容许该仔猪吮吸该母猪。
有利地，当向处于妊娠期的母猪施用时，本发明的免疫原性组合物已显示减少猪中的临床征象。
倘若利用本发明的免疫原性组合物对仔猪进行疫苗接种，则必须理解，在该仔猪中实际产生抗体需要时间。因此，在本发明方法的另一方面中，利用本发明的免疫原性组合物对怀孕的母猪进行疫苗接种。该疫苗接种使得在该母猪中产生对PEDV具有特异性的抗体。然后，来自该母猪的母源性抗体被动地经由初乳和/或乳汁转移至新生仔猪。
在本发明方法的另一具体方面中，施用免疫原性组合物的该母猪是怀孕母猪、尤其是怀有该仔猪的母猪。然而，应理解，仔猪可由产生初乳或乳汁的任一母猪进行哺乳，其中该母猪尤其是已施用该免疫原性组合物的母猪。
在另一具体方面中，本发明的方法包含以下步骤
-向怀有该仔猪的母猪施用如本文所阐述的免疫原性组合物，
-容许该母猪生下该仔猪，及
-容许该仔猪由该母猪进行哺乳。
在本发明方法的另一具体方面中，与相同物种的非免疫对照组的个体相比，该方法使得选自由以下组成的组的临床征象或效能参数改良：体重减轻降低、病毒载量降低、腹泻减少、病毒脱落减少、直肠温度降低、死亡率降低、肠中的严重病理性病灶减少或其组合。
在本发明方法的另一具体方面中，该个体是仔猪、猪或母猪。
优选地，在前两个月龄内、更优选地在第一月龄内向个体施用免疫原性组合物。
在本发明方法的另一具体方面中，在第一月龄内向个体施用免疫原性组合物。
因此，必须理解，可例示性地在前三周龄内或在前两周龄内向个体施用免疫原性组合物。
在本发明方法的另一具体方面中，向处于妊娠期及哺乳期的母猪施用该免疫原性组合物。
有利地，当向处于妊娠期的母猪施用时，本发明的免疫原性组合物已证明是安全的。
因此，提供针对PEDV对猪进行疫苗接种的方法，其是通过在分娩之前向怀孕母猪施用至少两次本发明的PEDV疫苗、优选地在分娩之前施用三次、更优选地在分娩之前施用两次(“重复剂量”)来实施。优选地，在分娩之前利用单一剂量的本发明的PEDV疫苗对怀孕母猪进行两次该疫苗的疫苗接种。然而，当向母猪施用两次疫苗时，第一次施用应发生在分娩之前的12周与4周之间、更优选地发生在分娩之前的9周与5周之间。第二次施用应发生在分娩之前的8周与1周之间、更优选地发生在分娩之前的6周与1周之间。
在本发明方法的另一具体方面中，以两个或更多个剂量施用免疫原性组合物。
有利地，本发明的免疫原性组合物在两个剂量后已显示诱导产生对PEDV具有特异性的抗体。
在本发明方法的另一具体方面中，向母猪施用两次该免疫原性组合物，第一次施用是在分娩之前的9周与5周之间且第二次施用是在分娩之前的6周与1周之间。
优选地，该免疫原性组合物是以局部或全身性施用。习用的适宜施用途径是经口或非经肠施用，例如鼻内、静脉内、肌内、腹膜内、皮下以及吸入。然而，取决于化合物的性质及作用模式，亦可通过其他途径施用该免疫原性组合物。然而，最优选地，该免疫原性组合物是鼻内或经口施用。
在本发明方法的另一具体方面中，该免疫原性组合物是经鼻内、经黏膜、经口、经皮内或肌内施用。
有利地，当以鼻内施用本发明的免疫原性组合物时，已证明其是有效的。
在本发明方法的另一具体方面中，该免疫原性组合物是经鼻内或经口施用。
优选地，该免疫原性组合物包含介于1×102至1×109之间的TCID50/ml、更优选地介于1×103至1×107之间的TCID50/ml且最优选地介于1×104至1×106之间的TCID50/ml。
在本发明方法的另一具体方面中，该免疫原性组合物包含介于1×103至1×107之间的TCID50/ml。
术语“TCID50/ml”是指感染性病毒效价的量度。具体而言，半数组织培养感染剂量/毫升(TCID50/ml)是指病毒制剂的如下稀释度：以该稀释度平行接种多个细胞培养物后有50％发生感染。
在本发明方法的另一具体方面中，该方法使得从攻击或感染后第2天病毒脱落(shedding)有所减少。
在本发明方法的另一具体方面中，该方法使得从攻击或感染后第3天病毒脱落有所减少。
在本发明方法的另一具体方面中，该方法使得从攻击或感染后第4天病毒脱落有所减少。
在本发明方法的另一具体方面中，该方法使得从攻击或感染后第5天病毒脱落有所减少。
在本发明方法的另一具体方面中，该方法使得从攻击或感染后第7天病毒脱落有所减少。
在本发明方法的另一具体方面中，该方法使得从攻击或感染后第10天病毒脱落有所减少。
在本发明方法的另一具体方面中，该方法使得从攻击或感染后第5天、第7天或第10天病毒脱落有所减少。
有利地，本发明的免疫原性组合物已证明减少感染或攻击后的病毒脱落。
术语“减少病毒脱落”意指与未经治疗(未实施免疫)但随后感染特定PEDV的个体相比，病毒脱落减少至少10％、更优选地至少20％、仍更优选地至少30％、甚至更优选地至少40％、仍更优选地至少50％、甚至更优选地至少60％、仍更优选地至少70％、甚至更优选地至少80％、甚至更优选地至少90％、仍更优选地至少95％、最优选地100％。本领域技术人员熟知如何量测病毒脱落。
术语“病毒脱落”是指在粪便排泄物或粪便中的PEDV分泌物。因此，脱落可通过检查粪便排泄物、粪便或直肠拭子中的病毒效价来测定。术语“病毒脱落”进一步涵盖病毒转移至易感动物中(即哨点(sentinels))。本领域技术人员熟知如何量测病毒脱落，例如通过PCR、qPCR或ELISA。
在本发明方法的另一具体方面中，该方法增加针对同源性攻击的保护。
有利地，本发明的免疫原性组合物已证明在攻击后具有保护性。
本发明提供如本文所阐述的编码猪流行性腹泻病毒(PEDV)刺突(S)蛋白的核酸分子、PEDV(S)蛋白或免疫原性组合物用于制造药剂的用途。
本发明亦提供如本文所阐述的编码猪流行性腹泻病毒(PEDV)刺突(S)蛋白的核酸分子、PEDV(S)蛋白或免疫原性组合物用于治疗和/或预防个体中由PEDV感染所引起的临床征象或减少个体腹泻的用途。
序列概述：
以下序列特此详细阐述并揭示于本发明中：
SEQ ID NO:1：RSXIEDXX，
SEQ ID NO:2：美国野生型G2a PEDV S氨基酸序列，
SEQ ID NO:3：欧洲野生型G2b PEDV S氨基酸序列，
SEQ ID NO:4：RSXIEDLLF，
SEQ ID NO:5：RSXIEDAAF，
SEQ ID NO:6：XXXFXKXXXX，
SEQ ID NO:7：YXXFXKXH，
SEQ ID NO:8：AXXFXKXR，
SEQ ID NO:9：具有突变897A的PEDV S欧洲品系基因型2b(G2b)序列，
SEQ ID NO:10：在氨基酸位置898处突变为A的PEDV S欧洲品系基因型2b(G2b)序列，
SEQ ID NO:11：具有突变897A及898A的PEDV S欧洲品系基因型2b(G2b)序列，
SEQ ID NO:12：具有突变897A及1374A以及1381R的PEDV S欧洲品系基因型2b(G2b)序列，
SEQ ID NO:13：具有突变898A及1374A以及1381R的PEDV S欧洲品系基因型2b(G2b)序列，
SEQ ID NO:14：具有突变897A、898A及1374A以及1381R的PEDV S欧洲品系基因型2b(G2b)序列，
SEQ ID NO:15：具有突变900A的PEDV S美国品系基因型2a(G2a)序列，
SEQ ID NO:16：在氨基酸位置901处突变为A的PEDV S美国品系基因型2a(G2a)序列，
SEQ ID NO:17：具有突变900A及901A的PEDV S美国品系基因型2a(G2a)序列，
SEQ ID NO:18：具有突变900A及1377A以及1384R的PEDV S美国品系基因型2a(G2a)序列，
SEQ ID NO:19：具有突变901A及1377A以及1384R的PEDV S美国品系基因型2a(G2a)序列，
SEQ ID NO:20：具有突变900A、901A及1377A以及1384R的PEDV S美国品系基因型2a(G2a)序列，
SEQ ID NO:21：RSXIEDLX，
SEQ ID NO:22：RSXIEDXL，
SEQ ID NO:23：RSXIEDLA，
SEQ ID NO:24：RSXIEDAL，
SEQ ID NO:25：RSXIEDAA，
SEQ ID NO:26：XXXFXKXHXX，
SEQ ID NO:27：YXXFXKXXXX，
SEQ ID NO:28：AXXFXKXHXX，
SEQ ID NO:29：YXXFXKXRXX，
SEQ ID NO:30：AXXFXKXRXX，
SEQ ID NO:31：RSXIEDLG，
SEQ ID NO:32：RSXIEDGL，
SEQ ID NO:33：RSXIEDGG，
SEQ ID NO:34：RSXIEDGA，
SEQ ID NO:35：RSXIEDAG，
SEQ ID NO:36包含PEDV刺突蛋白的克隆盒，包括插入基因的UTR区的复制，
SEQ ID NO:37(RNA)对应于编码SEQ ID NO:14的S蛋白的序列，
SEQ ID NO:38(RNA)对应于包含SEQ ID NO:37的序列，
SEQ ID NO:39：中国野生型G2a PEDV S氨基酸序列，
SEQ ID NO:40：具有突变900A、901A及1377A以及1384R的PEDV S中国品系基因型2a(G2a)序列，
SEQ ID NO:41-44：探针、引物及ultramer序列(表2)。
如同在序列表中，氨基酸序列是以三字母密码格式使用符号“Xaa”作为变量“X”的等效形式来呈现，尤其应理解，序列表中所提供的措辞“残基处的X”等同于“残基处的Xaa”。
方案
本文中阐述以下方案：
本发明提供以下方案：
1.一种核酸分子，其编码包含氨基酸序列RSX1IEDX2X3(SEQ ID NO:1)的猪流行性腹泻病毒(PEDV)刺突(S)蛋白，其中
(I)X2是除亮氨酸残基以外的氨基酸残基且X3是亮氨酸残基，或
(II)X2是亮氨酸残基且X3是除亮氨酸残基以外的氨基酸残基，或
(III)X2是除亮氨酸残基以外的氨基酸残基且X3是除亮氨酸残基以外的氨基酸残基。
2.如方案1的核酸分子，其包含氨基酸序列RSX1IEDX2X3(SEQ ID NO:1)，其中
-若PEDV S蛋白是基因型2a(G2a)PEDV S蛋白，则R是在氨基酸位置894处的精氨酸残基，且其中氨基酸位置的编号参考野生型G2a PEDV S蛋白的氨基酸序列，或
-若PEDV蛋白是基因型2b(G2b)PEDV S蛋白，则R是在氨基酸位置891处的精氨酸残基，且其中氨基酸位置的编号参考野生型G2b PEDV S蛋白的氨基酸序列。
3.如方案2的核酸分子，其中
-野生型G2a PEDV S蛋白的氨基酸序列是SEQ ID NO:2或SEQ ID NO:39的野生型G2a PEDV S蛋白的氨基酸序列，和/或
-野生型G2b PEDV S蛋白的氨基酸序列是SEQ ID NO:3的野生型G2b PEDV S蛋白的氨基酸序列。
4.一种核酸分子，其编码包含氨基酸序列RSX1IEDX2X3(SEQ ID NO:1)的猪流行性腹泻病毒(PEDV)刺突(S)蛋白，
其中R是该PEDV S蛋白的S1/S2裂解位点的保守精氨酸残基，X1可为任一氨基酸残基，且其中
(I)X2是除亮氨酸残基以外的氨基酸残基且X3是亮氨酸残基，或
(II)X2是亮氨酸残基且X3是除亮氨酸残基以外的氨基酸残基，或
(III)X2是除亮氨酸残基以外的氨基酸残基且X3是除亮氨酸残基以外的氨基酸残基。
5.一种核酸分子，其编码选自由以下(a)及(b)组成的组的猪流行性腹泻病毒(PEDV)刺突(S)蛋白：
(a)具有至少一个突变的基因型2a(G2a)PEDV S蛋白，其中
-氨基酸位置900处的亮氨酸残基由除亮氨酸残基以外的氨基酸残基取代，和/或
-氨基酸位置901处的亮氨酸残基由除亮氨酸残基以外的氨基酸残基取代，
其中氨基酸位置的编号参考SEQ ID NO:2或SEQ ID NO:39的野生型G2a PEDV S蛋白的氨基酸序列，
(b)具有至少一个突变的基因型2b(G2b)PEDV S，其中
-氨基酸位置897处的亮氨酸残基由除亮氨酸残基以外的氨基酸残基取代，和/或
-氨基酸位置898处的亮氨酸残基由除亮氨酸残基以外的氨基酸残基取代，
其中氨基酸位置的编号参考SEQ ID NO:3的野生型G2b PEDV S蛋白的氨基酸序列。
6.如方案1至5中任一方案的核酸分子，其中除亮氨酸残基以外的该氨基酸残基选自以下组成：丙氨酸残基、甘氨酸残基、异亮氨酸残基、甲硫氨酸残基及缬氨酸残基。
7.如方案1至6中任一方案的核酸分子，其中除亮氨酸残基以外的该氨基酸残基是丙氨酸残基。
8.如方案5至7中任一方案的核酸分子，其中氨基酸位置的编号参考野生型G PEDVS蛋白的氨基酸序列RSXIEDLLF(SEQ ID NO:4)，其中R是该PEDV S蛋白的S1/S2裂解位点的保守精氨酸残基且LL是在该基因型2a(G2a)PEDV S蛋白内的氨基酸位置900及901或LL是在该基因型2b(G2b)PEDV S蛋白内的氨基酸位置897及898。
9.如方案5至8中任一方案的核酸分子，其中氨基酸位置的编号参考野生型G PEDVS蛋白的氨基酸序列RSXIEDLLF(SEQ ID NO:4)，其中R是在氨基酸位置894处的精氨酸残基且LL是在该基因型2a(G2a)PEDV S蛋白内的氨基酸位置900及901，或R是在氨基酸位置891处的精氨酸残基且LL是在该基因型2b(G2b)PEDV S蛋白内的氨基酸位置897及898。
10.如方案1至9中任一方案的核酸分子，其中该PEDV S蛋白包含氨基酸序列RSXIEDAAF(SEQ ID NO:5)，其中R是该PEDV S蛋白的S1/S2裂解位点的保守精氨酸残基且AA是在该基因型2a(G2a)PEDV S蛋白内的氨基酸位置900及901或AA是在该基因型2b(G2b)PEDV S蛋白内的氨基酸位置897及898。
11.如方案1至10中任一方案的核酸分子，其中该PEDV S蛋白包含氨基酸序列RSXIEDAAF(SEQ ID NO:5)，其中R是在氨基酸位置894处的精氨酸残基且AA是在该基因型2a(G2a)PEDV S蛋白内的氨基酸位置900及901，或R是在氨基酸位置891处的精氨酸残基及AA是在该基因型2b(G2b)PEDV S蛋白内的氨基酸位置897及898。
12.如方案1至11中任一方案的核酸分子，其中该PEDV S蛋白进一步包含氨基酸序列X1X2X3FX4KX5X6X7X8(SEQ ID NO:6)，
其中X8是该PEDV S蛋白的C末端氨基酸残基或是相对于该PEDV S蛋白的C末端氨基酸位置在-2位置处的氨基酸残基，
X2至X5、X7及X8可为任一氨基酸残基，且其中
(i)X1是除酪氨酸残基以外的氨基酸残基且X6是组氨酸残基，或
(ii)X1是酪氨酸残基且X6是除组氨酸残基以外的氨基酸残基，或
(iii)X1是除酪氨酸残基以外的氨基酸残基且X6是除组氨酸残基以外的氨基酸残基。
13.如方案5至13中任一方案的核酸分子，其中
(a)在该G2a PEDV S蛋白中，此外
-氨基酸位置1377处的酪氨酸残基由除酪氨酸残基以外的氨基酸残基取代，和/或
-氨基酸位置1384处的组氨酸残基由除组氨酸残基以外的氨基酸残基取代，
或
(b)在该G2b PEDV S蛋白中，此外
-氨基酸位置1374处的酪氨酸残基由除酪氨酸残基以外的氨基酸残基取代，和/或
-氨基酸位置1381处的组氨酸残基由除组氨酸残基以外的氨基酸残基取代。
14.如方案12至13的核酸分子，其中
-除酪氨酸残基以外的该氨基酸残基选自以下组成：丙氨酸残基、甘氨酸残基、亮氨酸残基、异亮氨酸残基、甲硫氨酸残基及缬氨酸残基，和/或
-除组氨酸残基以外的该氨基酸残基是精氨酸残基。
15.如方案12至14中任一方案的核酸分子，其中
-除酪氨酸残基以外的该氨基酸残基是丙氨酸残基，和/或
-除组氨酸残基以外的该氨基酸残基是精氨酸残基。
16.如方案13至15中任一方案的核酸分子，其中氨基酸位置的编号参考野生型GPEDV S蛋白的氨基酸序列YXXFXKXH(SEQ ID NO:7)，其中Y及H是在该基因型2a(G2a)PEDV S蛋白内的氨基酸位置1377及1384或Y及H是在该基因型2b(G2b)PEDV S蛋白内的氨基酸位置1374及1381。
17.如方案12至16中任一方案的核酸分子，其中该核酸分子包含编码氨基酸序列AXXFXKXR(SEQ ID NO:8)的序列，其中A及R是在该基因型2a(G2a)PEDV S蛋白内的氨基酸位置1377及1384或A及R是在该基因型2b(G2b)PEDV S蛋白内的氨基酸位置1374及1381。
18.如方案1至17中任一方案的核酸分子，其中该PEDV S蛋白：
i)(a)包含与SEQ ID NO:15、16、17、18、19、20、40中任一者的氨基酸序列具有至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、至少99％、至少99.1％、至少99.2％、至少99.3％、至少99.4％、至少99.5％、至少99.6％、至少99.7％、至少99.8％或至少99.9％序列相同性的氨基酸序列或由其组成，或
(b)包含与SEQ ID NO:9、10、11、12、13、14中任一者的氨基酸序列具有至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、至少99％、至少99.1％、至少99.2％、至少99.3％、至少99.4％、至少99.5％、至少99.6％、至少99.7％、至少99.8％或至少99.9％序列相同性的氨基酸序列或由其组成；和/或
ii)(a)由编码与SEQ ID NO:15、16、17、18、19、20、40中任一者的氨基酸序列具有至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、至少99％、至少99.1％、至少99.2％、至少99.3％、至少99.4％、至少99.5％、至少99.6％、至少99.7％、至少99.8％或至少99.9％序列相同性的氨基酸序列的核苷酸序列编码，或
(b)由编码与SEQ ID NO:9、10、11、12、13、14中任一者的氨基酸序列具有至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、至少99％、至少99.1％、至少99.2％、至少99.3％、至少99.4％、至少99.5％、至少99.6％、至少99.7％、至少99.8％或至少99.9％序列相同性的氨基酸序列的核苷酸序列编码。
19.如方案1至18中任一方案的核酸分子，其中该PEDV S蛋白
(a)包含SEQ ID NO:15、16、17、18、19、20、40中任一者的氨基酸序列，或
(b)包含SEQ ID NO:9、10、11、12、13、14中任一者的氨基酸序列。
20.一种PEDV(S)蛋白，其由如方案1至19中任一方案的核酸分子编码。
21.如方案1至19中任一方案的核酸分子或如方案20的PEDV S蛋白，其中编码该PEDV S蛋白的该核酸分子或该PEDV S蛋白是重组的。
22.一种多核苷酸，其包含如方案1至19中任一方案的核酸分子。
23.一种载体，其包含如方案1至19中任一方案的核酸分子或如方案22的多核苷酸。
24.如方案23的载体，其中该载体是CDV、EHV、ORF病毒、PRV、CAV、PCMV或BoHV-4。
25.如方案23的载体，其中该载体是CDV或EHV。
26.一种免疫原性组合物，其包含如方案1至19中任一方案的编码PEDV S蛋白的核酸分子和/或如方案20的PEDV S蛋白和/或如方案23至25中任一方案的载体。
27.如方案26的免疫原性组合物，其中该免疫原性组合物进一步包含医药上可接受的载剂。
28.如方案26或27的免疫原性组合物，其中该免疫原性组合物是疫苗。
29.一种细胞，其包含如方案1至19中任一方案的核酸分子、如方案22的多核苷酸或如方案23至25中任一方案的载体。
30.一种产生如方案1至19中任一方案的编码PEDV S蛋白的核酸分子和/或如方案20的PEDV S蛋白的方法，其包含利用如方案23至25中任一方案的载体转染细胞。
31.一种制备用于治疗和/或预防个体的PEDV感染的免疫原性组合物的方法，其包含：
a.)利用如方案23至25中任一方案的载体感染细胞；
b.)获得该载体；及
c.)添加医药上可接受的载剂。
32.如方案29的细胞或如方案30或31的方法，其中该细胞系Vero细胞、ST细胞、BHK-21细胞、Ma104细胞、MDBK细胞、RK13细胞、MDCK细胞或PK15细胞。
33.如方案27的免疫原性组合物或如方案31的方法，其中该医药上可接受的载剂选自以下组成：溶剂、分散介质、包衣剂、稳定剂、稀释剂、防腐剂、抗细菌及抗真菌剂、等渗剂、吸附延迟剂、佐剂、免疫刺激剂及其组合。
34.一种对个体实施免疫的方法，其包含向该个体施用如方案26至28中任一方案的免疫原性组合物。
35.如方案26至28中任一方案的免疫原性组合物，其用于对个体实施免疫的方法中，该方法包含向该个体施用治疗有效量的该免疫原性组合物。
36.一种治疗和/或预防有需要的个体中由PEDV感染引起的临床征象的方法，该方法包含向该个体施用治疗有效量的如方案26至28中任一方案的免疫原性组合物。
37.如方案26至28中任一方案的免疫原性组合物，其用于治疗和/或预防有需要的个体中由PEDV感染引起的临床征象的方法中，该方法包含向该个体施用治疗有效量的该免疫原性组合物。
38.一种与相同物种的非免疫对照组的个体相比降低个体死亡率的方法，该方法包含向该个体施用治疗有效量的如方案26至28中任一方案的免疫原性组合物。
39.如方案26至28中任一方案的免疫原性组合物，其用于与相同物种的非免疫对照组的个体相比降低个体死亡率的方法中，该方法包含向该个体施用治疗有效量的该免疫原性组合物。
40.一种用于在母猪中诱导产生对PEDV具有特异性的抗体的方法，其中该方法包含向该母猪施用如方案26至28中任一方案的免疫原性组合物。
41.如方案26至28中任一方案的免疫原性组合物，其用于在母猪中诱导产生对PEDV具有特异性的抗体的方法中，该方法包含向该母猪施用治疗有效量的该免疫原性组合物。
42.一种与非免疫对照组的仔猪相比降低仔猪死亡率的方法，该方法包含向该仔猪的母猪施用治疗有效量的如方案26至28中任一方案的免疫原性组合物，其中该仔猪是由该母猪进行哺乳。
43.如方案26至28中任一方案的免疫原性组合物，其用于与非免疫对照组的仔猪相比降低仔猪死亡率的方法中，该方法包含向该仔猪的母猪施用治疗有效量的该免疫原性组合物，其中该仔猪是由该母猪进行哺乳。
44.一种减少或预防仔猪中因感染PEDV所引起的临床征象或疾病的方法，其中该仔猪是由经施用如方案26至28中任一方案的免疫原性组合物的母猪进行哺乳。
45.如方案26至28中任一方案的免疫原性组合物，其用于减少或预防仔猪中因感染PEDV所引起的临床征象或疾病的方法中，其中该仔猪是由经施用该免疫原性组合物的母猪进行哺乳。
46.一种减少或预防仔猪中因感染PEDV所引起的临床征象或疾病的方法，其中该方法包含
-向母猪施用如方案26至28中任一方案的免疫原性组合物，及
-容许该仔猪由该母猪进行哺乳。
47.如方案26至28中任一方案的免疫原性组合物，其用于减少或预防仔猪中因感染PEDV所引起的临床征象或疾病的方法中，其中该方法包含
-向母猪施用该免疫原性组合物，及
-容许该仔猪由该母猪进行哺乳。
48.如方案34至47中任一方案的方法，其中施用该免疫原性组合物的该母猪是怀孕母猪、尤其是怀有该仔猪的母猪。
49.如方案34及46至48中任一方案的方法，其包含以下步骤
-向怀有该仔猪的母猪施用如方案26至28中任一方案的免疫原性组合物，
-容许该母猪生下该仔猪，及
-容许该仔猪由该母猪进行哺乳。
50.如方案36、37、40、44、45、46、47、48或49中任一方案的方法，其中与相同物种的非免疫对照组的个体相比，该方法使得选自由以下组成的组的临床征象或效能参数改良：体重减轻降低、病毒载量降低、腹泻减少、病毒脱落减少、直肠温度降低、死亡率降低、肠中的严重病理性病灶减少或其组合。
51.如方案34至39中任一方案的方法，其中该个体是仔猪、猪或母猪。
52.如方案34至39或51中任一方案的方法，其中在第一月龄内向该个体施用该免疫原性组合物。
53.如方案34至52中任一方案的方法，其中向处于妊娠期及哺乳期的母猪施用该免疫原性组合物。
54.如方案34至53中任一方案的方法，其中以两个或更多个剂量施用该免疫原性组合物。
55.如方案34至44中任一方案的方法，其中向母猪施用两次该免疫原性组合物，第一次施用是在分娩之前的9周与5周之间且第二次施用是在分娩之前的6周与1周之间。
56.如方案34至55中任一方案的方法，其中鼻内、经黏膜、经口、经皮内或肌内施用该免疫原性组合物。
57.如方案34至56中任一方案的方法，其中鼻内或经口施用该免疫原性组合物。
58.如方案34至57中任一方案的方法，其中该免疫原性组合物包含介于1×103至1×107TCID50/ml之间的尤其如方案23至25中任一方案的载体。
59.如方案34至58中任一方案的方法，其中该方法使得从攻击或感染后第5天、第7天或第10天病毒脱落有所减少。
60.如方案34至59中任一方案的方法，其中该方法增加针对同源性攻击的保护。
优选实施例的详细阐述
根据本发明，以下实例陈述优选材料及程序。尽管任何类似或等效于本文所阐述那些的方法及材料可用于本发明的实践或测试中，但现在阐述优选的方法、装置及材料。然而，应理解，该等实例仅以说明方式提供，且其中的内容均不应视为对本发明的整体范围的限制。
实例1刺突修饰的制备
A)重组CDV载体的PEDV-S表达
在活体外实验中，使用SacII内核酸酶消化编码源自Lederle疫苗品系(Lederle；ATCC VR-128)的完整CDV基因组的全质粒(pBR322)，之后将PEDV刺突(S)蛋白编码盒克隆在P基因与M基因之间(产生包含SEQ ID NO:36的序列)。在克隆且使重组CDV-PEDV-S拯救后，可在CDV相关的荧光病灶中显示2b基因型的猪流行性腹泻病毒刺突蛋白的表达。相应CDV载体亦达成其各别结果(即仅编码2a基因型SEQ ID NO:20的猪流行性腹泻病毒刺突蛋白的序列有所不同)。通过免疫荧光针对两种载体所获得的结果指示，在所有CDV感染合胞体中，PEDV的刺突蛋白均具有强表达(数据未显示)。
B)表达PEDV刺突的EHV的制备
为产生表达刺突蛋白PEDV-S2b-wt及PEDV-S2b-mut的EHV1重组体，使用合成序列SEQ ID NO:3及SEQ ID NO:14。合成其序列且分别亚克隆于转移载体pUC19-ORF1/3-PEDV-S2b-wt及pUC19-ORF1/3-PEDV-S2b-mut中。
通过过往性诱变(en-passant mutagenesis)使用RED重组系统(Tischer等人2006)，将PEDV-S2b-wt或PEDV-S2b-mut的表达盒插入在pRacH-SE的orf1/3区中以产生最终BAC DNA pRacH-SE-PEDV-S2b-wt及pRacH-SE-PEDV-S2b-mut。
利用所产生的BAC DNA转染RK13细胞，使重组病毒rEHV-1拯救并进行噬菌斑纯化。通过对插入区的高保真度PCR产物进行测序来证实表达盒的正确插入。通过间接免疫荧光分析(IFA)来分析并确认转基因在受感染细胞中的表达(数据未显示)。此外，使病毒在RK-13细胞中传代20次细胞传代以确认构建体的活体外稳定性。
实例2刺突在质膜中的定位
将编码2b基因型的野生型(天然)PEDV-S蛋白的EHV-1重组载体(EHV1-PEDV-S2b-wt)与编码突变刺突蛋白的EHV-1重组载体(在氨基酸位置897/898/1374/1381处突变(SEQID NO:14)，命名为EHV1-PEDV-S2b-mut)进行比较。
简言之，向六孔板的一个孔中以2×105个细胞的密度将RK13细胞平铺于6孔细胞培养板中。在第二天(接种后24h)，利用EHV1-PEDV-S2b-wt或EHV1-PEDV-S2b-mut以0.01的MOI感染细胞。感染后2天(48小时)，使用3％多聚甲醛溶液将细胞固定1小时。然后使用0.1％Tween 20对固定的细胞单层进行渗透化处理，且然后使用小鼠抗PEDV单株抗体纯是7D7_G1(Abpro-Labs 2.4.16)使用于PBS中的1:200稀释度染色1小时。1小时后，利用室温PBS(1000μl/孔)将细胞洗涤两次。添加750μl 1:500稀释度的市售二级抗体(山羊抗小鼠-FITC(Life Technology目录号：A11029批号：1705900)/孔，且在黑暗中(避光)培育60分钟。培育之后，通过真空吸出二级抗体溶液，之后利用室温PBS(1000μl/孔)洗涤两次。使用Olimpus倒置荧光显微镜(型号IX81)，使用FITC滤波器检测细胞中PEDV刺突蛋白的特异性荧光获得结果(图1)。自EHV1-PEDV-S2b-wt重组载体表达的刺突蛋白主要定位于细胞质中，而自EHV1-PEDV-S2b-mut表达的刺突蛋白则主要定位在细胞膜内。
实例3在Vero细胞中的生长动力学
介绍：重组病毒载体的高效生长是关于疫苗的高效生产的基本特征的一。在Vero细胞(
CCL-81TM)上生产犬瘟热病毒(CDV)疫苗且极常使用滚瓶生产系统。对两种CDV重组体的生长动力学进行比较，该两种CDV重组体为：
(i)源自Lederle疫苗品系的CDV主链(参见实例1)，其在P基因与M基因之间插入有SEQ ID NO:39的序列(编码SEQ ID NO:20的PEDV刺突蛋白)，在本文中称为“CDV-PEDV-刺突-MUT”或“CDV-PEDV-刺突mut”，及(ii)编码相应野生型蛋白质(SEQ ID NO:2的PEDV刺突蛋白)的各自载体，在本文中称为“CDV-PEDV-刺突-WT”或“CDV-PEDV-刺突wt”。
实验设置：滚瓶(490cm3)接种有2×107个Vero细胞。在第二天，使用CDV-PEDV-刺突-MUT或CDV-PEDV-刺突-WT病毒储备液以0,01的MOI感染滚瓶中的Vero细胞。在接下来的7天中，以一式三份自每一滚瓶取1ml的等分试样。所有样品均储存在-80℃冷冻箱中直至分析。在分析当天，使样品在冰上解冻，且遵循以下方案实施病毒滴定：
CDV滴定方案
材料：
·细胞：24小时之前接种于96孔板中的VeroDogSLAM BI，6×103个细胞/孔
·培养基：MEM(SAFC,SLBX3503)
·供稀释用的48孔板
程序：
·使用48孔板进行稀释
·向孔中填充1080μl的MEM
·将120μl每一样品移液于第一列中
·混合程序，制备每一样品的自10-1至10-8的10倍稀释液。
·对于每次稀释，使用一个96孔细胞板。
·将稀释液转移至预先接种的细胞上(100μl/孔)
·对于每一样品进行8次重复
·在37℃细胞培育器中培育3天
·使用显微镜术，通过检测细胞上的典型CDV合胞体形成进行读出
结果及讨论：在感染Vero细胞后第1天、第2天、第3天、第4天、第5天及第6天，CDV-PEDV-刺突-MUT重组体显示出更高的感染性病毒效价。此外，两种重组体在感染后第4天均达到峰值上清液效价，但CDV-PEDV-刺突-MUT所达到的感染效价较CDV-PEDV-刺突-WT重组体高2倍(参见图2)，此指示刺突的突变有益于CDV载体的适应性。
所有那些病毒效价均在无细胞的上清液中量测。基于经验数据(数据未显示)，预期细胞部分中的效价至少高100倍，且因此在生产设置(当在生产设置中将收获包括细胞部分的滚瓶时)中，该两种重组体之间的效价差异成比例地甚至更高。
实例4疫苗动物数据
疫苗效能研究
猪流行性腹泻(PED)是可具有巨大经济影响的高度传染性猪疾病。虽然所有年龄级的猪均易于感染，但严重临床征象及死亡主要见于哺乳仔猪中。致病因子是PED病毒(PEDV)，其是冠状病毒科(Coronaviridae)内的α冠状病毒属的包膜、单链阳性RNA病毒。在欧洲，PEDV首次出现于1970年代后期的英格兰。之后，其在整个欧洲传播，引起散发性爆发。在1990年代后期，PEDV自欧洲养猪场消失，如通过极低的血清阳性率及不存在疾病报导所证实。爆发性及地方性感染仍报导于亚洲，在此该疾病高度影响工业化养猪场的生产力。自2005年开始，PED病例再次报导于欧洲(即意大利)。在极高毒性的PEDV于2013年引入至美国之后，病例亦报导于中欧，包括德国及周边国家。后续病例是由相关但不同的PEDV品系(所谓的S-INDEL品系)引起。在德国，自2014年5月开始在哺乳猪中报导具有高发病率及可变致死率的病例。
此研究包括6只母猪及其后代，在此研究中将源自Lederle疫苗品系(参见实例1)且在P基因与M基因之间插入SEQ ID NO:37的序列(编码PEDV刺突蛋白)的CDV骨架(载体由此包含SEQ ID NO:38的序列)作为载体疫苗(在下文中分别称为“CDV_PEDV-刺突疫苗”或“CDV PEDV-刺突载体疫苗”)进行测试。
通过靶向S基因的RT-qPCR来检查所有动物的PEDV及PEDV特异性抗体。仅阴性动物入选该研究。
三个治疗组(参见下文)接收随机分配的动物：
组1(阴性对照)：两只母猪(命名为1号及2号)，未进行疫苗接种；
组2(阳性对照)：两只母猪(命名为3号及4号)，未进行疫苗接种；
组3(CDV_PEDV-刺突)：两只母猪(命名为5号及6号)，利用CDV_PEDV-刺突载体疫苗进行疫苗接种。
根据以下方案进行组3的两只母猪的疫苗接种，其中通过终点滴定定义的CDV_PEDV-刺突疫苗的储备液效价为7.94×104TCID50/ml：
在预期分娩日期之前9周：使两只母猪中的每一者鼻内接受4ml疫苗(每一鼻孔中2ml)；
在预期分娩日期之前6周：使两只母猪中的每一者鼻内接受4ml疫苗(每一鼻孔中2ml)；
在预期分娩日期之前3周：使两只母猪中的每一者鼻内接受4ml各别疫苗(每一鼻孔中2ml)且另外肌内接受2ml。
以口服方式对组1的母猪所生育的仔猪(1号母猪的13只仔猪及2号母猪的12只仔猪)进行模拟接种。在生命的4天龄时，利用PEDV现场品系(在下文中称为“PEDV EU”)以口服方式攻击组2(3号母猪的12只仔猪及4号母猪的14只仔猪)及组3(5号母猪的5只仔猪及6号母猪的15只仔猪)的母猪所生育的仔猪。
为接种组2及3的仔猪，使用细胞培养适应性PEDV EU。效价为2.15×105TCID50/ml。以口服方式接种组2及3的仔猪。在此情形中，使用2ml注射器，使每一仔猪接受1ml经1:10稀释的病毒储备液(效价2.15×104TCID50)。
使用于2ml注射器中的1ml细胞培养基以口服方式对组1的仔猪进行模拟接种。
在整个试验期间，对于RT-qPCR分析，在接种当天及在接种后(pi)第1天至第10天以及在接种后第14天、第17天及第20天/第21天获取所有动物的直肠拭子(不含培养基的COPAN普通拭子)。在接种之前及在攻击后两天自每一母猪的4只仔猪获取其他直肠拭子以进行细菌学检查。此外，使用已确立的标准化累积评分系统每天记录指示PED的临床征象(参见下文)。在接种当天及接种后第14天及第20天/第21天(试验结束)或在各别动物的安乐死或死亡的日获取血液样品。
临床监测
使用已确立的累积临床评分每天监测指示PED的临床征象(参见下表)。
表1：指示PED的临床征象的累积临床评分
样品制备及核酸提取
将直肠拭子浸没于1ml杜贝克氏改良鹰氏培养基(Dulbecco's Modified EagleMedium)中，且在室温下培育1小时。使用QIAmp ViralRNA Mini试剂盒(Qiagen)或NucleoMagVet试剂盒与KingFisher提取平台的组合提取病毒RNA。将RNA储存在-20℃下直至进一步使用。
将血液样品在室温下以2031×g离心20min以获得血清。将所得血清等分且储存在-20℃下。
病毒检测
为检测PEDV病毒脱落，如先前所阐述使用靶向PEDV的S基因的RT-qPCR系统(Stadler等人，BMC Vet Res.11:142(2015))。对在接种后第0天至第7天(攻击病毒接种后天数)及接种后第10天及第20天/第21天所获取样品的PEDV基因组进行测试。使用内部标准计算基因组拷贝量/μl。
抗体检测
根据生产商手册，利用所有血清来实施市售间接ELISA(INgezim PEDV,INGENASA,Madrid,Spain)。
细菌学
在接种后第0天及第2天获取每窝4只仔猪的粪便拭子以用于差异细菌学分析。
统计学
使用Shapiro-Wilk测试来进行常态性测试且如在软件包中所执行进行Mann-Whitney秩和测试。使用SigmaPlot软件测试统计学显著性。
结果
血清中的抗体检测：
CDV组的所有仔猪在攻击接种之前均因抗体阳性初乳摄入而在ELISA(检测针对PEDV刺突蛋白的抗体)中显示阳性结果，而阳性及阴性对照组的所有动物均显示明显阴性的结果。
在接种后第14天，阳性对照组中的所有仔猪(三只除外)均发生血清转化，而疫苗组中的所有动物在血清样品中均仍显示较高量的PEDV特异性IgG。
在研究结束时，CDV组及阳性对照组的所有仔猪均在ELISA中显示强阳性结果。阴性对照中没有动物在整个试验期间发生血清转化。
在进一步研究中亦可看到，在经由鼻内途径对生育母猪仅接种两次疫苗时，同样达成各别抗体结果。
细菌学：
在接种后第0天及第2天获取的粪便拭子不显示任何致病性细菌。细菌群落在感染后并不经历显著变化。
临床征象：
阳性对照组(组2)的仔猪在7天内明确显示指示PEDV的临床征象，其中在接种后24小时开始呕吐，之后发生腹泻。由于严重脱水且临床评分值超过6(人道终点)，26只仔猪中的8只必须实施安乐死。在接种后36小时可检测到指示PEDV的第一临床征象。
总而言之，经CDV载体疫苗接种及PEDV攻击的仔猪(组3)关于一般行为的临床征象优选，且组3中的20只猪中仅2只(10％)由于严重脱水且临床评分值超过6而必须实施安乐死(相比的下，组2的仔猪为31％)。
阴性对照中的动物在整个试验期间保持健康。
病毒的脱落
可在受攻击组之间检测到病毒脱落的明确差异。在接种后第1天，所有受攻击仔猪的直肠拭子中的病毒基因组均为阳性，但CDV-PEDV疫苗接种组中的动物显示显著降低的PEDV基因组拷贝数(平均CT值32,79)，其次为攻击组(平均CT值26,65)。
同样，虽然在接种后接下来的5天，CDV组的直肠拭子中的基因组负荷极类似于阳性对照，但自接种后第7天开始，受疫苗接种母猪保护的仔猪中的病毒基因组的可检测量下降至截止值以下，而阳性对照组中的所有动物均仍脱落PEDV。
阴性对照组的拭子中检测不到PEDV基因组。
总之，研究结果为，与阳性对照相比，由经CDV PEDV-刺突重组疫苗进行疫苗接种的母猪所生育的仔猪显示临床征象减少，且特定而言，就仔猪的死亡率/致死率而言观察到极大改良。此外，PEDV攻击后的病毒脱落显著降低。
此外，实施对应于上文所阐述疫苗效能研究的动物研究，其中将源自Lederle疫苗品系(参见实例1)且在P基因与M基因之间具有编码SEQ ID NO:40的PEDV刺突蛋白的插入序列的CDV骨架施用两次(在分娩之前5周及在分娩之前2周)，且其中使用高毒性基因型2aPEDV现场品系进行攻击。与攻击对照相比，由利用此重组疫苗进行疫苗接种的母猪所生育的仔猪显示死亡率降低或临床征象减少。
实例5
此动物研究包括二十(20)只母猪及其后代，在此研究中将源自Lederle疫苗品系(参见实例1及4)且在P基因与M基因之间具有编码SEQ ID NO:20的PEDV刺突蛋白的插入序列的CDV骨架作为载体疫苗(在下文中分别称为“CDV_PEDV-G2a疫苗”或“CDV PEDV-G2a刺突载体疫苗”)进行测试。
仅通过qRT-PCR及ELISA认为是PEDV阴性的动物入选该研究。
三个治疗组(参见下文)接收随机分配的动物：
组1(严格阴性对照)：四只母猪(命名为1-4)，未进行疫苗接种；
组2(攻击对照)：八只母猪(命名为5-12)，未进行疫苗接种；
组3(CDV_PEDV-G2a-刺突)：八只母猪(命名为13-20)，利用CDV PEDV-G2a-刺突载体疫苗进行疫苗接种。
在该研究的分娩前5周(DO)及分娩前2周(D21)对组3的8只母猪进行疫苗接种，其中通过终点滴定定义的CDV_PEDV-G2a刺突疫苗的储备液效价为2.57×105TCID50/ml。在每次疫苗接种时，母猪鼻内接受4mL的疫苗(每一鼻孔中2mL)。
由组1的母猪所生育的仔猪(总计41只仔猪)不受攻击(严格对照)。在生命的3-7天龄时，利用属G2a基因型的高毒性PEDV现场品系以剂量2.0×103TCID50/2mL剂量(1mL鼻内+1mL口服)以口服方式攻击组2(总计81只仔猪)及组3(总计83只仔猪)的母猪所生育的仔猪。
在整个试验期间，在接种前一天及在接种后(攻击病毒接种后)第1天、第3天、第7天及第14天获取直肠拭子。
样品制备及核酸提取
在收集后将直肠拭子浸没于2ml最低必需培养基(MEM)中，且在处理之前储存在-70℃下。通过涡旋10秒、之后在4℃下以1,500×g离心10分钟来处理样品。处理后，使用BS96Vet 100BioSprint提取平台利用BioSprint One-For-All Vet试剂盒(Qiagen)，使用100μl/样品进行病毒RNA提取。将RNA储存在-20℃下直至进一步使用。
将血液样品在室温下以1960×g离心10min以获得血清。将所得血清等分且储存在-70℃下。
病毒检测
为检测PEDV病毒脱落，使用靶向PEDV的S基因的源自内部的RT-qPCR系统：使用定量一步RT-PCR试剂盒(iTaq通用一步RT-PCR试剂盒；BioRad，目录号1725140)用于分析。于25μl含有2μl所提取总核酸、0.75μl探针(4μM)、0.5μl每一引物(10μM)、12.5μl 2×RT-PCR混合物、0.5μl iScript反转录酶及8.25μl DEPC处理水的反应中实施实时RT-PCR。关于引物、探针及ultramer序列，参见下文表2。使用CFX96实时PCR检测系统(BioRad)在以下条件下进行该反应：在50℃下初始反转录30min，之后在95℃下初始变性5min，在95℃下变性15秒达40个循环且在57℃下退火并延伸30秒。为产生定量数据，在每一运行中纳入PEDVultramer(Integrated DNA Technologies)。将冻干的ultramer(4nmol)重新悬浮于经DEPC处理的不含核酸酶的无菌水中以得到1.0E+10个基因组拷贝/μl(gc/μl)的储备液浓度。自ultramer储备液，于DEPC处理水中制备自1.0E+08至1.0E+01的10倍连续稀释液。在使用之前通过量子位dsDNA HS分析确认浓度。使用CFX Manager软件分析光学数据。对于每次测定，使用循环临限值(Ct)测定模式的回归设置自动计算临限值线。使用基线扣除模式自动进行基线扣除。手动校正基线最终值小于10的曲线。
表2：源自内部的RT-qPCR系统所使用的探针(Pr)、引物(F/R)及ultramer序列。
抗体检测
使用内部开发的CCIF分析来测试来自此研究的血清及乳汁样品：将野生型PEDV分离株(基因群2a)以1:100稀释至PEDV生长培养基(MEM+2.5％HEPES+0.3％胰蛋白胨磷酸盐培养液+0.02％酵母+10μg/mL胰蛋白酶)中。将经稀释的病毒(100μL/孔)接种至已植入Vero细胞两天的96孔板上。在感染之前，将细胞生长培养基自板去除，且用100μLPEDV生长培养基将板洗涤两次。将板在37±2℃+CO2(4％-6％)下培育24小时。在培育后，弃掉上清液，且用200μL/孔1×PBS将板洗涤两次。为固定，添加200μL/孔的乙醇。将板在室温下培育30分钟，风干，然后储存在-20℃下直至使用。在用于该分析中之前，利用200μl/孔1×PBS(Gibco)将板在室温下再水化10min且利用100μl/孔缓冲液(1×PBS+1％正常山羊血清+0.1％triton X)在37℃下封阻15分钟。于含有1:1000稀释度的PEDV Mab抗体(Mediandiagnostics)的稀释缓冲液(1×PBS+5％BSA+1％正常山羊血清+0.1％titron-X 100)中制备血清样品的连续两倍稀释液。将经稀释的样品(50μl/孔)添加至准备好的板中且在37℃下培育1小时。在培育后，利用200μl/孔1×PBS将板洗涤三次。然后将总计50μl/孔的经稀释二级抗体[Alexa594山羊抗小鼠IgG(Fisher，1:500稀释度)；经FITC标记的山羊抗猪IgG(BioRad，1:500稀释度)；Hoechst 33342(Fisher，1:1000稀释度)]添加至每一板且在37℃下培育1小时。在培育后，利用200μl/孔1×PBS将板洗涤三次。在结合有Mab3F12的PEDV感染细胞显示特定红色荧光的处观察到荧光。绿色荧光的共定位指示结合猪IgG。检测到特定绿色荧光的最高稀释度相当于IgG效价。
结果
死亡率
在组1(严格对照)中，40只猪存活，在组2(攻击对照)中，16只猪存活，且在组3(经CDV-PEDV-G2a刺突疫苗接种)中，34只猪存活，此使得平均死亡率分别为2％(组1)、80％(组2)及59％(组3)。
抗体反应
攻击后的特异性PEDV抗体反应揭示，CDV-PEDV-G2a刺突疫苗接种组中的母猪血清及乳汁中的CCIF IgG抗体效价的平均值高于组2(攻击对照)。此指示，经疫苗接种的母猪接触来自攻击后受感染仔猪的病毒后通过提高乳汁及血清中的IgG含量而有强烈反应。与此相比，攻击对照的母猪中仅经由与受攻击仔猪(及其粪便)接触而感染PEDV引起的抗体效价则显著降低。
病毒的脱落
在攻击病毒接种后第3天，在接种疫苗及未接种疫苗的组中检测到相对相似的平均RNA载量，CDV-PEDV-G2a刺突疫苗接种组及攻击对照组分别达到9,2及9,8的组平均log10PEDV基因组拷贝。在第48天(接种后第7天)及第55天(接种后第14天)，CDV-PEDV-G2a刺突疫苗接种组中的平均log10 PEDV基因组拷贝数分别为3,2log10及2,0log10，而在攻击对照组中则分别为5,5log10及3,9log 10，此指示在接种后第7天及第14天分别降低2,3log及1,9log。尽管未实施更长期的病毒脱落监测，但根据如上文在实例4下所阐述的结果，在攻击病毒接种后第7天及第14天所观察到的病毒脱落动力学趋势明确地指示疫苗接种动物中的病毒脱落时间缩短。
在严格阴性对照组的拭子中未能检测到PEDV基因组。
总之，该研究的结果为，与对照组的仔猪相比，在受高毒性PEDV品系攻击时，由接种CDV PEDV-G2a刺突重组疫苗的母猪所生育或各别地由其进行哺乳的仔猪显示显著降低的死亡率。而且，在产后最初几天经由转移母体抗体而接受来自乳汁中的PEDV保护性IgG抗体的该等仔猪揭示，在感染后第7天及第14天，攻击后的病毒脱落显著降低，此是重要的流行病学参数。
序列表
<110> 勃林格殷格翰动物保健有限公司
<120> 经修饰的PEDV刺突蛋白
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<213> 猪流行性腹泻病毒
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Trp Tyr Cys Ala Gly Gln His Pro Thr Ala Ser Gly Val His Gly Ile
65 70 75 80
Phe Val Ser His Ile Arg Gly Gly His Gly Phe Glu Ile Gly Ile Ser
85 90 95
Gln Glu Pro Phe Asp Pro Ser Gly Tyr Gln Leu Tyr Leu His Lys Ala
100 105 110
Thr Asn Gly Asn Thr Asn Ala Thr Ala Arg Leu Arg Ile Cys Gln Phe
115 120 125
Pro Ser Ile Lys Thr Leu Gly Pro Thr Ala Asn Asn Asp Val Thr Thr
130 135 140
Gly Arg Asn Cys Leu Phe Asn Lys Ala Ile Pro Ala His Met Ser Glu
145 150 155 160
His Ser Val Val Gly Ile Thr Trp Asp Asn Asp Arg Val Thr Val Phe
165 170 175
Ser Asp Lys Ile Tyr Tyr Phe Tyr Phe Lys Asn Asp Trp Ser Arg Val
180 185 190
Ala Thr Lys Cys Tyr Asn Ser Gly Gly Cys Ala Met Gln Tyr Val Tyr
195 200 205
Glu Pro Thr Tyr Tyr Met Leu Asn Val Thr Ser Ala Gly Glu Asp Gly
210 215 220
Ile Ser Tyr Gln Pro Cys Thr Ala Asn Cys Ile Gly Tyr Ala Ala Asn
225 230 235 240
Val Phe Ala Thr Glu Pro Asn Gly His Ile Pro Glu Gly Phe Ser Phe
245 250 255
Asn Asn Trp Phe Leu Leu Ser Asn Asp Ser Thr Leu Val His Gly Lys
260 265 270
Val Val Ser Asn Gln Pro Leu Leu Val Asn Cys Leu Leu Ala Ile Pro
275 280 285
Lys Ile Tyr Gly Leu Gly Gln Phe Phe Ser Phe Asn Gln Thr Ile Asp
290 295 300
Gly Val Cys Asn Gly Ala Ala Val Gln Arg Ala Pro Glu Ala Leu Arg
305 310 315 320
Phe Asn Ile Asn Asp Thr Ser Val Ile Leu Ala Glu Gly Ser Ile Val
325 330 335
Leu His Thr Ala Leu Gly Thr Asn Phe Ser Phe Val Cys Ser Asn Ser
340 345 350
Ser Asn Pro His Leu Ala Thr Phe Ala Ile Pro Leu Gly Ala Thr Gln
355 360 365
Val Pro Tyr Tyr Cys Phe Leu Lys Val Asp Thr Tyr Asn Ser Thr Val
370 375 380
Tyr Lys Phe Leu Ala Val Leu Pro Pro Thr Val Arg Glu Ile Val Ile
385 390 395 400
Thr Lys Tyr Gly Asp Val Tyr Val Asn Gly Phe Gly Tyr Leu His Leu
405 410 415
Gly Leu Leu Asp Ala Val Thr Ile Asn Phe Thr Gly His Gly Thr Asp
420 425 430
Asp Asp Val Ser Gly Phe Trp Thr Ile Ala Ser Thr Asn Phe Val Asp
435 440 445
Ala Leu Ile Glu Val Gln Gly Thr Ala Ile Gln Arg Ile Leu Tyr Cys
450 455 460
Asp Asp Pro Val Ser Gln Leu Lys Cys Ser Gln Val Ala Phe Asp Leu
465 470 475 480
Asp Asp Gly Phe Tyr Pro Ile Ser Ser Arg Asn Leu Leu Ser His Glu
485 490 495
Gln Pro Ile Ser Phe Val Thr Leu Pro Ser Phe Asn Asp His Ser Phe
500 505 510
Val Asn Ile Thr Val Ser Ala Ser Phe Gly Gly His Ser Gly Ala Asn
515 520 525
Leu Ile Ala Ser Asp Thr Thr Ile Asn Gly Phe Ser Ser Phe Cys Val
530 535 540
Asp Thr Arg Gln Phe Thr Ile Ser Leu Phe Tyr Asn Val Thr Asn Ser
545 550 555 560
Tyr Gly Tyr Val Ser Lys Ser Gln Asp Ser Asn Cys Pro Phe Thr Leu
565 570 575
Gln Ser Val Asn Asp Tyr Leu Ser Phe Ser Lys Phe Cys Val Ser Thr
580 585 590
Ser Leu Leu Ala Ser Ala Cys Thr Ile Asp Leu Phe Gly Tyr Pro Glu
595 600 605
Phe Gly Ser Gly Val Lys Phe Thr Ser Leu Tyr Phe Gln Phe Thr Lys
610 615 620
Gly Glu Leu Ile Thr Gly Thr Pro Lys Pro Leu Glu Gly Val Thr Asp
625 630 635 640
Val Ser Phe Met Thr Leu Asp Val Cys Thr Lys Tyr Thr Ile Tyr Gly
645 650 655
Phe Lys Gly Glu Gly Ile Ile Thr Leu Thr Asn Ser Ser Phe Leu Ala
660 665 670
Gly Val Tyr Tyr Thr Ser Asp Ser Gly Gln Leu Leu Ala Phe Lys Asn
675 680 685
Val Thr Ser Gly Ala Val Tyr Ser Val Thr Pro Cys Ser Phe Ser Glu
690 695 700
Gln Ala Ala Tyr Val Asp Asp Asp Ile Val Gly Val Ile Ser Ser Leu
705 710 715 720
Ser Ser Ser Thr Phe Asn Ser Thr Arg Glu Leu Pro Gly Phe Phe Tyr
725 730 735
His Ser Asn Asp Gly Ser Asn Cys Thr Glu Pro Val Leu Val Tyr Ser
740 745 750
Asn Ile Gly Val Cys Lys Ser Gly Ser Ile Gly Tyr Val Pro Ser Gln
755 760 765
Ser Gly Gln Val Lys Ile Ala Pro Thr Val Thr Gly Asn Ile Ser Ile
770 775 780
Pro Thr Asn Phe Ser Met Ser Ile Arg Thr Glu Tyr Leu Gln Leu Tyr
785 790 795 800
Asn Thr Pro Val Ser Val Asp Cys Ala Thr Tyr Val Cys Asn Gly Asn
805 810 815
Ser Arg Cys Lys Gln Leu Leu Thr Gln Tyr Thr Ala Ala Cys Lys Thr
820 825 830
Ile Glu Ser Ala Leu Gln Leu Ser Ala Arg Leu Glu Ser Val Glu Val
835 840 845
Asn Ser Met Leu Thr Ile Ser Glu Glu Ala Leu Gln Leu Ala Thr Ile
850 855 860
Ser Ser Phe Asn Gly Asp Gly Tyr Asn Phe Thr Asn Val Leu Gly Val
865 870 875 880
Ser Val Tyr Asp Pro Ala Ser Gly Arg Val Val Gln Lys Arg Ser Phe
885 890 895
Ile Glu Asp Leu Leu Phe Asn Lys Val Val Thr Asn Gly Leu Gly Thr
900 905 910
Val Asp Glu Asp Tyr Lys Arg Cys Ser Asn Gly Arg Ser Val Ala Asp
915 920 925
Leu Val Cys Ala Gln Tyr Tyr Ser Gly Val Met Val Leu Pro Gly Val
930 935 940
Val Asp Ala Glu Lys Leu His Met Tyr Ser Ala Ser Leu Ile Gly Gly
945 950 955 960
Met Val Leu Gly Gly Phe Thr Ser Ala Ala Ala Leu Pro Phe Ser Tyr
965 970 975
Ala Val Gln Ala Arg Leu Asn Tyr Leu Ala Leu Gln Thr Asp Val Leu
980 985 990
Gln Arg Asn Gln Gln Leu Leu Ala Glu Ser Phe Asn Ser Ala Ile Gly
995 1000 1005
Asn Ile Thr Ser Ala Phe Glu Ser Val Lys Glu Ala Ile Ser Gln
1010 1015 1020
Thr Ser Lys Gly Leu Asn Thr Val Ala His Ala Leu Thr Lys Val
1025 1030 1035
Gln Glu Val Val Asn Ser Gln Gly Ala Ala Leu Thr Gln Leu Thr
1040 1045 1050
Val Gln Leu Gln His Asn Phe Gln Ala Ile Ser Ser Ser Ile Asp
1055 1060 1065
Asp Ile Tyr Ser Arg Leu Asp Ile Leu Ser Ala Asp Val Gln Val
1070 1075 1080
Asp Arg Leu Ile Thr Gly Arg Leu Ser Ala Leu Asn Ala Phe Val
1085 1090 1095
Ala Gln Thr Leu Thr Lys Tyr Thr Glu Val Gln Ala Ser Arg Lys
1100 1105 1110
Leu Ala Gln Gln Lys Val Asn Glu Cys Val Lys Ser Gln Ser Gln
1115 1120 1125
Arg Tyr Gly Phe Cys Gly Gly Asp Gly Glu His Ile Phe Ser Leu
1130 1135 1140
Val Gln Ala Ala Pro Gln Gly Leu Leu Phe Leu His Thr Val Leu
1145 1150 1155
Val Pro Ser Asp Phe Val Asp Val Ile Ala Ile Ala Gly Leu Cys
1160 1165 1170
Val Asn Asp Glu Ile Ala Leu Thr Leu Arg Glu Pro Gly Leu Val
1175 1180 1185
Leu Phe Thr His Glu Leu Gln Asn His Thr Ala Thr Glu Tyr Phe
1190 1195 1200
Val Ser Ser Arg Arg Met Phe Glu Pro Arg Lys Pro Thr Val Ser
1205 1210 1215
Asp Phe Val Gln Ile Glu Ser Cys Val Val Thr Tyr Val Asn Leu
1220 1225 1230
Thr Arg Asp Gln Leu Pro Asp Val Ile Pro Asp Tyr Ile Asp Val
1235 1240 1245
Asn Lys Thr Leu Asp Glu Ile Leu Ala Ser Leu Pro Asn Arg Thr
1250 1255 1260
Gly Pro Ser Leu Pro Leu Asp Val Phe Asn Ala Thr Tyr Leu Asn
1265 1270 1275
Leu Thr Gly Glu Ile Ala Asp Leu Glu Gln Arg Ser Glu Ser Leu
1280 1285 1290
Arg Asn Thr Thr Glu Glu Leu Gln Ser Leu Ile Tyr Asn Ile Asn
1295 1300 1305
Asn Thr Leu Val Asp Leu Glu Trp Leu Asn Arg Val Glu Thr Tyr
1310 1315 1320
Ile Lys Trp Pro Trp Trp Val Trp Leu Ile Ile Phe Ile Val Leu
1325 1330 1335
Ile Phe Val Val Ser Leu Leu Val Phe Cys Cys Ile Ser Thr Gly
1340 1345 1350
Cys Cys Gly Cys Cys Gly Cys Cys Cys Ala Cys Phe Ser Gly Cys
1355 1360 1365
Cys Arg Gly Pro Arg Leu Gln Pro Tyr Glu Val Phe Glu Lys Val
1370 1375 1380
His Val Gln Cys Gly
1385
<210> 3
<211> 1383
<212> PRT
<213> 猪流行性腹泻病毒
<400> 3
Met Lys Ser Leu Asn Tyr Phe Trp Leu Phe Leu Pro Val Leu Ser Thr
1 5 10 15
Leu Ser Leu Pro Gln Asp Val Thr Arg Cys Gln Ser Thr Ile Asn Phe
20 25 30
Arg Arg Phe Phe Ser Lys Phe Asn Val Gln Ala Pro Ala Val Val Val
35 40 45
Leu Gly Gly Tyr Leu Pro Ser Met Asn Ser Ser Ser Trp Tyr Cys Gly
50 55 60
Thr Gly Leu Glu Thr Ala Ser Gly Val His Gly Ile Phe Leu Ser Tyr
65 70 75 80
Ile Asp Ala Gly Gln Gly Phe Glu Ile Gly Ile Ser Gln Glu Pro Phe
85 90 95
Asp Pro Ser Gly Tyr Gln Leu Tyr Leu His Lys Ala Thr Asn Gly Asn
100 105 110
His Asn Ala Ile Ala Arg Leu Arg Ile Cys Gln Phe Pro Asn Asn Lys
115 120 125
Thr Leu Gly Pro Thr Val Asn Asp Val Thr Thr Gly Arg Asn Cys Leu
130 135 140
Phe Asn Lys Ala Ile Pro Ala Tyr Met Gln Asp Gly Lys Asn Ile Val
145 150 155 160
Val Gly Ile Thr Trp Asp Asn Asp Arg Val Thr Val Phe Ala Asp Lys
165 170 175
Ile Tyr His Phe Tyr Leu Lys Asn Asp Trp Ser Arg Val Ala Thr Arg
180 185 190
Cys Tyr Asn Lys Arg Ser Cys Ala Met Gln Tyr Val Tyr Thr Pro Thr
195 200 205
Tyr Tyr Met Leu Asn Val Thr Ser Ala Gly Glu Asp Gly Ile Tyr Tyr
210 215 220
Glu Pro Cys Thr Ala Asn Cys Ser Gly Tyr Ala Val Asn Val Phe Ala
225 230 235 240
Thr Asp Ser Asn Gly His Ile Pro Glu Gly Phe Ser Phe Asn Asn Trp
245 250 255
Phe Leu Leu Ser Asn Asp Ser Thr Leu Leu His Gly Lys Val Val Ser
260 265 270
Asn Gln Pro Leu Leu Val Asn Cys Leu Leu Ala Ile Pro Lys Ile Tyr
275 280 285
Gly Leu Gly Gln Phe Phe Ser Phe Asn Gln Thr Met Asp Gly Val Cys
290 295 300
Asn Gly Ala Ala Ala Gln Arg Ala Pro Glu Ala Leu Arg Phe Asn Ile
305 310 315 320
Asn Asp Thr Ser Val Ile Leu Ala Glu Gly Ser Ile Val Leu His Thr
325 330 335
Ala Leu Gly Thr Asn Leu Ser Phe Val Cys Ser Asn Ser Ser Asp Pro
340 345 350
His Leu Ala Thr Phe Thr Ile Pro Leu Gly Ala Thr Gln Val Pro Tyr
355 360 365
Tyr Cys Phe Leu Lys Val Asp Thr Tyr Asn Ser Asn Val Tyr Lys Phe
370 375 380
Leu Ala Val Leu Pro Pro Thr Val Arg Glu Ile Val Ile Thr Lys Tyr
385 390 395 400
Gly Asp Val Tyr Val Asn Gly Phe Gly Tyr Leu His Leu Gly Leu Leu
405 410 415
Asp Ala Val Thr Ile Asn Phe Thr Gly His Gly Thr Asp Asp Asp Val
420 425 430
Ser Gly Phe Trp Thr Ile Ala Ser Thr Asn Phe Val Asp Ala Leu Ile
435 440 445
Glu Val Gln Gly Thr Ala Ile Gln Arg Ile Leu Tyr Cys Asp Asp Pro
450 455 460
Val Ser Gln Leu Lys Cys Ser Gln Val Ala Phe Asp Leu Asp Asp Gly
465 470 475 480
Phe Tyr Pro Ile Ser Ser Arg Asn Leu Leu Ser His Glu Gln Pro Ile
485 490 495
Ser Phe Val Thr Leu Pro Ser Phe Asn Asp His Ser Phe Val Asn Ile
500 505 510
Thr Val Ser Ala Ser Phe Gly Gly His Ser Gly Ala Asn Leu Ile Ala
515 520 525
Ser Asp Thr Thr Ile Asn Gly Phe Ser Ser Phe Cys Val Asp Thr Arg
530 535 540
Gln Phe Thr Ile Ser Leu Phe Tyr Asn Val Thr Asn Ser Tyr Gly Tyr
545 550 555 560
Val Ser Lys Ser Gln Asp Ser Asn Cys Pro Phe Thr Leu Gln Ser Val
565 570 575
Asn Asp Tyr Leu Ser Phe Ser Lys Phe Cys Val Ser Thr Ser Leu Leu
580 585 590
Ala Ser Ala Cys Thr Ile Asp Leu Phe Gly Tyr Pro Glu Phe Gly Ser
595 600 605
Gly Val Lys Phe Thr Ser Leu Tyr Phe Gln Phe Thr Glu Gly Glu Leu
610 615 620
Ile Thr Gly Thr Pro Lys Pro Leu Glu Gly Val Thr Asp Val Ser Phe
625 630 635 640
Met Thr Leu Asp Val Cys Thr Lys Tyr Thr Ile Tyr Gly Phe Lys Gly
645 650 655
Glu Gly Ile Ile Thr Leu Thr Asn Ser Ser Phe Leu Ala Gly Val Tyr
660 665 670
Tyr Thr Ser Asp Ser Gly Gln Leu Leu Ala Phe Lys Asn Val Thr Ser
675 680 685
Gly Ala Val Tyr Ser Val Thr Pro Cys Ser Phe Ser Glu Gln Ala Ala
690 695 700
Tyr Val Asp Asp Asp Ile Val Gly Val Ile Ser Ser Leu Ser Ser Ser
705 710 715 720
Thr Phe Asn Ser Thr Arg Glu Leu Pro Gly Phe Phe Tyr His Ser Asn
725 730 735
Asp Gly Ser Asn Cys Thr Glu Pro Val Leu Val Tyr Ser Asn Ile Gly
740 745 750
Val Cys Lys Ser Gly Ser Ile Gly Tyr Val Pro Ser Gln Ser Gly Gln
755 760 765
Val Lys Ile Ala Pro Thr Val Thr Gly Asn Ile Ser Ile Pro Thr Asn
770 775 780
Phe Ser Met Ser Ile Arg Thr Glu Tyr Leu Gln Leu Tyr Asn Thr Pro
785 790 795 800
Val Ser Val Asp Cys Ala Thr Tyr Val Cys Asn Gly Asn Ser Arg Cys
805 810 815
Lys Gln Leu Leu Thr Gln Tyr Thr Ala Ala Cys Lys Thr Ile Glu Ser
820 825 830
Ala Leu Gln Leu Ser Ala Arg Leu Glu Ser Val Glu Val Asn Ser Met
835 840 845
Leu Thr Ile Ser Glu Glu Ala Leu Gln Leu Ala Thr Ile Ser Ser Phe
850 855 860
Asn Gly Asp Gly Tyr Asn Phe Thr Asn Val Leu Gly Val Ser Val Tyr
865 870 875 880
Asp Pro Ala Ser Gly Arg Val Val Gln Lys Arg Ser Phe Ile Glu Asp
885 890 895
Leu Leu Phe Asn Lys Val Val Thr Asn Gly Leu Gly Thr Val Asp Glu
900 905 910
Asp Tyr Lys Arg Cys Ser Asn Gly Arg Ser Val Ala Asp Leu Val Cys
915 920 925
Ala Gln Tyr Tyr Ser Gly Val Met Val Leu Pro Gly Val Val Asp Ala
930 935 940
Glu Lys Leu His Met Tyr Ser Ala Ser Leu Ile Gly Gly Met Val Leu
945 950 955 960
Gly Gly Phe Thr Ser Ala Ala Ala Leu Pro Phe Ser Tyr Ala Val Gln
965 970 975
Ala Arg Leu Asn Tyr Leu Ala Leu Gln Thr Asp Val Leu Gln Arg Asn
980 985 990
Gln Gln Leu Leu Ala Glu Ser Phe Asn Ser Ala Ile Gly Asn Ile Thr
995 1000 1005
Ser Ala Phe Glu Ser Val Lys Glu Ala Ile Ser Gln Thr Ser Lys
1010 1015 1020
Gly Leu Asn Thr Val Ala His Ala Leu Thr Lys Val Gln Glu Val
1025 1030 1035
Val Asn Ser Gln Gly Ala Ala Leu Thr Gln Leu Thr Val Gln Leu
1040 1045 1050
Gln His Asn Phe Gln Ala Ile Ser Ser Ser Ile Asp Asp Ile Tyr
1055 1060 1065
Ser Arg Leu Asp Ile Leu Ser Ala Asp Val Gln Val Asp Arg Leu
1070 1075 1080
Ile Thr Gly Arg Leu Ser Ala Leu Asn Ala Phe Val Ala Gln Thr
1085 1090 1095
Leu Thr Lys Tyr Thr Glu Val Gln Ala Ser Arg Lys Leu Ala Gln
1100 1105 1110
Gln Lys Val Asn Glu Cys Val Lys Ser Gln Ser Gln Arg Tyr Gly
1115 1120 1125
Phe Cys Gly Gly Asp Gly Glu His Ile Phe Ser Leu Val Gln Ala
1130 1135 1140
Ala Pro Gln Gly Leu Leu Phe Leu His Thr Val Leu Val Pro Gly
1145 1150 1155
Asp Phe Ile Asp Val Ile Ala Ile Ala Gly Leu Cys Val Asn Asp
1160 1165 1170
Glu Ile Ala Leu Thr Leu Arg Glu Pro Gly Leu Val Leu Phe Thr
1175 1180 1185
His Glu Leu Gln Asn His Thr Ala Thr Glu Tyr Phe Val Ser Ser
1190 1195 1200
Arg Arg Met Phe Glu Pro Arg Lys Pro Thr Val Ser Asp Phe Val
1205 1210 1215
Gln Ile Glu Ser Cys Val Val Thr Tyr Val Asn Leu Thr Arg Asp
1220 1225 1230
Gln Leu Pro Asp Val Ile Pro Asp Tyr Ile Asp Val Asn Lys Thr
1235 1240 1245
Leu Asp Glu Ile Leu Ala Ser Leu Pro Asn Arg Thr Gly Pro Ser
1250 1255 1260
Leu Pro Leu Asp Val Phe Asn Ala Thr Tyr Leu Asn Leu Thr Gly
1265 1270 1275
Glu Ile Ala Asp Leu Glu Gln Arg Ser Glu Ser Leu Arg Asn Thr
1280 1285 1290
Thr Glu Glu Leu Gln Ser Leu Ile Tyr Asn Ile Asn Asn Thr Leu
1295 1300 1305
Val Asp Leu Glu Trp Leu Asn Arg Val Glu Thr Tyr Ile Lys Trp
1310 1315 1320
Pro Trp Trp Val Trp Leu Ile Val Phe Ile Val Leu Ile Phe Val
1325 1330 1335
Val Ser Leu Leu Val Phe Cys Cys Ile Ser Thr Gly Cys Cys Gly
1340 1345 1350
Cys Cys Gly Cys Cys Cys Ala Cys Phe Ser Gly Cys Cys Arg Gly
1355 1360 1365
Pro Arg Leu Gln Pro Tyr Glu Val Phe Glu Lys Val His Val Gln
1370 1375 1380
<210> 4
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 包括X1之融合结构域之序列
<220>
<221> 变体
<222> (3)..(3)
<223> 残基3处之X可为任一氨基酸残基
<400> 4
Arg Ser Xaa Ile Glu Asp Leu Leu Phe
1 5
<210> 5
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 包括X1之融合结构域之序列
<220>
<221> 变体
<222> (3)..(3)
<223> 残基3处之X可为任一氨基酸残基
<400> 5
Arg Ser Xaa Ile Glu Asp Ala Ala Phe
1 5
<210> 6
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 包括X1、X2、X3、X4、X5、X6、X7及X8之融合结构域之序列
<220>
<221> 变体
<222> (1)..(1)
<223> 残基1处之X系酪氨酸残基，或残基1处之X系除酪氨酸残基以外之氨基酸残基
<220>
<221> 变体
<222> (2)..(2)
<223> 残基2处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (3)..(3)
<223> 残基3处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (5)..(5)
<223> 残基5处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (7)..(7)
<223> 残基7处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (8)..(8)
<223> 残基8处之X系组氨酸残基，或残基8处之X系除组氨酸残基以外之氨基酸残基
<220>
<221> 变体
<222> (9)..(9)
<223> 残基9处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (10)..(10)
<223> 残基10处之X可为任一氨基酸残基
<400> 6
Xaa Xaa Xaa Phe Xaa Lys Xaa Xaa Xaa Xaa
1 5 10
<210> 7
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 保留结构域之序列
<220>
<221> 变体
<222> (2)..(2)
<223> 残基2处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (3)..(3)
<223> 残基3处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (5)..(5)
<223> 残基5处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (7)..(7)
<223> 残基7处之X可为任一氨基酸残基
<400> 7
Tyr Xaa Xaa Phe Xaa Lys Xaa His
1 5
<210> 8
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 保留结构域之序列
<220>
<221> 变体
<222> (2)..(2)
<223> 残基2处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (3)..(3)
<223> 残基3处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (5)..(5)
<223> 残基5处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (7)..(7)
<223> 残基7处之X可为任一氨基酸残基
<400> 8
Ala Xaa Xaa Phe Xaa Lys Xaa Arg
1 5
<210> 9
<211> 1383
<212> PRT
<213> 猪流行性腹泻病毒
<400> 9
Met Lys Ser Leu Asn Tyr Phe Trp Leu Phe Leu Pro Val Leu Ser Thr
1 5 10 15
Leu Ser Leu Pro Gln Asp Val Thr Arg Cys Gln Ser Thr Ile Asn Phe
20 25 30
Arg Arg Phe Phe Ser Lys Phe Asn Val Gln Ala Pro Ala Val Val Val
35 40 45
Leu Gly Gly Tyr Leu Pro Ser Met Asn Ser Ser Ser Trp Tyr Cys Gly
50 55 60
Thr Gly Leu Glu Thr Ala Ser Gly Val His Gly Ile Phe Leu Ser Tyr
65 70 75 80
Ile Asp Ala Gly Gln Gly Phe Glu Ile Gly Ile Ser Gln Glu Pro Phe
85 90 95
Asp Pro Ser Gly Tyr Gln Leu Tyr Leu His Lys Ala Thr Asn Gly Asn
100 105 110
His Asn Ala Ile Ala Arg Leu Arg Ile Cys Gln Phe Pro Asn Asn Lys
115 120 125
Thr Leu Gly Pro Thr Val Asn Asp Val Thr Thr Gly Arg Asn Cys Leu
130 135 140
Phe Asn Lys Ala Ile Pro Ala Tyr Met Gln Asp Gly Lys Asn Ile Val
145 150 155 160
Val Gly Ile Thr Trp Asp Asn Asp Arg Val Thr Val Phe Ala Asp Lys
165 170 175
Ile Tyr His Phe Tyr Leu Lys Asn Asp Trp Ser Arg Val Ala Thr Arg
180 185 190
Cys Tyr Asn Lys Arg Ser Cys Ala Met Gln Tyr Val Tyr Thr Pro Thr
195 200 205
Tyr Tyr Met Leu Asn Val Thr Ser Ala Gly Glu Asp Gly Ile Tyr Tyr
210 215 220
Glu Pro Cys Thr Ala Asn Cys Ser Gly Tyr Ala Val Asn Val Phe Ala
225 230 235 240
Thr Asp Ser Asn Gly His Ile Pro Glu Gly Phe Ser Phe Asn Asn Trp
245 250 255
Phe Leu Leu Ser Asn Asp Ser Thr Leu Leu His Gly Lys Val Val Ser
260 265 270
Asn Gln Pro Leu Leu Val Asn Cys Leu Leu Ala Ile Pro Lys Ile Tyr
275 280 285
Gly Leu Gly Gln Phe Phe Ser Phe Asn Gln Thr Met Asp Gly Val Cys
290 295 300
Asn Gly Ala Ala Ala Gln Arg Ala Pro Glu Ala Leu Arg Phe Asn Ile
305 310 315 320
Asn Asp Thr Ser Val Ile Leu Ala Glu Gly Ser Ile Val Leu His Thr
325 330 335
Ala Leu Gly Thr Asn Leu Ser Phe Val Cys Ser Asn Ser Ser Asp Pro
340 345 350
His Leu Ala Thr Phe Thr Ile Pro Leu Gly Ala Thr Gln Val Pro Tyr
355 360 365
Tyr Cys Phe Leu Lys Val Asp Thr Tyr Asn Ser Asn Val Tyr Lys Phe
370 375 380
Leu Ala Val Leu Pro Pro Thr Val Arg Glu Ile Val Ile Thr Lys Tyr
385 390 395 400
Gly Asp Val Tyr Val Asn Gly Phe Gly Tyr Leu His Leu Gly Leu Leu
405 410 415
Asp Ala Val Thr Ile Asn Phe Thr Gly His Gly Thr Asp Asp Asp Val
420 425 430
Ser Gly Phe Trp Thr Ile Ala Ser Thr Asn Phe Val Asp Ala Leu Ile
435 440 445
Glu Val Gln Gly Thr Ala Ile Gln Arg Ile Leu Tyr Cys Asp Asp Pro
450 455 460
Val Ser Gln Leu Lys Cys Ser Gln Val Ala Phe Asp Leu Asp Asp Gly
465 470 475 480
Phe Tyr Pro Ile Ser Ser Arg Asn Leu Leu Ser His Glu Gln Pro Ile
485 490 495
Ser Phe Val Thr Leu Pro Ser Phe Asn Asp His Ser Phe Val Asn Ile
500 505 510
Thr Val Ser Ala Ser Phe Gly Gly His Ser Gly Ala Asn Leu Ile Ala
515 520 525
Ser Asp Thr Thr Ile Asn Gly Phe Ser Ser Phe Cys Val Asp Thr Arg
530 535 540
Gln Phe Thr Ile Ser Leu Phe Tyr Asn Val Thr Asn Ser Tyr Gly Tyr
545 550 555 560
Val Ser Lys Ser Gln Asp Ser Asn Cys Pro Phe Thr Leu Gln Ser Val
565 570 575
Asn Asp Tyr Leu Ser Phe Ser Lys Phe Cys Val Ser Thr Ser Leu Leu
580 585 590
Ala Ser Ala Cys Thr Ile Asp Leu Phe Gly Tyr Pro Glu Phe Gly Ser
595 600 605
Gly Val Lys Phe Thr Ser Leu Tyr Phe Gln Phe Thr Glu Gly Glu Leu
610 615 620
Ile Thr Gly Thr Pro Lys Pro Leu Glu Gly Val Thr Asp Val Ser Phe
625 630 635 640
Met Thr Leu Asp Val Cys Thr Lys Tyr Thr Ile Tyr Gly Phe Lys Gly
645 650 655
Glu Gly Ile Ile Thr Leu Thr Asn Ser Ser Phe Leu Ala Gly Val Tyr
660 665 670
Tyr Thr Ser Asp Ser Gly Gln Leu Leu Ala Phe Lys Asn Val Thr Ser
675 680 685
Gly Ala Val Tyr Ser Val Thr Pro Cys Ser Phe Ser Glu Gln Ala Ala
690 695 700
Tyr Val Asp Asp Asp Ile Val Gly Val Ile Ser Ser Leu Ser Ser Ser
705 710 715 720
Thr Phe Asn Ser Thr Arg Glu Leu Pro Gly Phe Phe Tyr His Ser Asn
725 730 735
Asp Gly Ser Asn Cys Thr Glu Pro Val Leu Val Tyr Ser Asn Ile Gly
740 745 750
Val Cys Lys Ser Gly Ser Ile Gly Tyr Val Pro Ser Gln Ser Gly Gln
755 760 765
Val Lys Ile Ala Pro Thr Val Thr Gly Asn Ile Ser Ile Pro Thr Asn
770 775 780
Phe Ser Met Ser Ile Arg Thr Glu Tyr Leu Gln Leu Tyr Asn Thr Pro
785 790 795 800
Val Ser Val Asp Cys Ala Thr Tyr Val Cys Asn Gly Asn Ser Arg Cys
805 810 815
Lys Gln Leu Leu Thr Gln Tyr Thr Ala Ala Cys Lys Thr Ile Glu Ser
820 825 830
Ala Leu Gln Leu Ser Ala Arg Leu Glu Ser Val Glu Val Asn Ser Met
835 840 845
Leu Thr Ile Ser Glu Glu Ala Leu Gln Leu Ala Thr Ile Ser Ser Phe
850 855 860
Asn Gly Asp Gly Tyr Asn Phe Thr Asn Val Leu Gly Val Ser Val Tyr
865 870 875 880
Asp Pro Ala Ser Gly Arg Val Val Gln Lys Arg Ser Phe Ile Glu Asp
885 890 895
Ala Leu Phe Asn Lys Val Val Thr Asn Gly Leu Gly Thr Val Asp Glu
900 905 910
Asp Tyr Lys Arg Cys Ser Asn Gly Arg Ser Val Ala Asp Leu Val Cys
915 920 925
Ala Gln Tyr Tyr Ser Gly Val Met Val Leu Pro Gly Val Val Asp Ala
930 935 940
Glu Lys Leu His Met Tyr Ser Ala Ser Leu Ile Gly Gly Met Val Leu
945 950 955 960
Gly Gly Phe Thr Ser Ala Ala Ala Leu Pro Phe Ser Tyr Ala Val Gln
965 970 975
Ala Arg Leu Asn Tyr Leu Ala Leu Gln Thr Asp Val Leu Gln Arg Asn
980 985 990
Gln Gln Leu Leu Ala Glu Ser Phe Asn Ser Ala Ile Gly Asn Ile Thr
995 1000 1005
Ser Ala Phe Glu Ser Val Lys Glu Ala Ile Ser Gln Thr Ser Lys
1010 1015 1020
Gly Leu Asn Thr Val Ala His Ala Leu Thr Lys Val Gln Glu Val
1025 1030 1035
Val Asn Ser Gln Gly Ala Ala Leu Thr Gln Leu Thr Val Gln Leu
1040 1045 1050
Gln His Asn Phe Gln Ala Ile Ser Ser Ser Ile Asp Asp Ile Tyr
1055 1060 1065
Ser Arg Leu Asp Ile Leu Ser Ala Asp Val Gln Val Asp Arg Leu
1070 1075 1080
Ile Thr Gly Arg Leu Ser Ala Leu Asn Ala Phe Val Ala Gln Thr
1085 1090 1095
Leu Thr Lys Tyr Thr Glu Val Gln Ala Ser Arg Lys Leu Ala Gln
1100 1105 1110
Gln Lys Val Asn Glu Cys Val Lys Ser Gln Ser Gln Arg Tyr Gly
1115 1120 1125
Phe Cys Gly Gly Asp Gly Glu His Ile Phe Ser Leu Val Gln Ala
1130 1135 1140
Ala Pro Gln Gly Leu Leu Phe Leu His Thr Val Leu Val Pro Gly
1145 1150 1155
Asp Phe Ile Asp Val Ile Ala Ile Ala Gly Leu Cys Val Asn Asp
1160 1165 1170
Glu Ile Ala Leu Thr Leu Arg Glu Pro Gly Leu Val Leu Phe Thr
1175 1180 1185
His Glu Leu Gln Asn His Thr Ala Thr Glu Tyr Phe Val Ser Ser
1190 1195 1200
Arg Arg Met Phe Glu Pro Arg Lys Pro Thr Val Ser Asp Phe Val
1205 1210 1215
Gln Ile Glu Ser Cys Val Val Thr Tyr Val Asn Leu Thr Arg Asp
1220 1225 1230
Gln Leu Pro Asp Val Ile Pro Asp Tyr Ile Asp Val Asn Lys Thr
1235 1240 1245
Leu Asp Glu Ile Leu Ala Ser Leu Pro Asn Arg Thr Gly Pro Ser
1250 1255 1260
Leu Pro Leu Asp Val Phe Asn Ala Thr Tyr Leu Asn Leu Thr Gly
1265 1270 1275
Glu Ile Ala Asp Leu Glu Gln Arg Ser Glu Ser Leu Arg Asn Thr
1280 1285 1290
Thr Glu Glu Leu Gln Ser Leu Ile Tyr Asn Ile Asn Asn Thr Leu
1295 1300 1305
Val Asp Leu Glu Trp Leu Asn Arg Val Glu Thr Tyr Ile Lys Trp
1310 1315 1320
Pro Trp Trp Val Trp Leu Ile Val Phe Ile Val Leu Ile Phe Val
1325 1330 1335
Val Ser Leu Leu Val Phe Cys Cys Ile Ser Thr Gly Cys Cys Gly
1340 1345 1350
Cys Cys Gly Cys Cys Cys Ala Cys Phe Ser Gly Cys Cys Arg Gly
1355 1360 1365
Pro Arg Leu Gln Pro Tyr Glu Val Phe Glu Lys Val His Val Gln
1370 1375 1380
<210> 10
<211> 1383
<212> PRT
<213> 猪流行性腹泻病毒
<400> 10
Met Lys Ser Leu Asn Tyr Phe Trp Leu Phe Leu Pro Val Leu Ser Thr
1 5 10 15
Leu Ser Leu Pro Gln Asp Val Thr Arg Cys Gln Ser Thr Ile Asn Phe
20 25 30
Arg Arg Phe Phe Ser Lys Phe Asn Val Gln Ala Pro Ala Val Val Val
35 40 45
Leu Gly Gly Tyr Leu Pro Ser Met Asn Ser Ser Ser Trp Tyr Cys Gly
50 55 60
Thr Gly Leu Glu Thr Ala Ser Gly Val His Gly Ile Phe Leu Ser Tyr
65 70 75 80
Ile Asp Ala Gly Gln Gly Phe Glu Ile Gly Ile Ser Gln Glu Pro Phe
85 90 95
Asp Pro Ser Gly Tyr Gln Leu Tyr Leu His Lys Ala Thr Asn Gly Asn
100 105 110
His Asn Ala Ile Ala Arg Leu Arg Ile Cys Gln Phe Pro Asn Asn Lys
115 120 125
Thr Leu Gly Pro Thr Val Asn Asp Val Thr Thr Gly Arg Asn Cys Leu
130 135 140
Phe Asn Lys Ala Ile Pro Ala Tyr Met Gln Asp Gly Lys Asn Ile Val
145 150 155 160
Val Gly Ile Thr Trp Asp Asn Asp Arg Val Thr Val Phe Ala Asp Lys
165 170 175
Ile Tyr His Phe Tyr Leu Lys Asn Asp Trp Ser Arg Val Ala Thr Arg
180 185 190
Cys Tyr Asn Lys Arg Ser Cys Ala Met Gln Tyr Val Tyr Thr Pro Thr
195 200 205
Tyr Tyr Met Leu Asn Val Thr Ser Ala Gly Glu Asp Gly Ile Tyr Tyr
210 215 220
Glu Pro Cys Thr Ala Asn Cys Ser Gly Tyr Ala Val Asn Val Phe Ala
225 230 235 240
Thr Asp Ser Asn Gly His Ile Pro Glu Gly Phe Ser Phe Asn Asn Trp
245 250 255
Phe Leu Leu Ser Asn Asp Ser Thr Leu Leu His Gly Lys Val Val Ser
260 265 270
Asn Gln Pro Leu Leu Val Asn Cys Leu Leu Ala Ile Pro Lys Ile Tyr
275 280 285
Gly Leu Gly Gln Phe Phe Ser Phe Asn Gln Thr Met Asp Gly Val Cys
290 295 300
Asn Gly Ala Ala Ala Gln Arg Ala Pro Glu Ala Leu Arg Phe Asn Ile
305 310 315 320
Asn Asp Thr Ser Val Ile Leu Ala Glu Gly Ser Ile Val Leu His Thr
325 330 335
Ala Leu Gly Thr Asn Leu Ser Phe Val Cys Ser Asn Ser Ser Asp Pro
340 345 350
His Leu Ala Thr Phe Thr Ile Pro Leu Gly Ala Thr Gln Val Pro Tyr
355 360 365
Tyr Cys Phe Leu Lys Val Asp Thr Tyr Asn Ser Asn Val Tyr Lys Phe
370 375 380
Leu Ala Val Leu Pro Pro Thr Val Arg Glu Ile Val Ile Thr Lys Tyr
385 390 395 400
Gly Asp Val Tyr Val Asn Gly Phe Gly Tyr Leu His Leu Gly Leu Leu
405 410 415
Asp Ala Val Thr Ile Asn Phe Thr Gly His Gly Thr Asp Asp Asp Val
420 425 430
Ser Gly Phe Trp Thr Ile Ala Ser Thr Asn Phe Val Asp Ala Leu Ile
435 440 445
Glu Val Gln Gly Thr Ala Ile Gln Arg Ile Leu Tyr Cys Asp Asp Pro
450 455 460
Val Ser Gln Leu Lys Cys Ser Gln Val Ala Phe Asp Leu Asp Asp Gly
465 470 475 480
Phe Tyr Pro Ile Ser Ser Arg Asn Leu Leu Ser His Glu Gln Pro Ile
485 490 495
Ser Phe Val Thr Leu Pro Ser Phe Asn Asp His Ser Phe Val Asn Ile
500 505 510
Thr Val Ser Ala Ser Phe Gly Gly His Ser Gly Ala Asn Leu Ile Ala
515 520 525
Ser Asp Thr Thr Ile Asn Gly Phe Ser Ser Phe Cys Val Asp Thr Arg
530 535 540
Gln Phe Thr Ile Ser Leu Phe Tyr Asn Val Thr Asn Ser Tyr Gly Tyr
545 550 555 560
Val Ser Lys Ser Gln Asp Ser Asn Cys Pro Phe Thr Leu Gln Ser Val
565 570 575
Asn Asp Tyr Leu Ser Phe Ser Lys Phe Cys Val Ser Thr Ser Leu Leu
580 585 590
Ala Ser Ala Cys Thr Ile Asp Leu Phe Gly Tyr Pro Glu Phe Gly Ser
595 600 605
Gly Val Lys Phe Thr Ser Leu Tyr Phe Gln Phe Thr Glu Gly Glu Leu
610 615 620
Ile Thr Gly Thr Pro Lys Pro Leu Glu Gly Val Thr Asp Val Ser Phe
625 630 635 640
Met Thr Leu Asp Val Cys Thr Lys Tyr Thr Ile Tyr Gly Phe Lys Gly
645 650 655
Glu Gly Ile Ile Thr Leu Thr Asn Ser Ser Phe Leu Ala Gly Val Tyr
660 665 670
Tyr Thr Ser Asp Ser Gly Gln Leu Leu Ala Phe Lys Asn Val Thr Ser
675 680 685
Gly Ala Val Tyr Ser Val Thr Pro Cys Ser Phe Ser Glu Gln Ala Ala
690 695 700
Tyr Val Asp Asp Asp Ile Val Gly Val Ile Ser Ser Leu Ser Ser Ser
705 710 715 720
Thr Phe Asn Ser Thr Arg Glu Leu Pro Gly Phe Phe Tyr His Ser Asn
725 730 735
Asp Gly Ser Asn Cys Thr Glu Pro Val Leu Val Tyr Ser Asn Ile Gly
740 745 750
Val Cys Lys Ser Gly Ser Ile Gly Tyr Val Pro Ser Gln Ser Gly Gln
755 760 765
Val Lys Ile Ala Pro Thr Val Thr Gly Asn Ile Ser Ile Pro Thr Asn
770 775 780
Phe Ser Met Ser Ile Arg Thr Glu Tyr Leu Gln Leu Tyr Asn Thr Pro
785 790 795 800
Val Ser Val Asp Cys Ala Thr Tyr Val Cys Asn Gly Asn Ser Arg Cys
805 810 815
Lys Gln Leu Leu Thr Gln Tyr Thr Ala Ala Cys Lys Thr Ile Glu Ser
820 825 830
Ala Leu Gln Leu Ser Ala Arg Leu Glu Ser Val Glu Val Asn Ser Met
835 840 845
Leu Thr Ile Ser Glu Glu Ala Leu Gln Leu Ala Thr Ile Ser Ser Phe
850 855 860
Asn Gly Asp Gly Tyr Asn Phe Thr Asn Val Leu Gly Val Ser Val Tyr
865 870 875 880
Asp Pro Ala Ser Gly Arg Val Val Gln Lys Arg Ser Phe Ile Glu Asp
885 890 895
Leu Ala Phe Asn Lys Val Val Thr Asn Gly Leu Gly Thr Val Asp Glu
900 905 910
Asp Tyr Lys Arg Cys Ser Asn Gly Arg Ser Val Ala Asp Leu Val Cys
915 920 925
Ala Gln Tyr Tyr Ser Gly Val Met Val Leu Pro Gly Val Val Asp Ala
930 935 940
Glu Lys Leu His Met Tyr Ser Ala Ser Leu Ile Gly Gly Met Val Leu
945 950 955 960
Gly Gly Phe Thr Ser Ala Ala Ala Leu Pro Phe Ser Tyr Ala Val Gln
965 970 975
Ala Arg Leu Asn Tyr Leu Ala Leu Gln Thr Asp Val Leu Gln Arg Asn
980 985 990
Gln Gln Leu Leu Ala Glu Ser Phe Asn Ser Ala Ile Gly Asn Ile Thr
995 1000 1005
Ser Ala Phe Glu Ser Val Lys Glu Ala Ile Ser Gln Thr Ser Lys
1010 1015 1020
Gly Leu Asn Thr Val Ala His Ala Leu Thr Lys Val Gln Glu Val
1025 1030 1035
Val Asn Ser Gln Gly Ala Ala Leu Thr Gln Leu Thr Val Gln Leu
1040 1045 1050
Gln His Asn Phe Gln Ala Ile Ser Ser Ser Ile Asp Asp Ile Tyr
1055 1060 1065
Ser Arg Leu Asp Ile Leu Ser Ala Asp Val Gln Val Asp Arg Leu
1070 1075 1080
Ile Thr Gly Arg Leu Ser Ala Leu Asn Ala Phe Val Ala Gln Thr
1085 1090 1095
Leu Thr Lys Tyr Thr Glu Val Gln Ala Ser Arg Lys Leu Ala Gln
1100 1105 1110
Gln Lys Val Asn Glu Cys Val Lys Ser Gln Ser Gln Arg Tyr Gly
1115 1120 1125
Phe Cys Gly Gly Asp Gly Glu His Ile Phe Ser Leu Val Gln Ala
1130 1135 1140
Ala Pro Gln Gly Leu Leu Phe Leu His Thr Val Leu Val Pro Gly
1145 1150 1155
Asp Phe Ile Asp Val Ile Ala Ile Ala Gly Leu Cys Val Asn Asp
1160 1165 1170
Glu Ile Ala Leu Thr Leu Arg Glu Pro Gly Leu Val Leu Phe Thr
1175 1180 1185
His Glu Leu Gln Asn His Thr Ala Thr Glu Tyr Phe Val Ser Ser
1190 1195 1200
Arg Arg Met Phe Glu Pro Arg Lys Pro Thr Val Ser Asp Phe Val
1205 1210 1215
Gln Ile Glu Ser Cys Val Val Thr Tyr Val Asn Leu Thr Arg Asp
1220 1225 1230
Gln Leu Pro Asp Val Ile Pro Asp Tyr Ile Asp Val Asn Lys Thr
1235 1240 1245
Leu Asp Glu Ile Leu Ala Ser Leu Pro Asn Arg Thr Gly Pro Ser
1250 1255 1260
Leu Pro Leu Asp Val Phe Asn Ala Thr Tyr Leu Asn Leu Thr Gly
1265 1270 1275
Glu Ile Ala Asp Leu Glu Gln Arg Ser Glu Ser Leu Arg Asn Thr
1280 1285 1290
Thr Glu Glu Leu Gln Ser Leu Ile Tyr Asn Ile Asn Asn Thr Leu
1295 1300 1305
Val Asp Leu Glu Trp Leu Asn Arg Val Glu Thr Tyr Ile Lys Trp
1310 1315 1320
Pro Trp Trp Val Trp Leu Ile Val Phe Ile Val Leu Ile Phe Val
1325 1330 1335
Val Ser Leu Leu Val Phe Cys Cys Ile Ser Thr Gly Cys Cys Gly
1340 1345 1350
Cys Cys Gly Cys Cys Cys Ala Cys Phe Ser Gly Cys Cys Arg Gly
1355 1360 1365
Pro Arg Leu Gln Pro Tyr Glu Val Phe Glu Lys Val His Val Gln
1370 1375 1380
<210> 11
<211> 1383
<212> PRT
<213> 猪流行性腹泻病毒
<400> 11
Met Lys Ser Leu Asn Tyr Phe Trp Leu Phe Leu Pro Val Leu Ser Thr
1 5 10 15
Leu Ser Leu Pro Gln Asp Val Thr Arg Cys Gln Ser Thr Ile Asn Phe
20 25 30
Arg Arg Phe Phe Ser Lys Phe Asn Val Gln Ala Pro Ala Val Val Val
35 40 45
Leu Gly Gly Tyr Leu Pro Ser Met Asn Ser Ser Ser Trp Tyr Cys Gly
50 55 60
Thr Gly Leu Glu Thr Ala Ser Gly Val His Gly Ile Phe Leu Ser Tyr
65 70 75 80
Ile Asp Ala Gly Gln Gly Phe Glu Ile Gly Ile Ser Gln Glu Pro Phe
85 90 95
Asp Pro Ser Gly Tyr Gln Leu Tyr Leu His Lys Ala Thr Asn Gly Asn
100 105 110
His Asn Ala Ile Ala Arg Leu Arg Ile Cys Gln Phe Pro Asn Asn Lys
115 120 125
Thr Leu Gly Pro Thr Val Asn Asp Val Thr Thr Gly Arg Asn Cys Leu
130 135 140
Phe Asn Lys Ala Ile Pro Ala Tyr Met Gln Asp Gly Lys Asn Ile Val
145 150 155 160
Val Gly Ile Thr Trp Asp Asn Asp Arg Val Thr Val Phe Ala Asp Lys
165 170 175
Ile Tyr His Phe Tyr Leu Lys Asn Asp Trp Ser Arg Val Ala Thr Arg
180 185 190
Cys Tyr Asn Lys Arg Ser Cys Ala Met Gln Tyr Val Tyr Thr Pro Thr
195 200 205
Tyr Tyr Met Leu Asn Val Thr Ser Ala Gly Glu Asp Gly Ile Tyr Tyr
210 215 220
Glu Pro Cys Thr Ala Asn Cys Ser Gly Tyr Ala Val Asn Val Phe Ala
225 230 235 240
Thr Asp Ser Asn Gly His Ile Pro Glu Gly Phe Ser Phe Asn Asn Trp
245 250 255
Phe Leu Leu Ser Asn Asp Ser Thr Leu Leu His Gly Lys Val Val Ser
260 265 270
Asn Gln Pro Leu Leu Val Asn Cys Leu Leu Ala Ile Pro Lys Ile Tyr
275 280 285
Gly Leu Gly Gln Phe Phe Ser Phe Asn Gln Thr Met Asp Gly Val Cys
290 295 300
Asn Gly Ala Ala Ala Gln Arg Ala Pro Glu Ala Leu Arg Phe Asn Ile
305 310 315 320
Asn Asp Thr Ser Val Ile Leu Ala Glu Gly Ser Ile Val Leu His Thr
325 330 335
Ala Leu Gly Thr Asn Leu Ser Phe Val Cys Ser Asn Ser Ser Asp Pro
340 345 350
His Leu Ala Thr Phe Thr Ile Pro Leu Gly Ala Thr Gln Val Pro Tyr
355 360 365
Tyr Cys Phe Leu Lys Val Asp Thr Tyr Asn Ser Asn Val Tyr Lys Phe
370 375 380
Leu Ala Val Leu Pro Pro Thr Val Arg Glu Ile Val Ile Thr Lys Tyr
385 390 395 400
Gly Asp Val Tyr Val Asn Gly Phe Gly Tyr Leu His Leu Gly Leu Leu
405 410 415
Asp Ala Val Thr Ile Asn Phe Thr Gly His Gly Thr Asp Asp Asp Val
420 425 430
Ser Gly Phe Trp Thr Ile Ala Ser Thr Asn Phe Val Asp Ala Leu Ile
435 440 445
Glu Val Gln Gly Thr Ala Ile Gln Arg Ile Leu Tyr Cys Asp Asp Pro
450 455 460
Val Ser Gln Leu Lys Cys Ser Gln Val Ala Phe Asp Leu Asp Asp Gly
465 470 475 480
Phe Tyr Pro Ile Ser Ser Arg Asn Leu Leu Ser His Glu Gln Pro Ile
485 490 495
Ser Phe Val Thr Leu Pro Ser Phe Asn Asp His Ser Phe Val Asn Ile
500 505 510
Thr Val Ser Ala Ser Phe Gly Gly His Ser Gly Ala Asn Leu Ile Ala
515 520 525
Ser Asp Thr Thr Ile Asn Gly Phe Ser Ser Phe Cys Val Asp Thr Arg
530 535 540
Gln Phe Thr Ile Ser Leu Phe Tyr Asn Val Thr Asn Ser Tyr Gly Tyr
545 550 555 560
Val Ser Lys Ser Gln Asp Ser Asn Cys Pro Phe Thr Leu Gln Ser Val
565 570 575
Asn Asp Tyr Leu Ser Phe Ser Lys Phe Cys Val Ser Thr Ser Leu Leu
580 585 590
Ala Ser Ala Cys Thr Ile Asp Leu Phe Gly Tyr Pro Glu Phe Gly Ser
595 600 605
Gly Val Lys Phe Thr Ser Leu Tyr Phe Gln Phe Thr Glu Gly Glu Leu
610 615 620
Ile Thr Gly Thr Pro Lys Pro Leu Glu Gly Val Thr Asp Val Ser Phe
625 630 635 640
Met Thr Leu Asp Val Cys Thr Lys Tyr Thr Ile Tyr Gly Phe Lys Gly
645 650 655
Glu Gly Ile Ile Thr Leu Thr Asn Ser Ser Phe Leu Ala Gly Val Tyr
660 665 670
Tyr Thr Ser Asp Ser Gly Gln Leu Leu Ala Phe Lys Asn Val Thr Ser
675 680 685
Gly Ala Val Tyr Ser Val Thr Pro Cys Ser Phe Ser Glu Gln Ala Ala
690 695 700
Tyr Val Asp Asp Asp Ile Val Gly Val Ile Ser Ser Leu Ser Ser Ser
705 710 715 720
Thr Phe Asn Ser Thr Arg Glu Leu Pro Gly Phe Phe Tyr His Ser Asn
725 730 735
Asp Gly Ser Asn Cys Thr Glu Pro Val Leu Val Tyr Ser Asn Ile Gly
740 745 750
Val Cys Lys Ser Gly Ser Ile Gly Tyr Val Pro Ser Gln Ser Gly Gln
755 760 765
Val Lys Ile Ala Pro Thr Val Thr Gly Asn Ile Ser Ile Pro Thr Asn
770 775 780
Phe Ser Met Ser Ile Arg Thr Glu Tyr Leu Gln Leu Tyr Asn Thr Pro
785 790 795 800
Val Ser Val Asp Cys Ala Thr Tyr Val Cys Asn Gly Asn Ser Arg Cys
805 810 815
Lys Gln Leu Leu Thr Gln Tyr Thr Ala Ala Cys Lys Thr Ile Glu Ser
820 825 830
Ala Leu Gln Leu Ser Ala Arg Leu Glu Ser Val Glu Val Asn Ser Met
835 840 845
Leu Thr Ile Ser Glu Glu Ala Leu Gln Leu Ala Thr Ile Ser Ser Phe
850 855 860
Asn Gly Asp Gly Tyr Asn Phe Thr Asn Val Leu Gly Val Ser Val Tyr
865 870 875 880
Asp Pro Ala Ser Gly Arg Val Val Gln Lys Arg Ser Phe Ile Glu Asp
885 890 895
Ala Ala Phe Asn Lys Val Val Thr Asn Gly Leu Gly Thr Val Asp Glu
900 905 910
Asp Tyr Lys Arg Cys Ser Asn Gly Arg Ser Val Ala Asp Leu Val Cys
915 920 925
Ala Gln Tyr Tyr Ser Gly Val Met Val Leu Pro Gly Val Val Asp Ala
930 935 940
Glu Lys Leu His Met Tyr Ser Ala Ser Leu Ile Gly Gly Met Val Leu
945 950 955 960
Gly Gly Phe Thr Ser Ala Ala Ala Leu Pro Phe Ser Tyr Ala Val Gln
965 970 975
Ala Arg Leu Asn Tyr Leu Ala Leu Gln Thr Asp Val Leu Gln Arg Asn
980 985 990
Gln Gln Leu Leu Ala Glu Ser Phe Asn Ser Ala Ile Gly Asn Ile Thr
995 1000 1005
Ser Ala Phe Glu Ser Val Lys Glu Ala Ile Ser Gln Thr Ser Lys
1010 1015 1020
Gly Leu Asn Thr Val Ala His Ala Leu Thr Lys Val Gln Glu Val
1025 1030 1035
Val Asn Ser Gln Gly Ala Ala Leu Thr Gln Leu Thr Val Gln Leu
1040 1045 1050
Gln His Asn Phe Gln Ala Ile Ser Ser Ser Ile Asp Asp Ile Tyr
1055 1060 1065
Ser Arg Leu Asp Ile Leu Ser Ala Asp Val Gln Val Asp Arg Leu
1070 1075 1080
Ile Thr Gly Arg Leu Ser Ala Leu Asn Ala Phe Val Ala Gln Thr
1085 1090 1095
Leu Thr Lys Tyr Thr Glu Val Gln Ala Ser Arg Lys Leu Ala Gln
1100 1105 1110
Gln Lys Val Asn Glu Cys Val Lys Ser Gln Ser Gln Arg Tyr Gly
1115 1120 1125
Phe Cys Gly Gly Asp Gly Glu His Ile Phe Ser Leu Val Gln Ala
1130 1135 1140
Ala Pro Gln Gly Leu Leu Phe Leu His Thr Val Leu Val Pro Gly
1145 1150 1155
Asp Phe Ile Asp Val Ile Ala Ile Ala Gly Leu Cys Val Asn Asp
1160 1165 1170
Glu Ile Ala Leu Thr Leu Arg Glu Pro Gly Leu Val Leu Phe Thr
1175 1180 1185
His Glu Leu Gln Asn His Thr Ala Thr Glu Tyr Phe Val Ser Ser
1190 1195 1200
Arg Arg Met Phe Glu Pro Arg Lys Pro Thr Val Ser Asp Phe Val
1205 1210 1215
Gln Ile Glu Ser Cys Val Val Thr Tyr Val Asn Leu Thr Arg Asp
1220 1225 1230
Gln Leu Pro Asp Val Ile Pro Asp Tyr Ile Asp Val Asn Lys Thr
1235 1240 1245
Leu Asp Glu Ile Leu Ala Ser Leu Pro Asn Arg Thr Gly Pro Ser
1250 1255 1260
Leu Pro Leu Asp Val Phe Asn Ala Thr Tyr Leu Asn Leu Thr Gly
1265 1270 1275
Glu Ile Ala Asp Leu Glu Gln Arg Ser Glu Ser Leu Arg Asn Thr
1280 1285 1290
Thr Glu Glu Leu Gln Ser Leu Ile Tyr Asn Ile Asn Asn Thr Leu
1295 1300 1305
Val Asp Leu Glu Trp Leu Asn Arg Val Glu Thr Tyr Ile Lys Trp
1310 1315 1320
Pro Trp Trp Val Trp Leu Ile Val Phe Ile Val Leu Ile Phe Val
1325 1330 1335
Val Ser Leu Leu Val Phe Cys Cys Ile Ser Thr Gly Cys Cys Gly
1340 1345 1350
Cys Cys Gly Cys Cys Cys Ala Cys Phe Ser Gly Cys Cys Arg Gly
1355 1360 1365
Pro Arg Leu Gln Pro Tyr Glu Val Phe Glu Lys Val His Val Gln
1370 1375 1380
<210> 12
<211> 1383
<212> PRT
<213> 猪流行性腹泻病毒
<400> 12
Met Lys Ser Leu Asn Tyr Phe Trp Leu Phe Leu Pro Val Leu Ser Thr
1 5 10 15
Leu Ser Leu Pro Gln Asp Val Thr Arg Cys Gln Ser Thr Ile Asn Phe
20 25 30
Arg Arg Phe Phe Ser Lys Phe Asn Val Gln Ala Pro Ala Val Val Val
35 40 45
Leu Gly Gly Tyr Leu Pro Ser Met Asn Ser Ser Ser Trp Tyr Cys Gly
50 55 60
Thr Gly Leu Glu Thr Ala Ser Gly Val His Gly Ile Phe Leu Ser Tyr
65 70 75 80
Ile Asp Ala Gly Gln Gly Phe Glu Ile Gly Ile Ser Gln Glu Pro Phe
85 90 95
Asp Pro Ser Gly Tyr Gln Leu Tyr Leu His Lys Ala Thr Asn Gly Asn
100 105 110
His Asn Ala Ile Ala Arg Leu Arg Ile Cys Gln Phe Pro Asn Asn Lys
115 120 125
Thr Leu Gly Pro Thr Val Asn Asp Val Thr Thr Gly Arg Asn Cys Leu
130 135 140
Phe Asn Lys Ala Ile Pro Ala Tyr Met Gln Asp Gly Lys Asn Ile Val
145 150 155 160
Val Gly Ile Thr Trp Asp Asn Asp Arg Val Thr Val Phe Ala Asp Lys
165 170 175
Ile Tyr His Phe Tyr Leu Lys Asn Asp Trp Ser Arg Val Ala Thr Arg
180 185 190
Cys Tyr Asn Lys Arg Ser Cys Ala Met Gln Tyr Val Tyr Thr Pro Thr
195 200 205
Tyr Tyr Met Leu Asn Val Thr Ser Ala Gly Glu Asp Gly Ile Tyr Tyr
210 215 220
Glu Pro Cys Thr Ala Asn Cys Ser Gly Tyr Ala Val Asn Val Phe Ala
225 230 235 240
Thr Asp Ser Asn Gly His Ile Pro Glu Gly Phe Ser Phe Asn Asn Trp
245 250 255
Phe Leu Leu Ser Asn Asp Ser Thr Leu Leu His Gly Lys Val Val Ser
260 265 270
Asn Gln Pro Leu Leu Val Asn Cys Leu Leu Ala Ile Pro Lys Ile Tyr
275 280 285
Gly Leu Gly Gln Phe Phe Ser Phe Asn Gln Thr Met Asp Gly Val Cys
290 295 300
Asn Gly Ala Ala Ala Gln Arg Ala Pro Glu Ala Leu Arg Phe Asn Ile
305 310 315 320
Asn Asp Thr Ser Val Ile Leu Ala Glu Gly Ser Ile Val Leu His Thr
325 330 335
Ala Leu Gly Thr Asn Leu Ser Phe Val Cys Ser Asn Ser Ser Asp Pro
340 345 350
His Leu Ala Thr Phe Thr Ile Pro Leu Gly Ala Thr Gln Val Pro Tyr
355 360 365
Tyr Cys Phe Leu Lys Val Asp Thr Tyr Asn Ser Asn Val Tyr Lys Phe
370 375 380
Leu Ala Val Leu Pro Pro Thr Val Arg Glu Ile Val Ile Thr Lys Tyr
385 390 395 400
Gly Asp Val Tyr Val Asn Gly Phe Gly Tyr Leu His Leu Gly Leu Leu
405 410 415
Asp Ala Val Thr Ile Asn Phe Thr Gly His Gly Thr Asp Asp Asp Val
420 425 430
Ser Gly Phe Trp Thr Ile Ala Ser Thr Asn Phe Val Asp Ala Leu Ile
435 440 445
Glu Val Gln Gly Thr Ala Ile Gln Arg Ile Leu Tyr Cys Asp Asp Pro
450 455 460
Val Ser Gln Leu Lys Cys Ser Gln Val Ala Phe Asp Leu Asp Asp Gly
465 470 475 480
Phe Tyr Pro Ile Ser Ser Arg Asn Leu Leu Ser His Glu Gln Pro Ile
485 490 495
Ser Phe Val Thr Leu Pro Ser Phe Asn Asp His Ser Phe Val Asn Ile
500 505 510
Thr Val Ser Ala Ser Phe Gly Gly His Ser Gly Ala Asn Leu Ile Ala
515 520 525
Ser Asp Thr Thr Ile Asn Gly Phe Ser Ser Phe Cys Val Asp Thr Arg
530 535 540
Gln Phe Thr Ile Ser Leu Phe Tyr Asn Val Thr Asn Ser Tyr Gly Tyr
545 550 555 560
Val Ser Lys Ser Gln Asp Ser Asn Cys Pro Phe Thr Leu Gln Ser Val
565 570 575
Asn Asp Tyr Leu Ser Phe Ser Lys Phe Cys Val Ser Thr Ser Leu Leu
580 585 590
Ala Ser Ala Cys Thr Ile Asp Leu Phe Gly Tyr Pro Glu Phe Gly Ser
595 600 605
Gly Val Lys Phe Thr Ser Leu Tyr Phe Gln Phe Thr Glu Gly Glu Leu
610 615 620
Ile Thr Gly Thr Pro Lys Pro Leu Glu Gly Val Thr Asp Val Ser Phe
625 630 635 640
Met Thr Leu Asp Val Cys Thr Lys Tyr Thr Ile Tyr Gly Phe Lys Gly
645 650 655
Glu Gly Ile Ile Thr Leu Thr Asn Ser Ser Phe Leu Ala Gly Val Tyr
660 665 670
Tyr Thr Ser Asp Ser Gly Gln Leu Leu Ala Phe Lys Asn Val Thr Ser
675 680 685
Gly Ala Val Tyr Ser Val Thr Pro Cys Ser Phe Ser Glu Gln Ala Ala
690 695 700
Tyr Val Asp Asp Asp Ile Val Gly Val Ile Ser Ser Leu Ser Ser Ser
705 710 715 720
Thr Phe Asn Ser Thr Arg Glu Leu Pro Gly Phe Phe Tyr His Ser Asn
725 730 735
Asp Gly Ser Asn Cys Thr Glu Pro Val Leu Val Tyr Ser Asn Ile Gly
740 745 750
Val Cys Lys Ser Gly Ser Ile Gly Tyr Val Pro Ser Gln Ser Gly Gln
755 760 765
Val Lys Ile Ala Pro Thr Val Thr Gly Asn Ile Ser Ile Pro Thr Asn
770 775 780
Phe Ser Met Ser Ile Arg Thr Glu Tyr Leu Gln Leu Tyr Asn Thr Pro
785 790 795 800
Val Ser Val Asp Cys Ala Thr Tyr Val Cys Asn Gly Asn Ser Arg Cys
805 810 815
Lys Gln Leu Leu Thr Gln Tyr Thr Ala Ala Cys Lys Thr Ile Glu Ser
820 825 830
Ala Leu Gln Leu Ser Ala Arg Leu Glu Ser Val Glu Val Asn Ser Met
835 840 845
Leu Thr Ile Ser Glu Glu Ala Leu Gln Leu Ala Thr Ile Ser Ser Phe
850 855 860
Asn Gly Asp Gly Tyr Asn Phe Thr Asn Val Leu Gly Val Ser Val Tyr
865 870 875 880
Asp Pro Ala Ser Gly Arg Val Val Gln Lys Arg Ser Phe Ile Glu Asp
885 890 895
Ala Leu Phe Asn Lys Val Val Thr Asn Gly Leu Gly Thr Val Asp Glu
900 905 910
Asp Tyr Lys Arg Cys Ser Asn Gly Arg Ser Val Ala Asp Leu Val Cys
915 920 925
Ala Gln Tyr Tyr Ser Gly Val Met Val Leu Pro Gly Val Val Asp Ala
930 935 940
Glu Lys Leu His Met Tyr Ser Ala Ser Leu Ile Gly Gly Met Val Leu
945 950 955 960
Gly Gly Phe Thr Ser Ala Ala Ala Leu Pro Phe Ser Tyr Ala Val Gln
965 970 975
Ala Arg Leu Asn Tyr Leu Ala Leu Gln Thr Asp Val Leu Gln Arg Asn
980 985 990
Gln Gln Leu Leu Ala Glu Ser Phe Asn Ser Ala Ile Gly Asn Ile Thr
995 1000 1005
Ser Ala Phe Glu Ser Val Lys Glu Ala Ile Ser Gln Thr Ser Lys
1010 1015 1020
Gly Leu Asn Thr Val Ala His Ala Leu Thr Lys Val Gln Glu Val
1025 1030 1035
Val Asn Ser Gln Gly Ala Ala Leu Thr Gln Leu Thr Val Gln Leu
1040 1045 1050
Gln His Asn Phe Gln Ala Ile Ser Ser Ser Ile Asp Asp Ile Tyr
1055 1060 1065
Ser Arg Leu Asp Ile Leu Ser Ala Asp Val Gln Val Asp Arg Leu
1070 1075 1080
Ile Thr Gly Arg Leu Ser Ala Leu Asn Ala Phe Val Ala Gln Thr
1085 1090 1095
Leu Thr Lys Tyr Thr Glu Val Gln Ala Ser Arg Lys Leu Ala Gln
1100 1105 1110
Gln Lys Val Asn Glu Cys Val Lys Ser Gln Ser Gln Arg Tyr Gly
1115 1120 1125
Phe Cys Gly Gly Asp Gly Glu His Ile Phe Ser Leu Val Gln Ala
1130 1135 1140
Ala Pro Gln Gly Leu Leu Phe Leu His Thr Val Leu Val Pro Gly
1145 1150 1155
Asp Phe Ile Asp Val Ile Ala Ile Ala Gly Leu Cys Val Asn Asp
1160 1165 1170
Glu Ile Ala Leu Thr Leu Arg Glu Pro Gly Leu Val Leu Phe Thr
1175 1180 1185
His Glu Leu Gln Asn His Thr Ala Thr Glu Tyr Phe Val Ser Ser
1190 1195 1200
Arg Arg Met Phe Glu Pro Arg Lys Pro Thr Val Ser Asp Phe Val
1205 1210 1215
Gln Ile Glu Ser Cys Val Val Thr Tyr Val Asn Leu Thr Arg Asp
1220 1225 1230
Gln Leu Pro Asp Val Ile Pro Asp Tyr Ile Asp Val Asn Lys Thr
1235 1240 1245
Leu Asp Glu Ile Leu Ala Ser Leu Pro Asn Arg Thr Gly Pro Ser
1250 1255 1260
Leu Pro Leu Asp Val Phe Asn Ala Thr Tyr Leu Asn Leu Thr Gly
1265 1270 1275
Glu Ile Ala Asp Leu Glu Gln Arg Ser Glu Ser Leu Arg Asn Thr
1280 1285 1290
Thr Glu Glu Leu Gln Ser Leu Ile Tyr Asn Ile Asn Asn Thr Leu
1295 1300 1305
Val Asp Leu Glu Trp Leu Asn Arg Val Glu Thr Tyr Ile Lys Trp
1310 1315 1320
Pro Trp Trp Val Trp Leu Ile Val Phe Ile Val Leu Ile Phe Val
1325 1330 1335
Val Ser Leu Leu Val Phe Cys Cys Ile Ser Thr Gly Cys Cys Gly
1340 1345 1350
Cys Cys Gly Cys Cys Cys Ala Cys Phe Ser Gly Cys Cys Arg Gly
1355 1360 1365
Pro Arg Leu Gln Pro Ala Glu Val Phe Glu Lys Val Arg Val Gln
1370 1375 1380
<210> 13
<211> 1383
<212> PRT
<213> 猪流行性腹泻病毒
<400> 13
Met Lys Ser Leu Asn Tyr Phe Trp Leu Phe Leu Pro Val Leu Ser Thr
1 5 10 15
Leu Ser Leu Pro Gln Asp Val Thr Arg Cys Gln Ser Thr Ile Asn Phe
20 25 30
Arg Arg Phe Phe Ser Lys Phe Asn Val Gln Ala Pro Ala Val Val Val
35 40 45
Leu Gly Gly Tyr Leu Pro Ser Met Asn Ser Ser Ser Trp Tyr Cys Gly
50 55 60
Thr Gly Leu Glu Thr Ala Ser Gly Val His Gly Ile Phe Leu Ser Tyr
65 70 75 80
Ile Asp Ala Gly Gln Gly Phe Glu Ile Gly Ile Ser Gln Glu Pro Phe
85 90 95
Asp Pro Ser Gly Tyr Gln Leu Tyr Leu His Lys Ala Thr Asn Gly Asn
100 105 110
His Asn Ala Ile Ala Arg Leu Arg Ile Cys Gln Phe Pro Asn Asn Lys
115 120 125
Thr Leu Gly Pro Thr Val Asn Asp Val Thr Thr Gly Arg Asn Cys Leu
130 135 140
Phe Asn Lys Ala Ile Pro Ala Tyr Met Gln Asp Gly Lys Asn Ile Val
145 150 155 160
Val Gly Ile Thr Trp Asp Asn Asp Arg Val Thr Val Phe Ala Asp Lys
165 170 175
Ile Tyr His Phe Tyr Leu Lys Asn Asp Trp Ser Arg Val Ala Thr Arg
180 185 190
Cys Tyr Asn Lys Arg Ser Cys Ala Met Gln Tyr Val Tyr Thr Pro Thr
195 200 205
Tyr Tyr Met Leu Asn Val Thr Ser Ala Gly Glu Asp Gly Ile Tyr Tyr
210 215 220
Glu Pro Cys Thr Ala Asn Cys Ser Gly Tyr Ala Val Asn Val Phe Ala
225 230 235 240
Thr Asp Ser Asn Gly His Ile Pro Glu Gly Phe Ser Phe Asn Asn Trp
245 250 255
Phe Leu Leu Ser Asn Asp Ser Thr Leu Leu His Gly Lys Val Val Ser
260 265 270
Asn Gln Pro Leu Leu Val Asn Cys Leu Leu Ala Ile Pro Lys Ile Tyr
275 280 285
Gly Leu Gly Gln Phe Phe Ser Phe Asn Gln Thr Met Asp Gly Val Cys
290 295 300
Asn Gly Ala Ala Ala Gln Arg Ala Pro Glu Ala Leu Arg Phe Asn Ile
305 310 315 320
Asn Asp Thr Ser Val Ile Leu Ala Glu Gly Ser Ile Val Leu His Thr
325 330 335
Ala Leu Gly Thr Asn Leu Ser Phe Val Cys Ser Asn Ser Ser Asp Pro
340 345 350
His Leu Ala Thr Phe Thr Ile Pro Leu Gly Ala Thr Gln Val Pro Tyr
355 360 365
Tyr Cys Phe Leu Lys Val Asp Thr Tyr Asn Ser Asn Val Tyr Lys Phe
370 375 380
Leu Ala Val Leu Pro Pro Thr Val Arg Glu Ile Val Ile Thr Lys Tyr
385 390 395 400
Gly Asp Val Tyr Val Asn Gly Phe Gly Tyr Leu His Leu Gly Leu Leu
405 410 415
Asp Ala Val Thr Ile Asn Phe Thr Gly His Gly Thr Asp Asp Asp Val
420 425 430
Ser Gly Phe Trp Thr Ile Ala Ser Thr Asn Phe Val Asp Ala Leu Ile
435 440 445
Glu Val Gln Gly Thr Ala Ile Gln Arg Ile Leu Tyr Cys Asp Asp Pro
450 455 460
Val Ser Gln Leu Lys Cys Ser Gln Val Ala Phe Asp Leu Asp Asp Gly
465 470 475 480
Phe Tyr Pro Ile Ser Ser Arg Asn Leu Leu Ser His Glu Gln Pro Ile
485 490 495
Ser Phe Val Thr Leu Pro Ser Phe Asn Asp His Ser Phe Val Asn Ile
500 505 510
Thr Val Ser Ala Ser Phe Gly Gly His Ser Gly Ala Asn Leu Ile Ala
515 520 525
Ser Asp Thr Thr Ile Asn Gly Phe Ser Ser Phe Cys Val Asp Thr Arg
530 535 540
Gln Phe Thr Ile Ser Leu Phe Tyr Asn Val Thr Asn Ser Tyr Gly Tyr
545 550 555 560
Val Ser Lys Ser Gln Asp Ser Asn Cys Pro Phe Thr Leu Gln Ser Val
565 570 575
Asn Asp Tyr Leu Ser Phe Ser Lys Phe Cys Val Ser Thr Ser Leu Leu
580 585 590
Ala Ser Ala Cys Thr Ile Asp Leu Phe Gly Tyr Pro Glu Phe Gly Ser
595 600 605
Gly Val Lys Phe Thr Ser Leu Tyr Phe Gln Phe Thr Glu Gly Glu Leu
610 615 620
Ile Thr Gly Thr Pro Lys Pro Leu Glu Gly Val Thr Asp Val Ser Phe
625 630 635 640
Met Thr Leu Asp Val Cys Thr Lys Tyr Thr Ile Tyr Gly Phe Lys Gly
645 650 655
Glu Gly Ile Ile Thr Leu Thr Asn Ser Ser Phe Leu Ala Gly Val Tyr
660 665 670
Tyr Thr Ser Asp Ser Gly Gln Leu Leu Ala Phe Lys Asn Val Thr Ser
675 680 685
Gly Ala Val Tyr Ser Val Thr Pro Cys Ser Phe Ser Glu Gln Ala Ala
690 695 700
Tyr Val Asp Asp Asp Ile Val Gly Val Ile Ser Ser Leu Ser Ser Ser
705 710 715 720
Thr Phe Asn Ser Thr Arg Glu Leu Pro Gly Phe Phe Tyr His Ser Asn
725 730 735
Asp Gly Ser Asn Cys Thr Glu Pro Val Leu Val Tyr Ser Asn Ile Gly
740 745 750
Val Cys Lys Ser Gly Ser Ile Gly Tyr Val Pro Ser Gln Ser Gly Gln
755 760 765
Val Lys Ile Ala Pro Thr Val Thr Gly Asn Ile Ser Ile Pro Thr Asn
770 775 780
Phe Ser Met Ser Ile Arg Thr Glu Tyr Leu Gln Leu Tyr Asn Thr Pro
785 790 795 800
Val Ser Val Asp Cys Ala Thr Tyr Val Cys Asn Gly Asn Ser Arg Cys
805 810 815
Lys Gln Leu Leu Thr Gln Tyr Thr Ala Ala Cys Lys Thr Ile Glu Ser
820 825 830
Ala Leu Gln Leu Ser Ala Arg Leu Glu Ser Val Glu Val Asn Ser Met
835 840 845
Leu Thr Ile Ser Glu Glu Ala Leu Gln Leu Ala Thr Ile Ser Ser Phe
850 855 860
Asn Gly Asp Gly Tyr Asn Phe Thr Asn Val Leu Gly Val Ser Val Tyr
865 870 875 880
Asp Pro Ala Ser Gly Arg Val Val Gln Lys Arg Ser Phe Ile Glu Asp
885 890 895
Leu Ala Phe Asn Lys Val Val Thr Asn Gly Leu Gly Thr Val Asp Glu
900 905 910
Asp Tyr Lys Arg Cys Ser Asn Gly Arg Ser Val Ala Asp Leu Val Cys
915 920 925
Ala Gln Tyr Tyr Ser Gly Val Met Val Leu Pro Gly Val Val Asp Ala
930 935 940
Glu Lys Leu His Met Tyr Ser Ala Ser Leu Ile Gly Gly Met Val Leu
945 950 955 960
Gly Gly Phe Thr Ser Ala Ala Ala Leu Pro Phe Ser Tyr Ala Val Gln
965 970 975
Ala Arg Leu Asn Tyr Leu Ala Leu Gln Thr Asp Val Leu Gln Arg Asn
980 985 990
Gln Gln Leu Leu Ala Glu Ser Phe Asn Ser Ala Ile Gly Asn Ile Thr
995 1000 1005
Ser Ala Phe Glu Ser Val Lys Glu Ala Ile Ser Gln Thr Ser Lys
1010 1015 1020
Gly Leu Asn Thr Val Ala His Ala Leu Thr Lys Val Gln Glu Val
1025 1030 1035
Val Asn Ser Gln Gly Ala Ala Leu Thr Gln Leu Thr Val Gln Leu
1040 1045 1050
Gln His Asn Phe Gln Ala Ile Ser Ser Ser Ile Asp Asp Ile Tyr
1055 1060 1065
Ser Arg Leu Asp Ile Leu Ser Ala Asp Val Gln Val Asp Arg Leu
1070 1075 1080
Ile Thr Gly Arg Leu Ser Ala Leu Asn Ala Phe Val Ala Gln Thr
1085 1090 1095
Leu Thr Lys Tyr Thr Glu Val Gln Ala Ser Arg Lys Leu Ala Gln
1100 1105 1110
Gln Lys Val Asn Glu Cys Val Lys Ser Gln Ser Gln Arg Tyr Gly
1115 1120 1125
Phe Cys Gly Gly Asp Gly Glu His Ile Phe Ser Leu Val Gln Ala
1130 1135 1140
Ala Pro Gln Gly Leu Leu Phe Leu His Thr Val Leu Val Pro Gly
1145 1150 1155
Asp Phe Ile Asp Val Ile Ala Ile Ala Gly Leu Cys Val Asn Asp
1160 1165 1170
Glu Ile Ala Leu Thr Leu Arg Glu Pro Gly Leu Val Leu Phe Thr
1175 1180 1185
His Glu Leu Gln Asn His Thr Ala Thr Glu Tyr Phe Val Ser Ser
1190 1195 1200
Arg Arg Met Phe Glu Pro Arg Lys Pro Thr Val Ser Asp Phe Val
1205 1210 1215
Gln Ile Glu Ser Cys Val Val Thr Tyr Val Asn Leu Thr Arg Asp
1220 1225 1230
Gln Leu Pro Asp Val Ile Pro Asp Tyr Ile Asp Val Asn Lys Thr
1235 1240 1245
Leu Asp Glu Ile Leu Ala Ser Leu Pro Asn Arg Thr Gly Pro Ser
1250 1255 1260
Leu Pro Leu Asp Val Phe Asn Ala Thr Tyr Leu Asn Leu Thr Gly
1265 1270 1275
Glu Ile Ala Asp Leu Glu Gln Arg Ser Glu Ser Leu Arg Asn Thr
1280 1285 1290
Thr Glu Glu Leu Gln Ser Leu Ile Tyr Asn Ile Asn Asn Thr Leu
1295 1300 1305
Val Asp Leu Glu Trp Leu Asn Arg Val Glu Thr Tyr Ile Lys Trp
1310 1315 1320
Pro Trp Trp Val Trp Leu Ile Val Phe Ile Val Leu Ile Phe Val
1325 1330 1335
Val Ser Leu Leu Val Phe Cys Cys Ile Ser Thr Gly Cys Cys Gly
1340 1345 1350
Cys Cys Gly Cys Cys Cys Ala Cys Phe Ser Gly Cys Cys Arg Gly
1355 1360 1365
Pro Arg Leu Gln Pro Ala Glu Val Phe Glu Lys Val Arg Val Gln
1370 1375 1380
<210> 14
<211> 1383
<212> PRT
<213> 猪流行性腹泻病毒
<400> 14
Met Lys Ser Leu Asn Tyr Phe Trp Leu Phe Leu Pro Val Leu Ser Thr
1 5 10 15
Leu Ser Leu Pro Gln Asp Val Thr Arg Cys Gln Ser Thr Ile Asn Phe
20 25 30
Arg Arg Phe Phe Ser Lys Phe Asn Val Gln Ala Pro Ala Val Val Val
35 40 45
Leu Gly Gly Tyr Leu Pro Ser Met Asn Ser Ser Ser Trp Tyr Cys Gly
50 55 60
Thr Gly Leu Glu Thr Ala Ser Gly Val His Gly Ile Phe Leu Ser Tyr
65 70 75 80
Ile Asp Ala Gly Gln Gly Phe Glu Ile Gly Ile Ser Gln Glu Pro Phe
85 90 95
Asp Pro Ser Gly Tyr Gln Leu Tyr Leu His Lys Ala Thr Asn Gly Asn
100 105 110
His Asn Ala Ile Ala Arg Leu Arg Ile Cys Gln Phe Pro Asn Asn Lys
115 120 125
Thr Leu Gly Pro Thr Val Asn Asp Val Thr Thr Gly Arg Asn Cys Leu
130 135 140
Phe Asn Lys Ala Ile Pro Ala Tyr Met Gln Asp Gly Lys Asn Ile Val
145 150 155 160
Val Gly Ile Thr Trp Asp Asn Asp Arg Val Thr Val Phe Ala Asp Lys
165 170 175
Ile Tyr His Phe Tyr Leu Lys Asn Asp Trp Ser Arg Val Ala Thr Arg
180 185 190
Cys Tyr Asn Lys Arg Ser Cys Ala Met Gln Tyr Val Tyr Thr Pro Thr
195 200 205
Tyr Tyr Met Leu Asn Val Thr Ser Ala Gly Glu Asp Gly Ile Tyr Tyr
210 215 220
Glu Pro Cys Thr Ala Asn Cys Ser Gly Tyr Ala Val Asn Val Phe Ala
225 230 235 240
Thr Asp Ser Asn Gly His Ile Pro Glu Gly Phe Ser Phe Asn Asn Trp
245 250 255
Phe Leu Leu Ser Asn Asp Ser Thr Leu Leu His Gly Lys Val Val Ser
260 265 270
Asn Gln Pro Leu Leu Val Asn Cys Leu Leu Ala Ile Pro Lys Ile Tyr
275 280 285
Gly Leu Gly Gln Phe Phe Ser Phe Asn Gln Thr Met Asp Gly Val Cys
290 295 300
Asn Gly Ala Ala Ala Gln Arg Ala Pro Glu Ala Leu Arg Phe Asn Ile
305 310 315 320
Asn Asp Thr Ser Val Ile Leu Ala Glu Gly Ser Ile Val Leu His Thr
325 330 335
Ala Leu Gly Thr Asn Leu Ser Phe Val Cys Ser Asn Ser Ser Asp Pro
340 345 350
His Leu Ala Thr Phe Thr Ile Pro Leu Gly Ala Thr Gln Val Pro Tyr
355 360 365
Tyr Cys Phe Leu Lys Val Asp Thr Tyr Asn Ser Asn Val Tyr Lys Phe
370 375 380
Leu Ala Val Leu Pro Pro Thr Val Arg Glu Ile Val Ile Thr Lys Tyr
385 390 395 400
Gly Asp Val Tyr Val Asn Gly Phe Gly Tyr Leu His Leu Gly Leu Leu
405 410 415
Asp Ala Val Thr Ile Asn Phe Thr Gly His Gly Thr Asp Asp Asp Val
420 425 430
Ser Gly Phe Trp Thr Ile Ala Ser Thr Asn Phe Val Asp Ala Leu Ile
435 440 445
Glu Val Gln Gly Thr Ala Ile Gln Arg Ile Leu Tyr Cys Asp Asp Pro
450 455 460
Val Ser Gln Leu Lys Cys Ser Gln Val Ala Phe Asp Leu Asp Asp Gly
465 470 475 480
Phe Tyr Pro Ile Ser Ser Arg Asn Leu Leu Ser His Glu Gln Pro Ile
485 490 495
Ser Phe Val Thr Leu Pro Ser Phe Asn Asp His Ser Phe Val Asn Ile
500 505 510
Thr Val Ser Ala Ser Phe Gly Gly His Ser Gly Ala Asn Leu Ile Ala
515 520 525
Ser Asp Thr Thr Ile Asn Gly Phe Ser Ser Phe Cys Val Asp Thr Arg
530 535 540
Gln Phe Thr Ile Ser Leu Phe Tyr Asn Val Thr Asn Ser Tyr Gly Tyr
545 550 555 560
Val Ser Lys Ser Gln Asp Ser Asn Cys Pro Phe Thr Leu Gln Ser Val
565 570 575
Asn Asp Tyr Leu Ser Phe Ser Lys Phe Cys Val Ser Thr Ser Leu Leu
580 585 590
Ala Ser Ala Cys Thr Ile Asp Leu Phe Gly Tyr Pro Glu Phe Gly Ser
595 600 605
Gly Val Lys Phe Thr Ser Leu Tyr Phe Gln Phe Thr Glu Gly Glu Leu
610 615 620
Ile Thr Gly Thr Pro Lys Pro Leu Glu Gly Val Thr Asp Val Ser Phe
625 630 635 640
Met Thr Leu Asp Val Cys Thr Lys Tyr Thr Ile Tyr Gly Phe Lys Gly
645 650 655
Glu Gly Ile Ile Thr Leu Thr Asn Ser Ser Phe Leu Ala Gly Val Tyr
660 665 670
Tyr Thr Ser Asp Ser Gly Gln Leu Leu Ala Phe Lys Asn Val Thr Ser
675 680 685
Gly Ala Val Tyr Ser Val Thr Pro Cys Ser Phe Ser Glu Gln Ala Ala
690 695 700
Tyr Val Asp Asp Asp Ile Val Gly Val Ile Ser Ser Leu Ser Ser Ser
705 710 715 720
Thr Phe Asn Ser Thr Arg Glu Leu Pro Gly Phe Phe Tyr His Ser Asn
725 730 735
Asp Gly Ser Asn Cys Thr Glu Pro Val Leu Val Tyr Ser Asn Ile Gly
740 745 750
Val Cys Lys Ser Gly Ser Ile Gly Tyr Val Pro Ser Gln Ser Gly Gln
755 760 765
Val Lys Ile Ala Pro Thr Val Thr Gly Asn Ile Ser Ile Pro Thr Asn
770 775 780
Phe Ser Met Ser Ile Arg Thr Glu Tyr Leu Gln Leu Tyr Asn Thr Pro
785 790 795 800
Val Ser Val Asp Cys Ala Thr Tyr Val Cys Asn Gly Asn Ser Arg Cys
805 810 815
Lys Gln Leu Leu Thr Gln Tyr Thr Ala Ala Cys Lys Thr Ile Glu Ser
820 825 830
Ala Leu Gln Leu Ser Ala Arg Leu Glu Ser Val Glu Val Asn Ser Met
835 840 845
Leu Thr Ile Ser Glu Glu Ala Leu Gln Leu Ala Thr Ile Ser Ser Phe
850 855 860
Asn Gly Asp Gly Tyr Asn Phe Thr Asn Val Leu Gly Val Ser Val Tyr
865 870 875 880
Asp Pro Ala Ser Gly Arg Val Val Gln Lys Arg Ser Phe Ile Glu Asp
885 890 895
Ala Ala Phe Asn Lys Val Val Thr Asn Gly Leu Gly Thr Val Asp Glu
900 905 910
Asp Tyr Lys Arg Cys Ser Asn Gly Arg Ser Val Ala Asp Leu Val Cys
915 920 925
Ala Gln Tyr Tyr Ser Gly Val Met Val Leu Pro Gly Val Val Asp Ala
930 935 940
Glu Lys Leu His Met Tyr Ser Ala Ser Leu Ile Gly Gly Met Val Leu
945 950 955 960
Gly Gly Phe Thr Ser Ala Ala Ala Leu Pro Phe Ser Tyr Ala Val Gln
965 970 975
Ala Arg Leu Asn Tyr Leu Ala Leu Gln Thr Asp Val Leu Gln Arg Asn
980 985 990
Gln Gln Leu Leu Ala Glu Ser Phe Asn Ser Ala Ile Gly Asn Ile Thr
995 1000 1005
Ser Ala Phe Glu Ser Val Lys Glu Ala Ile Ser Gln Thr Ser Lys
1010 1015 1020
Gly Leu Asn Thr Val Ala His Ala Leu Thr Lys Val Gln Glu Val
1025 1030 1035
Val Asn Ser Gln Gly Ala Ala Leu Thr Gln Leu Thr Val Gln Leu
1040 1045 1050
Gln His Asn Phe Gln Ala Ile Ser Ser Ser Ile Asp Asp Ile Tyr
1055 1060 1065
Ser Arg Leu Asp Ile Leu Ser Ala Asp Val Gln Val Asp Arg Leu
1070 1075 1080
Ile Thr Gly Arg Leu Ser Ala Leu Asn Ala Phe Val Ala Gln Thr
1085 1090 1095
Leu Thr Lys Tyr Thr Glu Val Gln Ala Ser Arg Lys Leu Ala Gln
1100 1105 1110
Gln Lys Val Asn Glu Cys Val Lys Ser Gln Ser Gln Arg Tyr Gly
1115 1120 1125
Phe Cys Gly Gly Asp Gly Glu His Ile Phe Ser Leu Val Gln Ala
1130 1135 1140
Ala Pro Gln Gly Leu Leu Phe Leu His Thr Val Leu Val Pro Gly
1145 1150 1155
Asp Phe Ile Asp Val Ile Ala Ile Ala Gly Leu Cys Val Asn Asp
1160 1165 1170
Glu Ile Ala Leu Thr Leu Arg Glu Pro Gly Leu Val Leu Phe Thr
1175 1180 1185
His Glu Leu Gln Asn His Thr Ala Thr Glu Tyr Phe Val Ser Ser
1190 1195 1200
Arg Arg Met Phe Glu Pro Arg Lys Pro Thr Val Ser Asp Phe Val
1205 1210 1215
Gln Ile Glu Ser Cys Val Val Thr Tyr Val Asn Leu Thr Arg Asp
1220 1225 1230
Gln Leu Pro Asp Val Ile Pro Asp Tyr Ile Asp Val Asn Lys Thr
1235 1240 1245
Leu Asp Glu Ile Leu Ala Ser Leu Pro Asn Arg Thr Gly Pro Ser
1250 1255 1260
Leu Pro Leu Asp Val Phe Asn Ala Thr Tyr Leu Asn Leu Thr Gly
1265 1270 1275
Glu Ile Ala Asp Leu Glu Gln Arg Ser Glu Ser Leu Arg Asn Thr
1280 1285 1290
Thr Glu Glu Leu Gln Ser Leu Ile Tyr Asn Ile Asn Asn Thr Leu
1295 1300 1305
Val Asp Leu Glu Trp Leu Asn Arg Val Glu Thr Tyr Ile Lys Trp
1310 1315 1320
Pro Trp Trp Val Trp Leu Ile Val Phe Ile Val Leu Ile Phe Val
1325 1330 1335
Val Ser Leu Leu Val Phe Cys Cys Ile Ser Thr Gly Cys Cys Gly
1340 1345 1350
Cys Cys Gly Cys Cys Cys Ala Cys Phe Ser Gly Cys Cys Arg Gly
1355 1360 1365
Pro Arg Leu Gln Pro Ala Glu Val Phe Glu Lys Val Arg Val Gln
1370 1375 1380
<210> 15
<211> 1388
<212> PRT
<213> 猪流行性腹泻病毒
<400> 15
Met Lys Ser Leu Thr Tyr Phe Trp Leu Phe Leu Pro Val Leu Ser Thr
1 5 10 15
Leu Ser Leu Pro Gln Asp Val Thr Arg Cys Ser Ala Asn Thr Asn Phe
20 25 30
Arg Arg Phe Phe Ser Lys Phe Asn Val Gln Ala Pro Ala Val Val Val
35 40 45
Leu Gly Gly Tyr Leu Pro Ile Gly Glu Asn Gln Gly Val Asn Ser Thr
50 55 60
Trp Tyr Cys Ala Gly Gln His Pro Thr Ala Ser Gly Val His Gly Ile
65 70 75 80
Phe Val Ser His Ile Arg Gly Gly His Gly Phe Glu Ile Gly Ile Ser
85 90 95
Gln Glu Pro Phe Asp Pro Ser Gly Tyr Gln Leu Tyr Leu His Lys Ala
100 105 110
Thr Asn Gly Asn Thr Asn Ala Thr Ala Arg Leu Arg Ile Cys Gln Phe
115 120 125
Pro Ser Ile Lys Thr Leu Gly Pro Thr Ala Asn Asn Asp Val Thr Thr
130 135 140
Gly Arg Asn Cys Leu Phe Asn Lys Ala Ile Pro Ala His Met Ser Glu
145 150 155 160
His Ser Val Val Gly Ile Thr Trp Asp Asn Asp Arg Val Thr Val Phe
165 170 175
Ser Asp Lys Ile Tyr Tyr Phe Tyr Phe Lys Asn Asp Trp Ser Arg Val
180 185 190
Ala Thr Lys Cys Tyr Asn Ser Gly Gly Cys Ala Met Gln Tyr Val Tyr
195 200 205
Glu Pro Thr Tyr Tyr Met Leu Asn Val Thr Ser Ala Gly Glu Asp Gly
210 215 220
Ile Ser Tyr Gln Pro Cys Thr Ala Asn Cys Ile Gly Tyr Ala Ala Asn
225 230 235 240
Val Phe Ala Thr Glu Pro Asn Gly His Ile Pro Glu Gly Phe Ser Phe
245 250 255
Asn Asn Trp Phe Leu Leu Ser Asn Asp Ser Thr Leu Val His Gly Lys
260 265 270
Val Val Ser Asn Gln Pro Leu Leu Val Asn Cys Leu Leu Ala Ile Pro
275 280 285
Lys Ile Tyr Gly Leu Gly Gln Phe Phe Ser Phe Asn Gln Thr Ile Asp
290 295 300
Gly Val Cys Asn Gly Ala Ala Val Gln Arg Ala Pro Glu Ala Leu Arg
305 310 315 320
Phe Asn Ile Asn Asp Thr Ser Val Ile Leu Ala Glu Gly Ser Ile Val
325 330 335
Leu His Thr Ala Leu Gly Thr Asn Phe Ser Phe Val Cys Ser Asn Ser
340 345 350
Ser Asn Pro His Leu Ala Thr Phe Ala Ile Pro Leu Gly Ala Thr Gln
355 360 365
Val Pro Tyr Tyr Cys Phe Leu Lys Val Asp Thr Tyr Asn Ser Thr Val
370 375 380
Tyr Lys Phe Leu Ala Val Leu Pro Pro Thr Val Arg Glu Ile Val Ile
385 390 395 400
Thr Lys Tyr Gly Asp Val Tyr Val Asn Gly Phe Gly Tyr Leu His Leu
405 410 415
Gly Leu Leu Asp Ala Val Thr Ile Asn Phe Thr Gly His Gly Thr Asp
420 425 430
Asp Asp Val Ser Gly Phe Trp Thr Ile Ala Ser Thr Asn Phe Val Asp
435 440 445
Ala Leu Ile Glu Val Gln Gly Thr Ala Ile Gln Arg Ile Leu Tyr Cys
450 455 460
Asp Asp Pro Val Ser Gln Leu Lys Cys Ser Gln Val Ala Phe Asp Leu
465 470 475 480
Asp Asp Gly Phe Tyr Pro Ile Ser Ser Arg Asn Leu Leu Ser His Glu
485 490 495
Gln Pro Ile Ser Phe Val Thr Leu Pro Ser Phe Asn Asp His Ser Phe
500 505 510
Val Asn Ile Thr Val Ser Ala Ser Phe Gly Gly His Ser Gly Ala Asn
515 520 525
Leu Ile Ala Ser Asp Thr Thr Ile Asn Gly Phe Ser Ser Phe Cys Val
530 535 540
Asp Thr Arg Gln Phe Thr Ile Ser Leu Phe Tyr Asn Val Thr Asn Ser
545 550 555 560
Tyr Gly Tyr Val Ser Lys Ser Gln Asp Ser Asn Cys Pro Phe Thr Leu
565 570 575
Gln Ser Val Asn Asp Tyr Leu Ser Phe Ser Lys Phe Cys Val Ser Thr
580 585 590
Ser Leu Leu Ala Ser Ala Cys Thr Ile Asp Leu Phe Gly Tyr Pro Glu
595 600 605
Phe Gly Ser Gly Val Lys Phe Thr Ser Leu Tyr Phe Gln Phe Thr Lys
610 615 620
Gly Glu Leu Ile Thr Gly Thr Pro Lys Pro Leu Glu Gly Val Thr Asp
625 630 635 640
Val Ser Phe Met Thr Leu Asp Val Cys Thr Lys Tyr Thr Ile Tyr Gly
645 650 655
Phe Lys Gly Glu Gly Ile Ile Thr Leu Thr Asn Ser Ser Phe Leu Ala
660 665 670
Gly Val Tyr Tyr Thr Ser Asp Ser Gly Gln Leu Leu Ala Phe Lys Asn
675 680 685
Val Thr Ser Gly Ala Val Tyr Ser Val Thr Pro Cys Ser Phe Ser Glu
690 695 700
Gln Ala Ala Tyr Val Asp Asp Asp Ile Val Gly Val Ile Ser Ser Leu
705 710 715 720
Ser Ser Ser Thr Phe Asn Ser Thr Arg Glu Leu Pro Gly Phe Phe Tyr
725 730 735
His Ser Asn Asp Gly Ser Asn Cys Thr Glu Pro Val Leu Val Tyr Ser
740 745 750
Asn Ile Gly Val Cys Lys Ser Gly Ser Ile Gly Tyr Val Pro Ser Gln
755 760 765
Ser Gly Gln Val Lys Ile Ala Pro Thr Val Thr Gly Asn Ile Ser Ile
770 775 780
Pro Thr Asn Phe Ser Met Ser Ile Arg Thr Glu Tyr Leu Gln Leu Tyr
785 790 795 800
Asn Thr Pro Val Ser Val Asp Cys Ala Thr Tyr Val Cys Asn Gly Asn
805 810 815
Ser Arg Cys Lys Gln Leu Leu Thr Gln Tyr Thr Ala Ala Cys Lys Thr
820 825 830
Ile Glu Ser Ala Leu Gln Leu Ser Ala Arg Leu Glu Ser Val Glu Val
835 840 845
Asn Ser Met Leu Thr Ile Ser Glu Glu Ala Leu Gln Leu Ala Thr Ile
850 855 860
Ser Ser Phe Asn Gly Asp Gly Tyr Asn Phe Thr Asn Val Leu Gly Val
865 870 875 880
Ser Val Tyr Asp Pro Ala Ser Gly Arg Val Val Gln Lys Arg Ser Phe
885 890 895
Ile Glu Asp Ala Leu Phe Asn Lys Val Val Thr Asn Gly Leu Gly Thr
900 905 910
Val Asp Glu Asp Tyr Lys Arg Cys Ser Asn Gly Arg Ser Val Ala Asp
915 920 925
Leu Val Cys Ala Gln Tyr Tyr Ser Gly Val Met Val Leu Pro Gly Val
930 935 940
Val Asp Ala Glu Lys Leu His Met Tyr Ser Ala Ser Leu Ile Gly Gly
945 950 955 960
Met Val Leu Gly Gly Phe Thr Ser Ala Ala Ala Leu Pro Phe Ser Tyr
965 970 975
Ala Val Gln Ala Arg Leu Asn Tyr Leu Ala Leu Gln Thr Asp Val Leu
980 985 990
Gln Arg Asn Gln Gln Leu Leu Ala Glu Ser Phe Asn Ser Ala Ile Gly
995 1000 1005
Asn Ile Thr Ser Ala Phe Glu Ser Val Lys Glu Ala Ile Ser Gln
1010 1015 1020
Thr Ser Lys Gly Leu Asn Thr Val Ala His Ala Leu Thr Lys Val
1025 1030 1035
Gln Glu Val Val Asn Ser Gln Gly Ala Ala Leu Thr Gln Leu Thr
1040 1045 1050
Val Gln Leu Gln His Asn Phe Gln Ala Ile Ser Ser Ser Ile Asp
1055 1060 1065
Asp Ile Tyr Ser Arg Leu Asp Ile Leu Ser Ala Asp Val Gln Val
1070 1075 1080
Asp Arg Leu Ile Thr Gly Arg Leu Ser Ala Leu Asn Ala Phe Val
1085 1090 1095
Ala Gln Thr Leu Thr Lys Tyr Thr Glu Val Gln Ala Ser Arg Lys
1100 1105 1110
Leu Ala Gln Gln Lys Val Asn Glu Cys Val Lys Ser Gln Ser Gln
1115 1120 1125
Arg Tyr Gly Phe Cys Gly Gly Asp Gly Glu His Ile Phe Ser Leu
1130 1135 1140
Val Gln Ala Ala Pro Gln Gly Leu Leu Phe Leu His Thr Val Leu
1145 1150 1155
Val Pro Ser Asp Phe Val Asp Val Ile Ala Ile Ala Gly Leu Cys
1160 1165 1170
Val Asn Asp Glu Ile Ala Leu Thr Leu Arg Glu Pro Gly Leu Val
1175 1180 1185
Leu Phe Thr His Glu Leu Gln Asn His Thr Ala Thr Glu Tyr Phe
1190 1195 1200
Val Ser Ser Arg Arg Met Phe Glu Pro Arg Lys Pro Thr Val Ser
1205 1210 1215
Asp Phe Val Gln Ile Glu Ser Cys Val Val Thr Tyr Val Asn Leu
1220 1225 1230
Thr Arg Asp Gln Leu Pro Asp Val Ile Pro Asp Tyr Ile Asp Val
1235 1240 1245
Asn Lys Thr Leu Asp Glu Ile Leu Ala Ser Leu Pro Asn Arg Thr
1250 1255 1260
Gly Pro Ser Leu Pro Leu Asp Val Phe Asn Ala Thr Tyr Leu Asn
1265 1270 1275
Leu Thr Gly Glu Ile Ala Asp Leu Glu Gln Arg Ser Glu Ser Leu
1280 1285 1290
Arg Asn Thr Thr Glu Glu Leu Gln Ser Leu Ile Tyr Asn Ile Asn
1295 1300 1305
Asn Thr Leu Val Asp Leu Glu Trp Leu Asn Arg Val Glu Thr Tyr
1310 1315 1320
Ile Lys Trp Pro Trp Trp Val Trp Leu Ile Ile Phe Ile Val Leu
1325 1330 1335
Ile Phe Val Val Ser Leu Leu Val Phe Cys Cys Ile Ser Thr Gly
1340 1345 1350
Cys Cys Gly Cys Cys Gly Cys Cys Cys Ala Cys Phe Ser Gly Cys
1355 1360 1365
Cys Arg Gly Pro Arg Leu Gln Pro Tyr Glu Val Phe Glu Lys Val
1370 1375 1380
His Val Gln Cys Gly
1385
<210> 16
<211> 1388
<212> PRT
<213> 猪流行性腹泻病毒
<400> 16
Met Lys Ser Leu Thr Tyr Phe Trp Leu Phe Leu Pro Val Leu Ser Thr
1 5 10 15
Leu Ser Leu Pro Gln Asp Val Thr Arg Cys Ser Ala Asn Thr Asn Phe
20 25 30
Arg Arg Phe Phe Ser Lys Phe Asn Val Gln Ala Pro Ala Val Val Val
35 40 45
Leu Gly Gly Tyr Leu Pro Ile Gly Glu Asn Gln Gly Val Asn Ser Thr
50 55 60
Trp Tyr Cys Ala Gly Gln His Pro Thr Ala Ser Gly Val His Gly Ile
65 70 75 80
Phe Val Ser His Ile Arg Gly Gly His Gly Phe Glu Ile Gly Ile Ser
85 90 95
Gln Glu Pro Phe Asp Pro Ser Gly Tyr Gln Leu Tyr Leu His Lys Ala
100 105 110
Thr Asn Gly Asn Thr Asn Ala Thr Ala Arg Leu Arg Ile Cys Gln Phe
115 120 125
Pro Ser Ile Lys Thr Leu Gly Pro Thr Ala Asn Asn Asp Val Thr Thr
130 135 140
Gly Arg Asn Cys Leu Phe Asn Lys Ala Ile Pro Ala His Met Ser Glu
145 150 155 160
His Ser Val Val Gly Ile Thr Trp Asp Asn Asp Arg Val Thr Val Phe
165 170 175
Ser Asp Lys Ile Tyr Tyr Phe Tyr Phe Lys Asn Asp Trp Ser Arg Val
180 185 190
Ala Thr Lys Cys Tyr Asn Ser Gly Gly Cys Ala Met Gln Tyr Val Tyr
195 200 205
Glu Pro Thr Tyr Tyr Met Leu Asn Val Thr Ser Ala Gly Glu Asp Gly
210 215 220
Ile Ser Tyr Gln Pro Cys Thr Ala Asn Cys Ile Gly Tyr Ala Ala Asn
225 230 235 240
Val Phe Ala Thr Glu Pro Asn Gly His Ile Pro Glu Gly Phe Ser Phe
245 250 255
Asn Asn Trp Phe Leu Leu Ser Asn Asp Ser Thr Leu Val His Gly Lys
260 265 270
Val Val Ser Asn Gln Pro Leu Leu Val Asn Cys Leu Leu Ala Ile Pro
275 280 285
Lys Ile Tyr Gly Leu Gly Gln Phe Phe Ser Phe Asn Gln Thr Ile Asp
290 295 300
Gly Val Cys Asn Gly Ala Ala Val Gln Arg Ala Pro Glu Ala Leu Arg
305 310 315 320
Phe Asn Ile Asn Asp Thr Ser Val Ile Leu Ala Glu Gly Ser Ile Val
325 330 335
Leu His Thr Ala Leu Gly Thr Asn Phe Ser Phe Val Cys Ser Asn Ser
340 345 350
Ser Asn Pro His Leu Ala Thr Phe Ala Ile Pro Leu Gly Ala Thr Gln
355 360 365
Val Pro Tyr Tyr Cys Phe Leu Lys Val Asp Thr Tyr Asn Ser Thr Val
370 375 380
Tyr Lys Phe Leu Ala Val Leu Pro Pro Thr Val Arg Glu Ile Val Ile
385 390 395 400
Thr Lys Tyr Gly Asp Val Tyr Val Asn Gly Phe Gly Tyr Leu His Leu
405 410 415
Gly Leu Leu Asp Ala Val Thr Ile Asn Phe Thr Gly His Gly Thr Asp
420 425 430
Asp Asp Val Ser Gly Phe Trp Thr Ile Ala Ser Thr Asn Phe Val Asp
435 440 445
Ala Leu Ile Glu Val Gln Gly Thr Ala Ile Gln Arg Ile Leu Tyr Cys
450 455 460
Asp Asp Pro Val Ser Gln Leu Lys Cys Ser Gln Val Ala Phe Asp Leu
465 470 475 480
Asp Asp Gly Phe Tyr Pro Ile Ser Ser Arg Asn Leu Leu Ser His Glu
485 490 495
Gln Pro Ile Ser Phe Val Thr Leu Pro Ser Phe Asn Asp His Ser Phe
500 505 510
Val Asn Ile Thr Val Ser Ala Ser Phe Gly Gly His Ser Gly Ala Asn
515 520 525
Leu Ile Ala Ser Asp Thr Thr Ile Asn Gly Phe Ser Ser Phe Cys Val
530 535 540
Asp Thr Arg Gln Phe Thr Ile Ser Leu Phe Tyr Asn Val Thr Asn Ser
545 550 555 560
Tyr Gly Tyr Val Ser Lys Ser Gln Asp Ser Asn Cys Pro Phe Thr Leu
565 570 575
Gln Ser Val Asn Asp Tyr Leu Ser Phe Ser Lys Phe Cys Val Ser Thr
580 585 590
Ser Leu Leu Ala Ser Ala Cys Thr Ile Asp Leu Phe Gly Tyr Pro Glu
595 600 605
Phe Gly Ser Gly Val Lys Phe Thr Ser Leu Tyr Phe Gln Phe Thr Lys
610 615 620
Gly Glu Leu Ile Thr Gly Thr Pro Lys Pro Leu Glu Gly Val Thr Asp
625 630 635 640
Val Ser Phe Met Thr Leu Asp Val Cys Thr Lys Tyr Thr Ile Tyr Gly
645 650 655
Phe Lys Gly Glu Gly Ile Ile Thr Leu Thr Asn Ser Ser Phe Leu Ala
660 665 670
Gly Val Tyr Tyr Thr Ser Asp Ser Gly Gln Leu Leu Ala Phe Lys Asn
675 680 685
Val Thr Ser Gly Ala Val Tyr Ser Val Thr Pro Cys Ser Phe Ser Glu
690 695 700
Gln Ala Ala Tyr Val Asp Asp Asp Ile Val Gly Val Ile Ser Ser Leu
705 710 715 720
Ser Ser Ser Thr Phe Asn Ser Thr Arg Glu Leu Pro Gly Phe Phe Tyr
725 730 735
His Ser Asn Asp Gly Ser Asn Cys Thr Glu Pro Val Leu Val Tyr Ser
740 745 750
Asn Ile Gly Val Cys Lys Ser Gly Ser Ile Gly Tyr Val Pro Ser Gln
755 760 765
Ser Gly Gln Val Lys Ile Ala Pro Thr Val Thr Gly Asn Ile Ser Ile
770 775 780
Pro Thr Asn Phe Ser Met Ser Ile Arg Thr Glu Tyr Leu Gln Leu Tyr
785 790 795 800
Asn Thr Pro Val Ser Val Asp Cys Ala Thr Tyr Val Cys Asn Gly Asn
805 810 815
Ser Arg Cys Lys Gln Leu Leu Thr Gln Tyr Thr Ala Ala Cys Lys Thr
820 825 830
Ile Glu Ser Ala Leu Gln Leu Ser Ala Arg Leu Glu Ser Val Glu Val
835 840 845
Asn Ser Met Leu Thr Ile Ser Glu Glu Ala Leu Gln Leu Ala Thr Ile
850 855 860
Ser Ser Phe Asn Gly Asp Gly Tyr Asn Phe Thr Asn Val Leu Gly Val
865 870 875 880
Ser Val Tyr Asp Pro Ala Ser Gly Arg Val Val Gln Lys Arg Ser Phe
885 890 895
Ile Glu Asp Leu Ala Phe Asn Lys Val Val Thr Asn Gly Leu Gly Thr
900 905 910
Val Asp Glu Asp Tyr Lys Arg Cys Ser Asn Gly Arg Ser Val Ala Asp
915 920 925
Leu Val Cys Ala Gln Tyr Tyr Ser Gly Val Met Val Leu Pro Gly Val
930 935 940
Val Asp Ala Glu Lys Leu His Met Tyr Ser Ala Ser Leu Ile Gly Gly
945 950 955 960
Met Val Leu Gly Gly Phe Thr Ser Ala Ala Ala Leu Pro Phe Ser Tyr
965 970 975
Ala Val Gln Ala Arg Leu Asn Tyr Leu Ala Leu Gln Thr Asp Val Leu
980 985 990
Gln Arg Asn Gln Gln Leu Leu Ala Glu Ser Phe Asn Ser Ala Ile Gly
995 1000 1005
Asn Ile Thr Ser Ala Phe Glu Ser Val Lys Glu Ala Ile Ser Gln
1010 1015 1020
Thr Ser Lys Gly Leu Asn Thr Val Ala His Ala Leu Thr Lys Val
1025 1030 1035
Gln Glu Val Val Asn Ser Gln Gly Ala Ala Leu Thr Gln Leu Thr
1040 1045 1050
Val Gln Leu Gln His Asn Phe Gln Ala Ile Ser Ser Ser Ile Asp
1055 1060 1065
Asp Ile Tyr Ser Arg Leu Asp Ile Leu Ser Ala Asp Val Gln Val
1070 1075 1080
Asp Arg Leu Ile Thr Gly Arg Leu Ser Ala Leu Asn Ala Phe Val
1085 1090 1095
Ala Gln Thr Leu Thr Lys Tyr Thr Glu Val Gln Ala Ser Arg Lys
1100 1105 1110
Leu Ala Gln Gln Lys Val Asn Glu Cys Val Lys Ser Gln Ser Gln
1115 1120 1125
Arg Tyr Gly Phe Cys Gly Gly Asp Gly Glu His Ile Phe Ser Leu
1130 1135 1140
Val Gln Ala Ala Pro Gln Gly Leu Leu Phe Leu His Thr Val Leu
1145 1150 1155
Val Pro Ser Asp Phe Val Asp Val Ile Ala Ile Ala Gly Leu Cys
1160 1165 1170
Val Asn Asp Glu Ile Ala Leu Thr Leu Arg Glu Pro Gly Leu Val
1175 1180 1185
Leu Phe Thr His Glu Leu Gln Asn His Thr Ala Thr Glu Tyr Phe
1190 1195 1200
Val Ser Ser Arg Arg Met Phe Glu Pro Arg Lys Pro Thr Val Ser
1205 1210 1215
Asp Phe Val Gln Ile Glu Ser Cys Val Val Thr Tyr Val Asn Leu
1220 1225 1230
Thr Arg Asp Gln Leu Pro Asp Val Ile Pro Asp Tyr Ile Asp Val
1235 1240 1245
Asn Lys Thr Leu Asp Glu Ile Leu Ala Ser Leu Pro Asn Arg Thr
1250 1255 1260
Gly Pro Ser Leu Pro Leu Asp Val Phe Asn Ala Thr Tyr Leu Asn
1265 1270 1275
Leu Thr Gly Glu Ile Ala Asp Leu Glu Gln Arg Ser Glu Ser Leu
1280 1285 1290
Arg Asn Thr Thr Glu Glu Leu Gln Ser Leu Ile Tyr Asn Ile Asn
1295 1300 1305
Asn Thr Leu Val Asp Leu Glu Trp Leu Asn Arg Val Glu Thr Tyr
1310 1315 1320
Ile Lys Trp Pro Trp Trp Val Trp Leu Ile Ile Phe Ile Val Leu
1325 1330 1335
Ile Phe Val Val Ser Leu Leu Val Phe Cys Cys Ile Ser Thr Gly
1340 1345 1350
Cys Cys Gly Cys Cys Gly Cys Cys Cys Ala Cys Phe Ser Gly Cys
1355 1360 1365
Cys Arg Gly Pro Arg Leu Gln Pro Tyr Glu Val Phe Glu Lys Val
1370 1375 1380
His Val Gln Cys Gly
1385
<210> 17
<211> 1388
<212> PRT
<213> 猪流行性腹泻病毒
<400> 17
Met Lys Ser Leu Thr Tyr Phe Trp Leu Phe Leu Pro Val Leu Ser Thr
1 5 10 15
Leu Ser Leu Pro Gln Asp Val Thr Arg Cys Ser Ala Asn Thr Asn Phe
20 25 30
Arg Arg Phe Phe Ser Lys Phe Asn Val Gln Ala Pro Ala Val Val Val
35 40 45
Leu Gly Gly Tyr Leu Pro Ile Gly Glu Asn Gln Gly Val Asn Ser Thr
50 55 60
Trp Tyr Cys Ala Gly Gln His Pro Thr Ala Ser Gly Val His Gly Ile
65 70 75 80
Phe Val Ser His Ile Arg Gly Gly His Gly Phe Glu Ile Gly Ile Ser
85 90 95
Gln Glu Pro Phe Asp Pro Ser Gly Tyr Gln Leu Tyr Leu His Lys Ala
100 105 110
Thr Asn Gly Asn Thr Asn Ala Thr Ala Arg Leu Arg Ile Cys Gln Phe
115 120 125
Pro Ser Ile Lys Thr Leu Gly Pro Thr Ala Asn Asn Asp Val Thr Thr
130 135 140
Gly Arg Asn Cys Leu Phe Asn Lys Ala Ile Pro Ala His Met Ser Glu
145 150 155 160
His Ser Val Val Gly Ile Thr Trp Asp Asn Asp Arg Val Thr Val Phe
165 170 175
Ser Asp Lys Ile Tyr Tyr Phe Tyr Phe Lys Asn Asp Trp Ser Arg Val
180 185 190
Ala Thr Lys Cys Tyr Asn Ser Gly Gly Cys Ala Met Gln Tyr Val Tyr
195 200 205
Glu Pro Thr Tyr Tyr Met Leu Asn Val Thr Ser Ala Gly Glu Asp Gly
210 215 220
Ile Ser Tyr Gln Pro Cys Thr Ala Asn Cys Ile Gly Tyr Ala Ala Asn
225 230 235 240
Val Phe Ala Thr Glu Pro Asn Gly His Ile Pro Glu Gly Phe Ser Phe
245 250 255
Asn Asn Trp Phe Leu Leu Ser Asn Asp Ser Thr Leu Val His Gly Lys
260 265 270
Val Val Ser Asn Gln Pro Leu Leu Val Asn Cys Leu Leu Ala Ile Pro
275 280 285
Lys Ile Tyr Gly Leu Gly Gln Phe Phe Ser Phe Asn Gln Thr Ile Asp
290 295 300
Gly Val Cys Asn Gly Ala Ala Val Gln Arg Ala Pro Glu Ala Leu Arg
305 310 315 320
Phe Asn Ile Asn Asp Thr Ser Val Ile Leu Ala Glu Gly Ser Ile Val
325 330 335
Leu His Thr Ala Leu Gly Thr Asn Phe Ser Phe Val Cys Ser Asn Ser
340 345 350
Ser Asn Pro His Leu Ala Thr Phe Ala Ile Pro Leu Gly Ala Thr Gln
355 360 365
Val Pro Tyr Tyr Cys Phe Leu Lys Val Asp Thr Tyr Asn Ser Thr Val
370 375 380
Tyr Lys Phe Leu Ala Val Leu Pro Pro Thr Val Arg Glu Ile Val Ile
385 390 395 400
Thr Lys Tyr Gly Asp Val Tyr Val Asn Gly Phe Gly Tyr Leu His Leu
405 410 415
Gly Leu Leu Asp Ala Val Thr Ile Asn Phe Thr Gly His Gly Thr Asp
420 425 430
Asp Asp Val Ser Gly Phe Trp Thr Ile Ala Ser Thr Asn Phe Val Asp
435 440 445
Ala Leu Ile Glu Val Gln Gly Thr Ala Ile Gln Arg Ile Leu Tyr Cys
450 455 460
Asp Asp Pro Val Ser Gln Leu Lys Cys Ser Gln Val Ala Phe Asp Leu
465 470 475 480
Asp Asp Gly Phe Tyr Pro Ile Ser Ser Arg Asn Leu Leu Ser His Glu
485 490 495
Gln Pro Ile Ser Phe Val Thr Leu Pro Ser Phe Asn Asp His Ser Phe
500 505 510
Val Asn Ile Thr Val Ser Ala Ser Phe Gly Gly His Ser Gly Ala Asn
515 520 525
Leu Ile Ala Ser Asp Thr Thr Ile Asn Gly Phe Ser Ser Phe Cys Val
530 535 540
Asp Thr Arg Gln Phe Thr Ile Ser Leu Phe Tyr Asn Val Thr Asn Ser
545 550 555 560
Tyr Gly Tyr Val Ser Lys Ser Gln Asp Ser Asn Cys Pro Phe Thr Leu
565 570 575
Gln Ser Val Asn Asp Tyr Leu Ser Phe Ser Lys Phe Cys Val Ser Thr
580 585 590
Ser Leu Leu Ala Ser Ala Cys Thr Ile Asp Leu Phe Gly Tyr Pro Glu
595 600 605
Phe Gly Ser Gly Val Lys Phe Thr Ser Leu Tyr Phe Gln Phe Thr Lys
610 615 620
Gly Glu Leu Ile Thr Gly Thr Pro Lys Pro Leu Glu Gly Val Thr Asp
625 630 635 640
Val Ser Phe Met Thr Leu Asp Val Cys Thr Lys Tyr Thr Ile Tyr Gly
645 650 655
Phe Lys Gly Glu Gly Ile Ile Thr Leu Thr Asn Ser Ser Phe Leu Ala
660 665 670
Gly Val Tyr Tyr Thr Ser Asp Ser Gly Gln Leu Leu Ala Phe Lys Asn
675 680 685
Val Thr Ser Gly Ala Val Tyr Ser Val Thr Pro Cys Ser Phe Ser Glu
690 695 700
Gln Ala Ala Tyr Val Asp Asp Asp Ile Val Gly Val Ile Ser Ser Leu
705 710 715 720
Ser Ser Ser Thr Phe Asn Ser Thr Arg Glu Leu Pro Gly Phe Phe Tyr
725 730 735
His Ser Asn Asp Gly Ser Asn Cys Thr Glu Pro Val Leu Val Tyr Ser
740 745 750
Asn Ile Gly Val Cys Lys Ser Gly Ser Ile Gly Tyr Val Pro Ser Gln
755 760 765
Ser Gly Gln Val Lys Ile Ala Pro Thr Val Thr Gly Asn Ile Ser Ile
770 775 780
Pro Thr Asn Phe Ser Met Ser Ile Arg Thr Glu Tyr Leu Gln Leu Tyr
785 790 795 800
Asn Thr Pro Val Ser Val Asp Cys Ala Thr Tyr Val Cys Asn Gly Asn
805 810 815
Ser Arg Cys Lys Gln Leu Leu Thr Gln Tyr Thr Ala Ala Cys Lys Thr
820 825 830
Ile Glu Ser Ala Leu Gln Leu Ser Ala Arg Leu Glu Ser Val Glu Val
835 840 845
Asn Ser Met Leu Thr Ile Ser Glu Glu Ala Leu Gln Leu Ala Thr Ile
850 855 860
Ser Ser Phe Asn Gly Asp Gly Tyr Asn Phe Thr Asn Val Leu Gly Val
865 870 875 880
Ser Val Tyr Asp Pro Ala Ser Gly Arg Val Val Gln Lys Arg Ser Phe
885 890 895
Ile Glu Asp Ala Ala Phe Asn Lys Val Val Thr Asn Gly Leu Gly Thr
900 905 910
Val Asp Glu Asp Tyr Lys Arg Cys Ser Asn Gly Arg Ser Val Ala Asp
915 920 925
Leu Val Cys Ala Gln Tyr Tyr Ser Gly Val Met Val Leu Pro Gly Val
930 935 940
Val Asp Ala Glu Lys Leu His Met Tyr Ser Ala Ser Leu Ile Gly Gly
945 950 955 960
Met Val Leu Gly Gly Phe Thr Ser Ala Ala Ala Leu Pro Phe Ser Tyr
965 970 975
Ala Val Gln Ala Arg Leu Asn Tyr Leu Ala Leu Gln Thr Asp Val Leu
980 985 990
Gln Arg Asn Gln Gln Leu Leu Ala Glu Ser Phe Asn Ser Ala Ile Gly
995 1000 1005
Asn Ile Thr Ser Ala Phe Glu Ser Val Lys Glu Ala Ile Ser Gln
1010 1015 1020
Thr Ser Lys Gly Leu Asn Thr Val Ala His Ala Leu Thr Lys Val
1025 1030 1035
Gln Glu Val Val Asn Ser Gln Gly Ala Ala Leu Thr Gln Leu Thr
1040 1045 1050
Val Gln Leu Gln His Asn Phe Gln Ala Ile Ser Ser Ser Ile Asp
1055 1060 1065
Asp Ile Tyr Ser Arg Leu Asp Ile Leu Ser Ala Asp Val Gln Val
1070 1075 1080
Asp Arg Leu Ile Thr Gly Arg Leu Ser Ala Leu Asn Ala Phe Val
1085 1090 1095
Ala Gln Thr Leu Thr Lys Tyr Thr Glu Val Gln Ala Ser Arg Lys
1100 1105 1110
Leu Ala Gln Gln Lys Val Asn Glu Cys Val Lys Ser Gln Ser Gln
1115 1120 1125
Arg Tyr Gly Phe Cys Gly Gly Asp Gly Glu His Ile Phe Ser Leu
1130 1135 1140
Val Gln Ala Ala Pro Gln Gly Leu Leu Phe Leu His Thr Val Leu
1145 1150 1155
Val Pro Ser Asp Phe Val Asp Val Ile Ala Ile Ala Gly Leu Cys
1160 1165 1170
Val Asn Asp Glu Ile Ala Leu Thr Leu Arg Glu Pro Gly Leu Val
1175 1180 1185
Leu Phe Thr His Glu Leu Gln Asn His Thr Ala Thr Glu Tyr Phe
1190 1195 1200
Val Ser Ser Arg Arg Met Phe Glu Pro Arg Lys Pro Thr Val Ser
1205 1210 1215
Asp Phe Val Gln Ile Glu Ser Cys Val Val Thr Tyr Val Asn Leu
1220 1225 1230
Thr Arg Asp Gln Leu Pro Asp Val Ile Pro Asp Tyr Ile Asp Val
1235 1240 1245
Asn Lys Thr Leu Asp Glu Ile Leu Ala Ser Leu Pro Asn Arg Thr
1250 1255 1260
Gly Pro Ser Leu Pro Leu Asp Val Phe Asn Ala Thr Tyr Leu Asn
1265 1270 1275
Leu Thr Gly Glu Ile Ala Asp Leu Glu Gln Arg Ser Glu Ser Leu
1280 1285 1290
Arg Asn Thr Thr Glu Glu Leu Gln Ser Leu Ile Tyr Asn Ile Asn
1295 1300 1305
Asn Thr Leu Val Asp Leu Glu Trp Leu Asn Arg Val Glu Thr Tyr
1310 1315 1320
Ile Lys Trp Pro Trp Trp Val Trp Leu Ile Ile Phe Ile Val Leu
1325 1330 1335
Ile Phe Val Val Ser Leu Leu Val Phe Cys Cys Ile Ser Thr Gly
1340 1345 1350
Cys Cys Gly Cys Cys Gly Cys Cys Cys Ala Cys Phe Ser Gly Cys
1355 1360 1365
Cys Arg Gly Pro Arg Leu Gln Pro Tyr Glu Val Phe Glu Lys Val
1370 1375 1380
His Val Gln Cys Gly
1385
<210> 18
<211> 1388
<212> PRT
<213> 猪流行性腹泻病毒
<400> 18
Met Lys Ser Leu Thr Tyr Phe Trp Leu Phe Leu Pro Val Leu Ser Thr
1 5 10 15
Leu Ser Leu Pro Gln Asp Val Thr Arg Cys Ser Ala Asn Thr Asn Phe
20 25 30
Arg Arg Phe Phe Ser Lys Phe Asn Val Gln Ala Pro Ala Val Val Val
35 40 45
Leu Gly Gly Tyr Leu Pro Ile Gly Glu Asn Gln Gly Val Asn Ser Thr
50 55 60
Trp Tyr Cys Ala Gly Gln His Pro Thr Ala Ser Gly Val His Gly Ile
65 70 75 80
Phe Val Ser His Ile Arg Gly Gly His Gly Phe Glu Ile Gly Ile Ser
85 90 95
Gln Glu Pro Phe Asp Pro Ser Gly Tyr Gln Leu Tyr Leu His Lys Ala
100 105 110
Thr Asn Gly Asn Thr Asn Ala Thr Ala Arg Leu Arg Ile Cys Gln Phe
115 120 125
Pro Ser Ile Lys Thr Leu Gly Pro Thr Ala Asn Asn Asp Val Thr Thr
130 135 140
Gly Arg Asn Cys Leu Phe Asn Lys Ala Ile Pro Ala His Met Ser Glu
145 150 155 160
His Ser Val Val Gly Ile Thr Trp Asp Asn Asp Arg Val Thr Val Phe
165 170 175
Ser Asp Lys Ile Tyr Tyr Phe Tyr Phe Lys Asn Asp Trp Ser Arg Val
180 185 190
Ala Thr Lys Cys Tyr Asn Ser Gly Gly Cys Ala Met Gln Tyr Val Tyr
195 200 205
Glu Pro Thr Tyr Tyr Met Leu Asn Val Thr Ser Ala Gly Glu Asp Gly
210 215 220
Ile Ser Tyr Gln Pro Cys Thr Ala Asn Cys Ile Gly Tyr Ala Ala Asn
225 230 235 240
Val Phe Ala Thr Glu Pro Asn Gly His Ile Pro Glu Gly Phe Ser Phe
245 250 255
Asn Asn Trp Phe Leu Leu Ser Asn Asp Ser Thr Leu Val His Gly Lys
260 265 270
Val Val Ser Asn Gln Pro Leu Leu Val Asn Cys Leu Leu Ala Ile Pro
275 280 285
Lys Ile Tyr Gly Leu Gly Gln Phe Phe Ser Phe Asn Gln Thr Ile Asp
290 295 300
Gly Val Cys Asn Gly Ala Ala Val Gln Arg Ala Pro Glu Ala Leu Arg
305 310 315 320
Phe Asn Ile Asn Asp Thr Ser Val Ile Leu Ala Glu Gly Ser Ile Val
325 330 335
Leu His Thr Ala Leu Gly Thr Asn Phe Ser Phe Val Cys Ser Asn Ser
340 345 350
Ser Asn Pro His Leu Ala Thr Phe Ala Ile Pro Leu Gly Ala Thr Gln
355 360 365
Val Pro Tyr Tyr Cys Phe Leu Lys Val Asp Thr Tyr Asn Ser Thr Val
370 375 380
Tyr Lys Phe Leu Ala Val Leu Pro Pro Thr Val Arg Glu Ile Val Ile
385 390 395 400
Thr Lys Tyr Gly Asp Val Tyr Val Asn Gly Phe Gly Tyr Leu His Leu
405 410 415
Gly Leu Leu Asp Ala Val Thr Ile Asn Phe Thr Gly His Gly Thr Asp
420 425 430
Asp Asp Val Ser Gly Phe Trp Thr Ile Ala Ser Thr Asn Phe Val Asp
435 440 445
Ala Leu Ile Glu Val Gln Gly Thr Ala Ile Gln Arg Ile Leu Tyr Cys
450 455 460
Asp Asp Pro Val Ser Gln Leu Lys Cys Ser Gln Val Ala Phe Asp Leu
465 470 475 480
Asp Asp Gly Phe Tyr Pro Ile Ser Ser Arg Asn Leu Leu Ser His Glu
485 490 495
Gln Pro Ile Ser Phe Val Thr Leu Pro Ser Phe Asn Asp His Ser Phe
500 505 510
Val Asn Ile Thr Val Ser Ala Ser Phe Gly Gly His Ser Gly Ala Asn
515 520 525
Leu Ile Ala Ser Asp Thr Thr Ile Asn Gly Phe Ser Ser Phe Cys Val
530 535 540
Asp Thr Arg Gln Phe Thr Ile Ser Leu Phe Tyr Asn Val Thr Asn Ser
545 550 555 560
Tyr Gly Tyr Val Ser Lys Ser Gln Asp Ser Asn Cys Pro Phe Thr Leu
565 570 575
Gln Ser Val Asn Asp Tyr Leu Ser Phe Ser Lys Phe Cys Val Ser Thr
580 585 590
Ser Leu Leu Ala Ser Ala Cys Thr Ile Asp Leu Phe Gly Tyr Pro Glu
595 600 605
Phe Gly Ser Gly Val Lys Phe Thr Ser Leu Tyr Phe Gln Phe Thr Lys
610 615 620
Gly Glu Leu Ile Thr Gly Thr Pro Lys Pro Leu Glu Gly Val Thr Asp
625 630 635 640
Val Ser Phe Met Thr Leu Asp Val Cys Thr Lys Tyr Thr Ile Tyr Gly
645 650 655
Phe Lys Gly Glu Gly Ile Ile Thr Leu Thr Asn Ser Ser Phe Leu Ala
660 665 670
Gly Val Tyr Tyr Thr Ser Asp Ser Gly Gln Leu Leu Ala Phe Lys Asn
675 680 685
Val Thr Ser Gly Ala Val Tyr Ser Val Thr Pro Cys Ser Phe Ser Glu
690 695 700
Gln Ala Ala Tyr Val Asp Asp Asp Ile Val Gly Val Ile Ser Ser Leu
705 710 715 720
Ser Ser Ser Thr Phe Asn Ser Thr Arg Glu Leu Pro Gly Phe Phe Tyr
725 730 735
His Ser Asn Asp Gly Ser Asn Cys Thr Glu Pro Val Leu Val Tyr Ser
740 745 750
Asn Ile Gly Val Cys Lys Ser Gly Ser Ile Gly Tyr Val Pro Ser Gln
755 760 765
Ser Gly Gln Val Lys Ile Ala Pro Thr Val Thr Gly Asn Ile Ser Ile
770 775 780
Pro Thr Asn Phe Ser Met Ser Ile Arg Thr Glu Tyr Leu Gln Leu Tyr
785 790 795 800
Asn Thr Pro Val Ser Val Asp Cys Ala Thr Tyr Val Cys Asn Gly Asn
805 810 815
Ser Arg Cys Lys Gln Leu Leu Thr Gln Tyr Thr Ala Ala Cys Lys Thr
820 825 830
Ile Glu Ser Ala Leu Gln Leu Ser Ala Arg Leu Glu Ser Val Glu Val
835 840 845
Asn Ser Met Leu Thr Ile Ser Glu Glu Ala Leu Gln Leu Ala Thr Ile
850 855 860
Ser Ser Phe Asn Gly Asp Gly Tyr Asn Phe Thr Asn Val Leu Gly Val
865 870 875 880
Ser Val Tyr Asp Pro Ala Ser Gly Arg Val Val Gln Lys Arg Ser Phe
885 890 895
Ile Glu Asp Ala Leu Phe Asn Lys Val Val Thr Asn Gly Leu Gly Thr
900 905 910
Val Asp Glu Asp Tyr Lys Arg Cys Ser Asn Gly Arg Ser Val Ala Asp
915 920 925
Leu Val Cys Ala Gln Tyr Tyr Ser Gly Val Met Val Leu Pro Gly Val
930 935 940
Val Asp Ala Glu Lys Leu His Met Tyr Ser Ala Ser Leu Ile Gly Gly
945 950 955 960
Met Val Leu Gly Gly Phe Thr Ser Ala Ala Ala Leu Pro Phe Ser Tyr
965 970 975
Ala Val Gln Ala Arg Leu Asn Tyr Leu Ala Leu Gln Thr Asp Val Leu
980 985 990
Gln Arg Asn Gln Gln Leu Leu Ala Glu Ser Phe Asn Ser Ala Ile Gly
995 1000 1005
Asn Ile Thr Ser Ala Phe Glu Ser Val Lys Glu Ala Ile Ser Gln
1010 1015 1020
Thr Ser Lys Gly Leu Asn Thr Val Ala His Ala Leu Thr Lys Val
1025 1030 1035
Gln Glu Val Val Asn Ser Gln Gly Ala Ala Leu Thr Gln Leu Thr
1040 1045 1050
Val Gln Leu Gln His Asn Phe Gln Ala Ile Ser Ser Ser Ile Asp
1055 1060 1065
Asp Ile Tyr Ser Arg Leu Asp Ile Leu Ser Ala Asp Val Gln Val
1070 1075 1080
Asp Arg Leu Ile Thr Gly Arg Leu Ser Ala Leu Asn Ala Phe Val
1085 1090 1095
Ala Gln Thr Leu Thr Lys Tyr Thr Glu Val Gln Ala Ser Arg Lys
1100 1105 1110
Leu Ala Gln Gln Lys Val Asn Glu Cys Val Lys Ser Gln Ser Gln
1115 1120 1125
Arg Tyr Gly Phe Cys Gly Gly Asp Gly Glu His Ile Phe Ser Leu
1130 1135 1140
Val Gln Ala Ala Pro Gln Gly Leu Leu Phe Leu His Thr Val Leu
1145 1150 1155
Val Pro Ser Asp Phe Val Asp Val Ile Ala Ile Ala Gly Leu Cys
1160 1165 1170
Val Asn Asp Glu Ile Ala Leu Thr Leu Arg Glu Pro Gly Leu Val
1175 1180 1185
Leu Phe Thr His Glu Leu Gln Asn His Thr Ala Thr Glu Tyr Phe
1190 1195 1200
Val Ser Ser Arg Arg Met Phe Glu Pro Arg Lys Pro Thr Val Ser
1205 1210 1215
Asp Phe Val Gln Ile Glu Ser Cys Val Val Thr Tyr Val Asn Leu
1220 1225 1230
Thr Arg Asp Gln Leu Pro Asp Val Ile Pro Asp Tyr Ile Asp Val
1235 1240 1245
Asn Lys Thr Leu Asp Glu Ile Leu Ala Ser Leu Pro Asn Arg Thr
1250 1255 1260
Gly Pro Ser Leu Pro Leu Asp Val Phe Asn Ala Thr Tyr Leu Asn
1265 1270 1275
Leu Thr Gly Glu Ile Ala Asp Leu Glu Gln Arg Ser Glu Ser Leu
1280 1285 1290
Arg Asn Thr Thr Glu Glu Leu Gln Ser Leu Ile Tyr Asn Ile Asn
1295 1300 1305
Asn Thr Leu Val Asp Leu Glu Trp Leu Asn Arg Val Glu Thr Tyr
1310 1315 1320
Ile Lys Trp Pro Trp Trp Val Trp Leu Ile Ile Phe Ile Val Leu
1325 1330 1335
Ile Phe Val Val Ser Leu Leu Val Phe Cys Cys Ile Ser Thr Gly
1340 1345 1350
Cys Cys Gly Cys Cys Gly Cys Cys Cys Ala Cys Phe Ser Gly Cys
1355 1360 1365
Cys Arg Gly Pro Arg Leu Gln Pro Ala Glu Val Phe Glu Lys Val
1370 1375 1380
Arg Val Gln Cys Gly
1385
<210> 19
<211> 1388
<212> PRT
<213> 猪流行性腹泻病毒
<400> 19
Met Lys Ser Leu Thr Tyr Phe Trp Leu Phe Leu Pro Val Leu Ser Thr
1 5 10 15
Leu Ser Leu Pro Gln Asp Val Thr Arg Cys Ser Ala Asn Thr Asn Phe
20 25 30
Arg Arg Phe Phe Ser Lys Phe Asn Val Gln Ala Pro Ala Val Val Val
35 40 45
Leu Gly Gly Tyr Leu Pro Ile Gly Glu Asn Gln Gly Val Asn Ser Thr
50 55 60
Trp Tyr Cys Ala Gly Gln His Pro Thr Ala Ser Gly Val His Gly Ile
65 70 75 80
Phe Val Ser His Ile Arg Gly Gly His Gly Phe Glu Ile Gly Ile Ser
85 90 95
Gln Glu Pro Phe Asp Pro Ser Gly Tyr Gln Leu Tyr Leu His Lys Ala
100 105 110
Thr Asn Gly Asn Thr Asn Ala Thr Ala Arg Leu Arg Ile Cys Gln Phe
115 120 125
Pro Ser Ile Lys Thr Leu Gly Pro Thr Ala Asn Asn Asp Val Thr Thr
130 135 140
Gly Arg Asn Cys Leu Phe Asn Lys Ala Ile Pro Ala His Met Ser Glu
145 150 155 160
His Ser Val Val Gly Ile Thr Trp Asp Asn Asp Arg Val Thr Val Phe
165 170 175
Ser Asp Lys Ile Tyr Tyr Phe Tyr Phe Lys Asn Asp Trp Ser Arg Val
180 185 190
Ala Thr Lys Cys Tyr Asn Ser Gly Gly Cys Ala Met Gln Tyr Val Tyr
195 200 205
Glu Pro Thr Tyr Tyr Met Leu Asn Val Thr Ser Ala Gly Glu Asp Gly
210 215 220
Ile Ser Tyr Gln Pro Cys Thr Ala Asn Cys Ile Gly Tyr Ala Ala Asn
225 230 235 240
Val Phe Ala Thr Glu Pro Asn Gly His Ile Pro Glu Gly Phe Ser Phe
245 250 255
Asn Asn Trp Phe Leu Leu Ser Asn Asp Ser Thr Leu Val His Gly Lys
260 265 270
Val Val Ser Asn Gln Pro Leu Leu Val Asn Cys Leu Leu Ala Ile Pro
275 280 285
Lys Ile Tyr Gly Leu Gly Gln Phe Phe Ser Phe Asn Gln Thr Ile Asp
290 295 300
Gly Val Cys Asn Gly Ala Ala Val Gln Arg Ala Pro Glu Ala Leu Arg
305 310 315 320
Phe Asn Ile Asn Asp Thr Ser Val Ile Leu Ala Glu Gly Ser Ile Val
325 330 335
Leu His Thr Ala Leu Gly Thr Asn Phe Ser Phe Val Cys Ser Asn Ser
340 345 350
Ser Asn Pro His Leu Ala Thr Phe Ala Ile Pro Leu Gly Ala Thr Gln
355 360 365
Val Pro Tyr Tyr Cys Phe Leu Lys Val Asp Thr Tyr Asn Ser Thr Val
370 375 380
Tyr Lys Phe Leu Ala Val Leu Pro Pro Thr Val Arg Glu Ile Val Ile
385 390 395 400
Thr Lys Tyr Gly Asp Val Tyr Val Asn Gly Phe Gly Tyr Leu His Leu
405 410 415
Gly Leu Leu Asp Ala Val Thr Ile Asn Phe Thr Gly His Gly Thr Asp
420 425 430
Asp Asp Val Ser Gly Phe Trp Thr Ile Ala Ser Thr Asn Phe Val Asp
435 440 445
Ala Leu Ile Glu Val Gln Gly Thr Ala Ile Gln Arg Ile Leu Tyr Cys
450 455 460
Asp Asp Pro Val Ser Gln Leu Lys Cys Ser Gln Val Ala Phe Asp Leu
465 470 475 480
Asp Asp Gly Phe Tyr Pro Ile Ser Ser Arg Asn Leu Leu Ser His Glu
485 490 495
Gln Pro Ile Ser Phe Val Thr Leu Pro Ser Phe Asn Asp His Ser Phe
500 505 510
Val Asn Ile Thr Val Ser Ala Ser Phe Gly Gly His Ser Gly Ala Asn
515 520 525
Leu Ile Ala Ser Asp Thr Thr Ile Asn Gly Phe Ser Ser Phe Cys Val
530 535 540
Asp Thr Arg Gln Phe Thr Ile Ser Leu Phe Tyr Asn Val Thr Asn Ser
545 550 555 560
Tyr Gly Tyr Val Ser Lys Ser Gln Asp Ser Asn Cys Pro Phe Thr Leu
565 570 575
Gln Ser Val Asn Asp Tyr Leu Ser Phe Ser Lys Phe Cys Val Ser Thr
580 585 590
Ser Leu Leu Ala Ser Ala Cys Thr Ile Asp Leu Phe Gly Tyr Pro Glu
595 600 605
Phe Gly Ser Gly Val Lys Phe Thr Ser Leu Tyr Phe Gln Phe Thr Lys
610 615 620
Gly Glu Leu Ile Thr Gly Thr Pro Lys Pro Leu Glu Gly Val Thr Asp
625 630 635 640
Val Ser Phe Met Thr Leu Asp Val Cys Thr Lys Tyr Thr Ile Tyr Gly
645 650 655
Phe Lys Gly Glu Gly Ile Ile Thr Leu Thr Asn Ser Ser Phe Leu Ala
660 665 670
Gly Val Tyr Tyr Thr Ser Asp Ser Gly Gln Leu Leu Ala Phe Lys Asn
675 680 685
Val Thr Ser Gly Ala Val Tyr Ser Val Thr Pro Cys Ser Phe Ser Glu
690 695 700
Gln Ala Ala Tyr Val Asp Asp Asp Ile Val Gly Val Ile Ser Ser Leu
705 710 715 720
Ser Ser Ser Thr Phe Asn Ser Thr Arg Glu Leu Pro Gly Phe Phe Tyr
725 730 735
His Ser Asn Asp Gly Ser Asn Cys Thr Glu Pro Val Leu Val Tyr Ser
740 745 750
Asn Ile Gly Val Cys Lys Ser Gly Ser Ile Gly Tyr Val Pro Ser Gln
755 760 765
Ser Gly Gln Val Lys Ile Ala Pro Thr Val Thr Gly Asn Ile Ser Ile
770 775 780
Pro Thr Asn Phe Ser Met Ser Ile Arg Thr Glu Tyr Leu Gln Leu Tyr
785 790 795 800
Asn Thr Pro Val Ser Val Asp Cys Ala Thr Tyr Val Cys Asn Gly Asn
805 810 815
Ser Arg Cys Lys Gln Leu Leu Thr Gln Tyr Thr Ala Ala Cys Lys Thr
820 825 830
Ile Glu Ser Ala Leu Gln Leu Ser Ala Arg Leu Glu Ser Val Glu Val
835 840 845
Asn Ser Met Leu Thr Ile Ser Glu Glu Ala Leu Gln Leu Ala Thr Ile
850 855 860
Ser Ser Phe Asn Gly Asp Gly Tyr Asn Phe Thr Asn Val Leu Gly Val
865 870 875 880
Ser Val Tyr Asp Pro Ala Ser Gly Arg Val Val Gln Lys Arg Ser Phe
885 890 895
Ile Glu Asp Leu Ala Phe Asn Lys Val Val Thr Asn Gly Leu Gly Thr
900 905 910
Val Asp Glu Asp Tyr Lys Arg Cys Ser Asn Gly Arg Ser Val Ala Asp
915 920 925
Leu Val Cys Ala Gln Tyr Tyr Ser Gly Val Met Val Leu Pro Gly Val
930 935 940
Val Asp Ala Glu Lys Leu His Met Tyr Ser Ala Ser Leu Ile Gly Gly
945 950 955 960
Met Val Leu Gly Gly Phe Thr Ser Ala Ala Ala Leu Pro Phe Ser Tyr
965 970 975
Ala Val Gln Ala Arg Leu Asn Tyr Leu Ala Leu Gln Thr Asp Val Leu
980 985 990
Gln Arg Asn Gln Gln Leu Leu Ala Glu Ser Phe Asn Ser Ala Ile Gly
995 1000 1005
Asn Ile Thr Ser Ala Phe Glu Ser Val Lys Glu Ala Ile Ser Gln
1010 1015 1020
Thr Ser Lys Gly Leu Asn Thr Val Ala His Ala Leu Thr Lys Val
1025 1030 1035
Gln Glu Val Val Asn Ser Gln Gly Ala Ala Leu Thr Gln Leu Thr
1040 1045 1050
Val Gln Leu Gln His Asn Phe Gln Ala Ile Ser Ser Ser Ile Asp
1055 1060 1065
Asp Ile Tyr Ser Arg Leu Asp Ile Leu Ser Ala Asp Val Gln Val
1070 1075 1080
Asp Arg Leu Ile Thr Gly Arg Leu Ser Ala Leu Asn Ala Phe Val
1085 1090 1095
Ala Gln Thr Leu Thr Lys Tyr Thr Glu Val Gln Ala Ser Arg Lys
1100 1105 1110
Leu Ala Gln Gln Lys Val Asn Glu Cys Val Lys Ser Gln Ser Gln
1115 1120 1125
Arg Tyr Gly Phe Cys Gly Gly Asp Gly Glu His Ile Phe Ser Leu
1130 1135 1140
Val Gln Ala Ala Pro Gln Gly Leu Leu Phe Leu His Thr Val Leu
1145 1150 1155
Val Pro Ser Asp Phe Val Asp Val Ile Ala Ile Ala Gly Leu Cys
1160 1165 1170
Val Asn Asp Glu Ile Ala Leu Thr Leu Arg Glu Pro Gly Leu Val
1175 1180 1185
Leu Phe Thr His Glu Leu Gln Asn His Thr Ala Thr Glu Tyr Phe
1190 1195 1200
Val Ser Ser Arg Arg Met Phe Glu Pro Arg Lys Pro Thr Val Ser
1205 1210 1215
Asp Phe Val Gln Ile Glu Ser Cys Val Val Thr Tyr Val Asn Leu
1220 1225 1230
Thr Arg Asp Gln Leu Pro Asp Val Ile Pro Asp Tyr Ile Asp Val
1235 1240 1245
Asn Lys Thr Leu Asp Glu Ile Leu Ala Ser Leu Pro Asn Arg Thr
1250 1255 1260
Gly Pro Ser Leu Pro Leu Asp Val Phe Asn Ala Thr Tyr Leu Asn
1265 1270 1275
Leu Thr Gly Glu Ile Ala Asp Leu Glu Gln Arg Ser Glu Ser Leu
1280 1285 1290
Arg Asn Thr Thr Glu Glu Leu Gln Ser Leu Ile Tyr Asn Ile Asn
1295 1300 1305
Asn Thr Leu Val Asp Leu Glu Trp Leu Asn Arg Val Glu Thr Tyr
1310 1315 1320
Ile Lys Trp Pro Trp Trp Val Trp Leu Ile Ile Phe Ile Val Leu
1325 1330 1335
Ile Phe Val Val Ser Leu Leu Val Phe Cys Cys Ile Ser Thr Gly
1340 1345 1350
Cys Cys Gly Cys Cys Gly Cys Cys Cys Ala Cys Phe Ser Gly Cys
1355 1360 1365
Cys Arg Gly Pro Arg Leu Gln Pro Ala Glu Val Phe Glu Lys Val
1370 1375 1380
Arg Val Gln Cys Gly
1385
<210> 20
<211> 1388
<212> PRT
<213> 猪流行性腹泻病毒
<400> 20
Met Lys Ser Leu Thr Tyr Phe Trp Leu Phe Leu Pro Val Leu Ser Thr
1 5 10 15
Leu Ser Leu Pro Gln Asp Val Thr Arg Cys Ser Ala Asn Thr Asn Phe
20 25 30
Arg Arg Phe Phe Ser Lys Phe Asn Val Gln Ala Pro Ala Val Val Val
35 40 45
Leu Gly Gly Tyr Leu Pro Ile Gly Glu Asn Gln Gly Val Asn Ser Thr
50 55 60
Trp Tyr Cys Ala Gly Gln His Pro Thr Ala Ser Gly Val His Gly Ile
65 70 75 80
Phe Val Ser His Ile Arg Gly Gly His Gly Phe Glu Ile Gly Ile Ser
85 90 95
Gln Glu Pro Phe Asp Pro Ser Gly Tyr Gln Leu Tyr Leu His Lys Ala
100 105 110
Thr Asn Gly Asn Thr Asn Ala Thr Ala Arg Leu Arg Ile Cys Gln Phe
115 120 125
Pro Ser Ile Lys Thr Leu Gly Pro Thr Ala Asn Asn Asp Val Thr Thr
130 135 140
Gly Arg Asn Cys Leu Phe Asn Lys Ala Ile Pro Ala His Met Ser Glu
145 150 155 160
His Ser Val Val Gly Ile Thr Trp Asp Asn Asp Arg Val Thr Val Phe
165 170 175
Ser Asp Lys Ile Tyr Tyr Phe Tyr Phe Lys Asn Asp Trp Ser Arg Val
180 185 190
Ala Thr Lys Cys Tyr Asn Ser Gly Gly Cys Ala Met Gln Tyr Val Tyr
195 200 205
Glu Pro Thr Tyr Tyr Met Leu Asn Val Thr Ser Ala Gly Glu Asp Gly
210 215 220
Ile Ser Tyr Gln Pro Cys Thr Ala Asn Cys Ile Gly Tyr Ala Ala Asn
225 230 235 240
Val Phe Ala Thr Glu Pro Asn Gly His Ile Pro Glu Gly Phe Ser Phe
245 250 255
Asn Asn Trp Phe Leu Leu Ser Asn Asp Ser Thr Leu Val His Gly Lys
260 265 270
Val Val Ser Asn Gln Pro Leu Leu Val Asn Cys Leu Leu Ala Ile Pro
275 280 285
Lys Ile Tyr Gly Leu Gly Gln Phe Phe Ser Phe Asn Gln Thr Ile Asp
290 295 300
Gly Val Cys Asn Gly Ala Ala Val Gln Arg Ala Pro Glu Ala Leu Arg
305 310 315 320
Phe Asn Ile Asn Asp Thr Ser Val Ile Leu Ala Glu Gly Ser Ile Val
325 330 335
Leu His Thr Ala Leu Gly Thr Asn Phe Ser Phe Val Cys Ser Asn Ser
340 345 350
Ser Asn Pro His Leu Ala Thr Phe Ala Ile Pro Leu Gly Ala Thr Gln
355 360 365
Val Pro Tyr Tyr Cys Phe Leu Lys Val Asp Thr Tyr Asn Ser Thr Val
370 375 380
Tyr Lys Phe Leu Ala Val Leu Pro Pro Thr Val Arg Glu Ile Val Ile
385 390 395 400
Thr Lys Tyr Gly Asp Val Tyr Val Asn Gly Phe Gly Tyr Leu His Leu
405 410 415
Gly Leu Leu Asp Ala Val Thr Ile Asn Phe Thr Gly His Gly Thr Asp
420 425 430
Asp Asp Val Ser Gly Phe Trp Thr Ile Ala Ser Thr Asn Phe Val Asp
435 440 445
Ala Leu Ile Glu Val Gln Gly Thr Ala Ile Gln Arg Ile Leu Tyr Cys
450 455 460
Asp Asp Pro Val Ser Gln Leu Lys Cys Ser Gln Val Ala Phe Asp Leu
465 470 475 480
Asp Asp Gly Phe Tyr Pro Ile Ser Ser Arg Asn Leu Leu Ser His Glu
485 490 495
Gln Pro Ile Ser Phe Val Thr Leu Pro Ser Phe Asn Asp His Ser Phe
500 505 510
Val Asn Ile Thr Val Ser Ala Ser Phe Gly Gly His Ser Gly Ala Asn
515 520 525
Leu Ile Ala Ser Asp Thr Thr Ile Asn Gly Phe Ser Ser Phe Cys Val
530 535 540
Asp Thr Arg Gln Phe Thr Ile Ser Leu Phe Tyr Asn Val Thr Asn Ser
545 550 555 560
Tyr Gly Tyr Val Ser Lys Ser Gln Asp Ser Asn Cys Pro Phe Thr Leu
565 570 575
Gln Ser Val Asn Asp Tyr Leu Ser Phe Ser Lys Phe Cys Val Ser Thr
580 585 590
Ser Leu Leu Ala Ser Ala Cys Thr Ile Asp Leu Phe Gly Tyr Pro Glu
595 600 605
Phe Gly Ser Gly Val Lys Phe Thr Ser Leu Tyr Phe Gln Phe Thr Lys
610 615 620
Gly Glu Leu Ile Thr Gly Thr Pro Lys Pro Leu Glu Gly Val Thr Asp
625 630 635 640
Val Ser Phe Met Thr Leu Asp Val Cys Thr Lys Tyr Thr Ile Tyr Gly
645 650 655
Phe Lys Gly Glu Gly Ile Ile Thr Leu Thr Asn Ser Ser Phe Leu Ala
660 665 670
Gly Val Tyr Tyr Thr Ser Asp Ser Gly Gln Leu Leu Ala Phe Lys Asn
675 680 685
Val Thr Ser Gly Ala Val Tyr Ser Val Thr Pro Cys Ser Phe Ser Glu
690 695 700
Gln Ala Ala Tyr Val Asp Asp Asp Ile Val Gly Val Ile Ser Ser Leu
705 710 715 720
Ser Ser Ser Thr Phe Asn Ser Thr Arg Glu Leu Pro Gly Phe Phe Tyr
725 730 735
His Ser Asn Asp Gly Ser Asn Cys Thr Glu Pro Val Leu Val Tyr Ser
740 745 750
Asn Ile Gly Val Cys Lys Ser Gly Ser Ile Gly Tyr Val Pro Ser Gln
755 760 765
Ser Gly Gln Val Lys Ile Ala Pro Thr Val Thr Gly Asn Ile Ser Ile
770 775 780
Pro Thr Asn Phe Ser Met Ser Ile Arg Thr Glu Tyr Leu Gln Leu Tyr
785 790 795 800
Asn Thr Pro Val Ser Val Asp Cys Ala Thr Tyr Val Cys Asn Gly Asn
805 810 815
Ser Arg Cys Lys Gln Leu Leu Thr Gln Tyr Thr Ala Ala Cys Lys Thr
820 825 830
Ile Glu Ser Ala Leu Gln Leu Ser Ala Arg Leu Glu Ser Val Glu Val
835 840 845
Asn Ser Met Leu Thr Ile Ser Glu Glu Ala Leu Gln Leu Ala Thr Ile
850 855 860
Ser Ser Phe Asn Gly Asp Gly Tyr Asn Phe Thr Asn Val Leu Gly Val
865 870 875 880
Ser Val Tyr Asp Pro Ala Ser Gly Arg Val Val Gln Lys Arg Ser Phe
885 890 895
Ile Glu Asp Ala Ala Phe Asn Lys Val Val Thr Asn Gly Leu Gly Thr
900 905 910
Val Asp Glu Asp Tyr Lys Arg Cys Ser Asn Gly Arg Ser Val Ala Asp
915 920 925
Leu Val Cys Ala Gln Tyr Tyr Ser Gly Val Met Val Leu Pro Gly Val
930 935 940
Val Asp Ala Glu Lys Leu His Met Tyr Ser Ala Ser Leu Ile Gly Gly
945 950 955 960
Met Val Leu Gly Gly Phe Thr Ser Ala Ala Ala Leu Pro Phe Ser Tyr
965 970 975
Ala Val Gln Ala Arg Leu Asn Tyr Leu Ala Leu Gln Thr Asp Val Leu
980 985 990
Gln Arg Asn Gln Gln Leu Leu Ala Glu Ser Phe Asn Ser Ala Ile Gly
995 1000 1005
Asn Ile Thr Ser Ala Phe Glu Ser Val Lys Glu Ala Ile Ser Gln
1010 1015 1020
Thr Ser Lys Gly Leu Asn Thr Val Ala His Ala Leu Thr Lys Val
1025 1030 1035
Gln Glu Val Val Asn Ser Gln Gly Ala Ala Leu Thr Gln Leu Thr
1040 1045 1050
Val Gln Leu Gln His Asn Phe Gln Ala Ile Ser Ser Ser Ile Asp
1055 1060 1065
Asp Ile Tyr Ser Arg Leu Asp Ile Leu Ser Ala Asp Val Gln Val
1070 1075 1080
Asp Arg Leu Ile Thr Gly Arg Leu Ser Ala Leu Asn Ala Phe Val
1085 1090 1095
Ala Gln Thr Leu Thr Lys Tyr Thr Glu Val Gln Ala Ser Arg Lys
1100 1105 1110
Leu Ala Gln Gln Lys Val Asn Glu Cys Val Lys Ser Gln Ser Gln
1115 1120 1125
Arg Tyr Gly Phe Cys Gly Gly Asp Gly Glu His Ile Phe Ser Leu
1130 1135 1140
Val Gln Ala Ala Pro Gln Gly Leu Leu Phe Leu His Thr Val Leu
1145 1150 1155
Val Pro Ser Asp Phe Val Asp Val Ile Ala Ile Ala Gly Leu Cys
1160 1165 1170
Val Asn Asp Glu Ile Ala Leu Thr Leu Arg Glu Pro Gly Leu Val
1175 1180 1185
Leu Phe Thr His Glu Leu Gln Asn His Thr Ala Thr Glu Tyr Phe
1190 1195 1200
Val Ser Ser Arg Arg Met Phe Glu Pro Arg Lys Pro Thr Val Ser
1205 1210 1215
Asp Phe Val Gln Ile Glu Ser Cys Val Val Thr Tyr Val Asn Leu
1220 1225 1230
Thr Arg Asp Gln Leu Pro Asp Val Ile Pro Asp Tyr Ile Asp Val
1235 1240 1245
Asn Lys Thr Leu Asp Glu Ile Leu Ala Ser Leu Pro Asn Arg Thr
1250 1255 1260
Gly Pro Ser Leu Pro Leu Asp Val Phe Asn Ala Thr Tyr Leu Asn
1265 1270 1275
Leu Thr Gly Glu Ile Ala Asp Leu Glu Gln Arg Ser Glu Ser Leu
1280 1285 1290
Arg Asn Thr Thr Glu Glu Leu Gln Ser Leu Ile Tyr Asn Ile Asn
1295 1300 1305
Asn Thr Leu Val Asp Leu Glu Trp Leu Asn Arg Val Glu Thr Tyr
1310 1315 1320
Ile Lys Trp Pro Trp Trp Val Trp Leu Ile Ile Phe Ile Val Leu
1325 1330 1335
Ile Phe Val Val Ser Leu Leu Val Phe Cys Cys Ile Ser Thr Gly
1340 1345 1350
Cys Cys Gly Cys Cys Gly Cys Cys Cys Ala Cys Phe Ser Gly Cys
1355 1360 1365
Cys Arg Gly Pro Arg Leu Gln Pro Ala Glu Val Phe Glu Lys Val
1370 1375 1380
Arg Val Gln Cys Gly
1385
<210> 21
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 融合结构域之序列
<220>
<221> 变体
<222> (3)..(3)
<223> 残基3处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (8)..(8)
<223> 残基8处之X系除亮氨酸残基以外之氨基酸残基
<400> 21
Arg Ser Xaa Ile Glu Asp Leu Xaa
1 5
<210> 22
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 融合结构域之序列
<220>
<221> 变体
<222> (3)..(3)
<223> 残基3处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (7)..(7)
<223> 残基7处之X系除亮氨酸残基以外之氨基酸残基
<400> 22
Arg Ser Xaa Ile Glu Asp Xaa Leu
1 5
<210> 23
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 融合结构域之序列
<220>
<221> 变体
<222> (3)..(3)
<223> 残基3处之X可为任一氨基酸残基
<400> 23
Arg Ser Xaa Ile Glu Asp Leu Ala
1 5
<210> 24
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 融合结构域之序列
<220>
<221> 变体
<222> (3)..(3)
<223> 残基3处之X可为任一氨基酸残基
<400> 24
Arg Ser Xaa Ile Glu Asp Ala Leu
1 5
<210> 25
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 融合结构域之序列
<220>
<221> 变体
<222> (3)..(3)
<223> 残基3处之X可为任一氨基酸残基
<400> 25
Arg Ser Xaa Ile Glu Asp Ala Ala
1 5
<210> 26
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 保留结构域之序列
<220>
<221> 变体
<222> (1)..(1)
<223> 残基1处之X系除酪氨酸残基以外之氨基酸残基
<220>
<221> 变体
<222> (2)..(2)
<223> 残基2处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (3)..(3)
<223> 残基3处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (5)..(5)
<223> 残基5处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (7)..(7)
<223> 残基7处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (9)..(9)
<223> 残基9处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (10)..(10)
<223> 残基10处之X可为任一氨基酸残基
<400> 26
Xaa Xaa Xaa Phe Xaa Lys Xaa His Xaa Xaa
1 5 10
<210> 27
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 保留结构域之序列
<220>
<221> 变体
<222> (2)..(2)
<223> 残基2处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (3)..(3)
<223> 残基3处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (5)..(5)
<223> 残基5处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (7)..(7)
<223> 残基7处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (8)..(8)
<223> 残基8处之X系除组氨酸残基以外之氨基酸残基
<220>
<221> 变体
<222> (9)..(9)
<223> 残基9处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (10)..(10)
<223> 残基10处之X可为任一氨基酸残基
<400> 27
Tyr Xaa Xaa Phe Xaa Lys Xaa Xaa Xaa Xaa
1 5 10
<210> 28
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 保留结构域之序列
<220>
<221> 变体
<222> (2)..(2)
<223> 残基2处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (3)..(3)
<223> 残基3处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (5)..(5)
<223> 残基5处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (7)..(7)
<223> 残基7处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (9)..(9)
<223> 残基9处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (10)..(10)
<223> 残基10处之X可为任一氨基酸残基
<400> 28
Ala Xaa Xaa Phe Xaa Lys Xaa His Xaa Xaa
1 5 10
<210> 29
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 保留结构域之序列
<220>
<221> 变体
<222> (2)..(2)
<223> 残基2处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (3)..(3)
<223> 残基3处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (5)..(5)
<223> 残基5处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (7)..(7)
<223> 残基7处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (9)..(9)
<223> 残基9处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (10)..(10)
<223> 残基10处之X可为任一氨基酸残基
<400> 29
Tyr Xaa Xaa Phe Xaa Lys Xaa Arg Xaa Xaa
1 5 10
<210> 30
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 保留结构域之序列
<220>
<221> 变体
<222> (2)..(2)
<223> 残基2处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (3)..(3)
<223> 残基3处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (5)..(5)
<223> 残基5处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (7)..(7)
<223> 残基7处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (9)..(9)
<223> 残基9处之X可为任一氨基酸残基
<220>
<221> 变体
<222> (10)..(10)
<223> 残基10处之X可为任一氨基酸残基
<400> 30
Ala Xaa Xaa Phe Xaa Lys Xaa Arg Xaa Xaa
1 5 10
<210> 31
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 融合结构域之序列
<220>
<221> 变体
<222> (3)..(3)
<223> 残基3处之X可为任一氨基酸残基
<400> 31
Arg Ser Xaa Ile Glu Asp Leu Gly
1 5
<210> 32
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 保留结构域之序列
<220>
<221> 变体
<222> (3)..(3)
<223> 残基3处之X可为任一氨基酸残基
<400> 32
Arg Ser Xaa Ile Glu Asp Gly Leu
1 5
<210> 33
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 融合结构域之序列
<220>
<221> 变体
<222> (3)..(3)
<223> 残基3处之X可为任一氨基酸残基
<400> 33
Arg Ser Xaa Ile Glu Asp Gly Gly
1 5
<210> 34
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 融合结构域之序列
<220>
<221> 变体
<222> (3)..(3)
<223> 残基3处之X可为任一氨基酸残基
<400> 34
Arg Ser Xaa Ile Glu Asp Gly Ala
1 5
<210> 35
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 融合结构域之序列
<220>
<221> 变体
<222> (3)..(3)
<223> 残基3处之X可为任一氨基酸残基
<400> 35
Arg Ser Xaa Ile Glu Asp Ala Gly
1 5
<210> 36
<211> 5153
<212> DNA
<213> 人工序列
<220>
<223> PEDV棘蛋白编码盒
<400> 36
ccgcggtaat cggaaggaca gtggtattac tctgggctca aaaggtcaac tattgagaga 60
cctccagctg aaacccattg acaaagagtc tagctcggca atcggataca aaccaaagga 120
taccgcacct tctaaagctg tacttgcatc attgatcaga tcaagcagag ttgatcaaag 180
tcacaaacat aacatgctgg ttctgcttaa aaatatcaag ggagatgaca acctaaacga 240
gttctaccag atggtcaaga gtattactca tgcttaatct gtagcgttga ctaatctact 300
aaccggcgca aaactgcttt cactatcgct taaaagcaat tataaaaaac ttaggactca 360
ggtagtccag cagcaccatg aaatccctca actacttctg gctcttcctc cccgtgctct 420
ccaccctcag cctccctcag gatgtcacaa gatgccagtc cacaatcaac ttcagacggt 480
tcttctccaa gttcaacgtg caggcccccg ccgtggtggt gctgggcggc tacctgccaa 540
gcatgaactc cagctcctgg tactgcggca ccggcctgga gaccgcctcc ggcgtgcacg 600
gcatcttcct gagctacatc gacgccggcc agggcttcga gatcggcatc agccaggagc 660
ccttcgaccc aagcggctac cagctgtacc tgcacaaggc caccaacggc aaccacaacg 720
ccatcgccag gctgagaatc tgccagttcc ccaacaacaa gaccctgggc cccaccgtga 780
acgacgtgac caccggcaga aactgcctgt tcaacaaggc catcccagcc tacatgcagg 840
acggcaagaa catcgtggtg ggcatcacct gggacaacga cagagtgacc gtgttcgccg 900
acaagatcta ccacttctac ctgaagaacg actggtccag agtggccacc aggtgctaca 960
acaagcggag ctgcgccatg cagtacgtgt acaccccaac ctactacatg ctgaacgtga 1020
ccagcgccgg cgaggacggc atctactacg agccctgcac cgccaactgc agcggctacg 1080
ccgtgaacgt gttcgccacc gacagcaacg gccacatccc cgagggcttc tccttcaaca 1140
actggttcct gctgagcaac gactccaccc tgctgcacgg caaggtggtg tccaaccagc 1200
cactgctggt gaactgcctg ctggccatcc caaagatcta cggcctgggc cagttcttca 1260
gcttcaacca gaccatggac ggcgtgtgca acggcgccgc cgcccagagg gccccagagg 1320
ccctgagatt caacatcaac gacacctccg tgatcctggc cgagggcagc atcgtgctgc 1380
acaccgccct gggcaccaac ctgagcttcg tgtgctccaa cagctccgac ccccacctgg 1440
ccaccttcac catcccactg ggcgccaccc aggtgccata ctactgcttc ctgaaggtgg 1500
acacctacaa cagcaacgtg tacaagttcc tggccgtgct gccacccacc gtgagagaga 1560
tcgtgatcac caagtacggc gacgtgtacg tgaacggctt cggctacctg cacctgggcc 1620
tgctggacgc cgtgaccatc aacttcaccg gccacggcac cgacgacgac gtgagcggct 1680
tctggaccat cgcctccacc aacttcgtgg acgccctgat cgaggtgcag ggcaccgcca 1740
tccagcgcat cctgtactgc gacgacccag tgtcccagct gaagtgcagc caggtggcct 1800
tcgacctgga cgacggcttc taccccatca gctccagaaa cctgctgagc cacgagcagc 1860
caatcagctt cgtgaccctg ccatccttca acgaccactc cttcgtgaac atcaccgtga 1920
gcgcctcctt cggcggccac tccggcgcca acctgatcgc ctccgacacc accatcaacg 1980
gcttctccag cttctgcgtg gacaccaggc agttcaccat cagcctgttc tacaacgtga 2040
ccaacagcta cggctacgtg agcaagagcc aggactccaa ctgccccttc accctgcagt 2100
ccgtgaacga ctacctgtcc ttcagcaagt tctgcgtgtc caccagcctg ctggccagcg 2160
cctgcaccat cgacctgttc ggctacccag agttcggctc cggcgtgaag ttcaccagcc 2220
tgtacttcca gttcaccgag ggcgagctga tcaccggcac cccaaagccc ctggagggcg 2280
tgaccgacgt gagcttcatg accctggacg tgtgcaccaa gtacaccatc tacggcttca 2340
agggcgaggg catcatcacc ctgaccaaca gctccttcct ggccggcgtg tactacacct 2400
ccgacagcgg ccagctgctg gccttcaaga acgtgacctc cggcgccgtg tacagcgtga 2460
ccccctgctc cttcagcgag caggccgcct acgtggacga cgacatcgtg ggcgtgatct 2520
ccagcctgtc ctccagcacc ttcaactcca ccagagagct gccaggcttc ttctaccaca 2580
gcaacgacgg ctccaactgc accgagccag tgctggtgta ctccaacatc ggcgtgtgca 2640
agagcggctc catcggctac gtgccatccc agagcggcca ggtgaagatc gcccccaccg 2700
tgaccggcaa catctccatc cccaccaact tctccatgag catcagaacc gagtacctgc 2760
agctgtacaa cacccccgtg tccgtggact gcgccaccta cgtgtgcaac ggcaactcca 2820
gatgcaagca gctgctgacc cagtacaccg ccgcctgcaa gaccatcgag agcgccctgc 2880
agctgagcgc caggctggag tccgtggagg tgaacagcat gctgaccatc tccgaggagg 2940
ccctgcagct ggccaccatc agctccttca acggcgacgg ctacaacttc accaacgtgc 3000
tgggcgtgag cgtgtacgac ccagccagcg gcagagtggt gcagaagagg agcttcatcg 3060
aggacgccgc cttcaacaag gtggtgacca acggcctggg caccgtggac gaggactaca 3120
agagatgcag caacggcaga tccgtggccg acctggtgtg cgcccagtat tacagcggcg 3180
tgatggtgct gccaggcgtg gtggacgccg agaagctgca catgtacagc gcctccctga 3240
tcggcggcat ggtgctgggc ggcttcacct ccgccgccgc cctgcccttc agctacgccg 3300
tgcaggccag actgaactac ctggccctgc agaccgacgt gctgcagaga aaccagcagc 3360
tgctggccga gagcttcaac agcgccatcg gcaacatcac ctccgccttc gagagcgtga 3420
aggaggccat cagccagacc tccaagggcc tgaacaccgt ggcccacgcc ctgaccaagg 3480
tgcaggaggt ggtgaactcc cagggcgccg ccctgaccca gctgaccgtg cagctgcagc 3540
acaacttcca ggccatctcc agctccatcg acgacatcta ctccaggctg gacatcctgt 3600
ccgccgacgt gcaggtggac agactgatca ccggcagact gtccgccctg aacgccttcg 3660
tggcccagac cctgaccaag tacaccgagg tgcaggcctc cagaaagctg gcccagcaga 3720
aggtgaacga gtgcgtgaag tcccagagcc agagatacgg cttctgcggc ggcgacggcg 3780
agcacatctt ctccctggtg caggccgccc cacagggcct gctgttcctg cacaccgtgc 3840
tggtgccagg cgacttcatc gacgtgatcg ccatcgccgg cctgtgcgtg aacgacgaga 3900
tcgccctgac cctgagagag cccggcctgg tgctgttcac ccacgagctg cagaaccaca 3960
ccgccaccga gtatttcgtg agctccagac ggatgttcga gccaagaaag cccaccgtga 4020
gcgacttcgt gcagatcgag tcctgcgtgg tgacctacgt gaacctgacc agagaccagc 4080
tgccagacgt gatcccagac tacatcgacg tgaacaagac cctggacgag atcctggcct 4140
ccctgccaaa cagaaccggc cccagcctgc ccctggacgt gttcaacgcc acctacctga 4200
acctgaccgg cgagatcgcc gacctggagc agagaagcga gtccctgaga aacaccaccg 4260
aggagctgca gtccctgatc tacaacatca acaacaccct ggtggacctg gagtggctga 4320
acagagtgga gacctacatc aagtggccat ggtgggtgtg gctgatcgtg ttcatcgtgc 4380
tgatcttcgt ggtgtccctg ctggtgttct gctgcatctc caccggctgc tgcggctgct 4440
gcggctgctg ctgcgcctgc ttcagcggct gctgtagagg accccggctc cagcccgctg 4500
aggtgtttga gaaagtgaga gtgcagtgat aaatattcaa gaccagtcct gcatcagtca 4560
acaattatca ttctaaactc attataaaaa acttaggaca caagagccta agtcctctcc 4620
taaaaaatga ctgaggtgta cgacttcgat cagtcttctt gggacaccaa gggcttattg 4680
gcccctattt tgcctaccac ttatcccgat ggtaggctca taccccaagt cagagtaata 4740
gatccaggac tcggcgatag gaaagatgaa tgcttcatgt atatttttct actgggtata 4800
atagaagaca atgatggcct cggaccccca attggaagaa catttggatt gctgcctttg 4860
ggagttgggc gtactacagc cagacctgag gagttattga aagaagccac cctgttggat 4920
attgtggtaa ggcgaactgc aggtgtcaag gaacaactgg tattttataa taacacccca 4980
ttgcacatct taactccgtg gaaaaaggtc cttacgagtg gaagtgtgtt cagtgcaaat 5040
caagtctgta acgcagtcaa tctaatacca ttagacatag cacaaagatt cagggtggta 5100
tatatgagca tcactcgact atcagacgat ggaagttaca gaattccccg cgg 5153
<210> 37
<211> 4155
<212> RNA
<213> 人工序列
<220>
<223> 编码PEDV S蛋白
<400> 37
uuaucacugc acucucacuu ucucaaacac cucagcgggc uggagccggg guccucuaca 60
gcagccgcug aagcaggcgc agcagcagcc gcagcagccg cagcagccgg uggagaugca 120
gcagaacacc agcagggaca ccacgaagau cagcacgaug aacacgauca gccacaccca 180
ccauggccac uugauguagg ucuccacucu guucagccac uccaggucca ccaggguguu 240
guugauguug uagaucaggg acugcagcuc cucgguggug uuucucaggg acucgcuucu 300
cugcuccagg ucggcgaucu cgccggucag guucagguag guggcguuga acacguccag 360
gggcaggcug gggccgguuc uguuuggcag ggaggccagg aucucgucca gggucuuguu 420
cacgucgaug uagucuggga ucacgucugg cagcuggucu cuggucaggu ucacguaggu 480
caccacgcag gacucgaucu gcacgaaguc gcucacggug ggcuuucuug gcucgaacau 540
ccgucuggag cucacgaaau acucgguggc ggugugguuc ugcagcucgu gggugaacag 600
caccaggccg ggcucucuca gggucagggc gaucucgucg uucacgcaca ggccggcgau 660
ggcgaucacg ucgaugaagu cgccuggcac cagcacggug ugcaggaaca gcaggcccug 720
uggggcggcc ugcaccaggg agaagaugug cucgccgucg ccgccgcaga agccguaucu 780
cuggcucugg gacuucacgc acucguucac cuucugcugg gccagcuuuc uggaggccug 840
caccucggug uacuugguca gggucugggc cacgaaggcg uucagggcgg acagucugcc 900
ggugaucagu cuguccaccu gcacgucggc ggacaggaug uccagccugg aguagauguc 960
gucgauggag cuggagaugg ccuggaaguu gugcugcagc ugcacgguca gcugggucag 1020
ggcggcgccc ugggaguuca ccaccuccug caccuugguc agggcguggg ccacgguguu 1080
caggcccuug gaggucuggc ugauggccuc cuucacgcuc ucgaaggcgg aggugauguu 1140
gccgauggcg cuguugaagc ucucggccag cagcugcugg uuucucugca gcacgucggu 1200
cugcagggcc agguaguuca gucuggccug cacggcguag cugaagggca gggcggcggc 1260
ggaggugaag ccgcccagca ccaugccgcc gaucagggag gcgcuguaca ugugcagcuu 1320
cucggcgucc accacgccug gcagcaccau cacgccgcug uaauacuggg cgcacaccag 1380
gucggccacg gaucugccgu ugcugcaucu cuuguagucc ucguccacgg ugcccaggcc 1440
guuggucacc accuuguuga aggcggcguc cucgaugaag cuccucuucu gcaccacucu 1500
gccgcuggcu gggucguaca cgcucacgcc cagcacguug gugaaguugu agccgucgcc 1560
guugaaggag cugauggugg ccagcugcag ggccuccucg gagaugguca gcaugcuguu 1620
caccuccacg gacuccagcc uggcgcucag cugcagggcg cucucgaugg ucuugcaggc 1680
ggcgguguac ugggucagca gcugcuugca ucuggaguug ccguugcaca cguagguggc 1740
gcaguccacg gacacggggg uguuguacag cugcagguac ucgguucuga ugcucaugga 1800
gaaguuggug gggauggaga uguugccggu cacggugggg gcgaucuuca ccuggccgcu 1860
cugggauggc acguagccga uggagccgcu cuugcacacg ccgauguugg aguacaccag 1920
cacuggcucg gugcaguugg agccgucguu gcugugguag aagaagccug gcagcucucu 1980
gguggaguug aaggugcugg aggacaggcu ggagaucacg cccacgaugu cgucguccac 2040
guaggcggcc ugcucgcuga aggagcaggg ggucacgcug uacacggcgc cggaggucac 2100
guucuugaag gccagcagcu ggccgcuguc ggagguguag uacacgccgg ccaggaagga 2160
gcuguugguc agggugauga ugcccucgcc cuugaagccg uagauggugu acuuggugca 2220
cacguccagg gucaugaagc ucacgucggu cacgcccucc aggggcuuug gggugccggu 2280
gaucagcucg cccucgguga acuggaagua caggcuggug aacuucacgc cggagccgaa 2340
cucuggguag ccgaacaggu cgauggugca ggcgcuggcc agcaggcugg uggacacgca 2400
gaacuugcug aaggacaggu agucguucac ggacugcagg gugaaggggc aguuggaguc 2460
cuggcucuug cucacguagc cguagcuguu ggucacguug uagaacaggc ugauggugaa 2520
cugccuggug uccacgcaga agcuggagaa gccguugaug guggugucgg aggcgaucag 2580
guuggcgccg gaguggccgc cgaaggaggc gcucacggug auguucacga aggagugguc 2640
guugaaggau ggcaggguca cgaagcugau uggcugcucg uggcucagca gguuucugga 2700
gcugaugggg uagaagccgu cguccagguc gaaggccacc uggcugcacu ucagcuggga 2760
cacugggucg ucgcaguaca ggaugcgcug gauggcggug cccugcaccu cgaucagggc 2820
guccacgaag uugguggagg cgauggucca gaagccgcuc acgucgucgu cggugccgug 2880
gccggugaag uugaugguca cggcguccag caggcccagg ugcagguagc cgaagccguu 2940
cacguacacg ucgccguacu uggugaucac gaucucucuc acggugggug gcagcacggc 3000
caggaacuug uacacguugc uguuguaggu guccaccuuc aggaagcagu aguauggcac 3060
cuggguggcg cccaguggga uggugaaggu ggccaggugg gggucggagc uguuggagca 3120
cacgaagcuc agguuggugc ccagggcggu gugcagcacg augcugcccu cggccaggau 3180
cacggaggug ucguugaugu ugaaucucag ggccucuggg gcccucuggg cggcggcgcc 3240
guugcacacg ccguccaugg ucugguugaa gcugaagaac uggcccaggc cguagaucuu 3300
ugggauggcc agcaggcagu ucaccagcag uggcugguug gacaccaccu ugccgugcag 3360
caggguggag ucguugcuca gcaggaacca guuguugaag gagaagcccu cggggaugug 3420
gccguugcug ucgguggcga acacguucac ggcguagccg cugcaguugg cggugcaggg 3480
cucguaguag augccguccu cgccggcgcu ggucacguuc agcauguagu agguuggggu 3540
guacacguac ugcauggcgc agcuccgcuu guuguagcac cugguggcca cucuggacca 3600
gucguucuuc agguagaagu gguagaucuu gucggcgaac acggucacuc ugucguuguc 3660
ccaggugaug cccaccacga uguucuugcc guccugcaug uaggcuggga uggccuuguu 3720
gaacaggcag uuucugccgg uggucacguc guucacggug gggcccaggg ucuuguuguu 3780
ggggaacugg cagauucuca gccuggcgau ggcguugugg uugccguugg uggccuugug 3840
cagguacagc ugguagccgc uugggucgaa gggcuccugg cugaugccga ucucgaagcc 3900
cuggccggcg ucgauguagc ucaggaagau gccgugcacg ccggaggcgg ucuccaggcc 3960
ggugccgcag uaccaggagc uggaguucau gcuuggcagg uagccgccca gcaccaccac 4020
ggcgggggcc ugcacguuga acuuggagaa gaaccgucug aaguugauug uggacuggca 4080
ucuugugaca uccugaggga ggcugagggu ggagagcacg gggaggaaga gccagaagua 4140
guugagggau uucau 4155
<210> 38
<211> 4245
<212> RNA
<213> 人工序列
<220>
<223> 包含编码PEDV S蛋白之序列
<400> 38
aaguuuuuua uaaugaguuu agaaugauaa uuguugacug augcaggacu ggucuugaau 60
auuuaucacu gcacucucac uuucucaaac accucagcgg gcuggagccg ggguccucua 120
cagcagccgc ugaagcaggc gcagcagcag ccgcagcagc cgcagcagcc gguggagaug 180
cagcagaaca ccagcaggga caccacgaag aucagcacga ugaacacgau cagccacacc 240
caccauggcc acuugaugua ggucuccacu cuguucagcc acuccagguc caccagggug 300
uuguugaugu uguagaucag ggacugcagc uccucggugg uguuucucag ggacucgcuu 360
cucugcucca ggucggcgau cucgccgguc agguucaggu agguggcguu gaacacgucc 420
aggggcaggc uggggccggu ucuguuuggc agggaggcca ggaucucguc cagggucuug 480
uucacgucga uguagucugg gaucacgucu ggcagcuggu cucuggucag guucacguag 540
gucaccacgc aggacucgau cugcacgaag ucgcucacgg ugggcuuucu uggcucgaac 600
auccgucugg agcucacgaa auacucggug gcgguguggu ucugcagcuc gugggugaac 660
agcaccaggc cgggcucucu cagggucagg gcgaucucgu cguucacgca caggccggcg 720
auggcgauca cgucgaugaa gucgccuggc accagcacgg ugugcaggaa cagcaggccc 780
uguggggcgg ccugcaccag ggagaagaug ugcucgccgu cgccgccgca gaagccguau 840
cucuggcucu gggacuucac gcacucguuc accuucugcu gggccagcuu ucuggaggcc 900
ugcaccucgg uguacuuggu cagggucugg gccacgaagg cguucagggc ggacagucug 960
ccggugauca gucuguccac cugcacgucg gcggacagga uguccagccu ggaguagaug 1020
ucgucgaugg agcuggagau ggccuggaag uugugcugca gcugcacggu cagcuggguc 1080
agggcggcgc ccugggaguu caccaccucc ugcaccuugg ucagggcgug ggccacggug 1140
uucaggcccu uggaggucug gcugauggcc uccuucacgc ucucgaaggc ggaggugaug 1200
uugccgaugg cgcuguugaa gcucucggcc agcagcugcu gguuucucug cagcacgucg 1260
gucugcaggg ccagguaguu cagucuggcc ugcacggcgu agcugaaggg cagggcggcg 1320
gcggagguga agccgcccag caccaugccg ccgaucaggg aggcgcugua caugugcagc 1380
uucucggcgu ccaccacgcc uggcagcacc aucacgccgc uguaauacug ggcgcacacc 1440
aggucggcca cggaucugcc guugcugcau cucuuguagu ccucguccac ggugcccagg 1500
ccguugguca ccaccuuguu gaaggcggcg uccucgauga agcuccucuu cugcaccacu 1560
cugccgcugg cugggucgua cacgcucacg cccagcacgu uggugaaguu guagccgucg 1620
ccguugaagg agcugauggu ggccagcugc agggccuccu cggagauggu cagcaugcug 1680
uucaccucca cggacuccag ccuggcgcuc agcugcaggg cgcucucgau ggucuugcag 1740
gcggcggugu acugggucag cagcugcuug caucuggagu ugccguugca cacguaggug 1800
gcgcagucca cggacacggg gguguuguac agcugcaggu acucgguucu gaugcucaug 1860
gagaaguugg uggggaugga gauguugccg gucacggugg gggcgaucuu caccuggccg 1920
cucugggaug gcacguagcc gauggagccg cucuugcaca cgccgauguu ggaguacacc 1980
agcacuggcu cggugcaguu ggagccgucg uugcuguggu agaagaagcc uggcagcucu 2040
cugguggagu ugaaggugcu ggaggacagg cuggagauca cgcccacgau gucgucgucc 2100
acguaggcgg ccugcucgcu gaaggagcag ggggucacgc uguacacggc gccggagguc 2160
acguucuuga aggccagcag cuggccgcug ucggaggugu aguacacgcc ggccaggaag 2220
gagcuguugg ucagggugau gaugcccucg cccuugaagc cguagauggu guacuuggug 2280
cacacgucca gggucaugaa gcucacgucg gucacgcccu ccaggggcuu uggggugccg 2340
gugaucagcu cgcccucggu gaacuggaag uacaggcugg ugaacuucac gccggagccg 2400
aacucugggu agccgaacag gucgauggug caggcgcugg ccagcaggcu gguggacacg 2460
cagaacuugc ugaaggacag guagucguuc acggacugca gggugaaggg gcaguuggag 2520
uccuggcucu ugcucacgua gccguagcug uuggucacgu uguagaacag gcugauggug 2580
aacugccugg uguccacgca gaagcuggag aagccguuga uggugguguc ggaggcgauc 2640
agguuggcgc cggaguggcc gccgaaggag gcgcucacgg ugauguucac gaaggagugg 2700
ucguugaagg auggcagggu cacgaagcug auuggcugcu cguggcucag cagguuucug 2760
gagcugaugg gguagaagcc gucguccagg ucgaaggcca ccuggcugca cuucagcugg 2820
gacacugggu cgucgcagua caggaugcgc uggauggcgg ugcccugcac cucgaucagg 2880
gcguccacga aguuggugga ggcgaugguc cagaagccgc ucacgucguc gucggugccg 2940
uggccgguga aguugauggu cacggcgucc agcaggccca ggugcaggua gccgaagccg 3000
uucacguaca cgucgccgua cuuggugauc acgaucucuc ucacgguggg uggcagcacg 3060
gccaggaacu uguacacguu gcuguuguag guguccaccu ucaggaagca guaguauggc 3120
accugggugg cgcccagugg gauggugaag guggccaggu gggggucgga gcuguuggag 3180
cacacgaagc ucagguuggu gcccagggcg gugugcagca cgaugcugcc cucggccagg 3240
aucacggagg ugucguugau guugaaucuc agggccucug gggcccucug ggcggcggcg 3300
ccguugcaca cgccguccau ggucugguug aagcugaaga acuggcccag gccguagauc 3360
uuugggaugg ccagcaggca guucaccagc aguggcuggu uggacaccac cuugccgugc 3420
agcagggugg agucguugcu cagcaggaac caguuguuga aggagaagcc cucggggaug 3480
uggccguugc ugucgguggc gaacacguuc acggcguagc cgcugcaguu ggcggugcag 3540
ggcucguagu agaugccguc cucgccggcg cuggucacgu ucagcaugua guagguuggg 3600
guguacacgu acugcauggc gcagcuccgc uuguuguagc accugguggc cacucuggac 3660
cagucguucu ucagguagaa gugguagauc uugucggcga acacggucac ucugucguug 3720
ucccagguga ugcccaccac gauguucuug ccguccugca uguaggcugg gauggccuug 3780
uugaacaggc aguuucugcc gguggucacg ucguucacgg uggggcccag ggucuuguug 3840
uuggggaacu ggcagauucu cagccuggcg auggcguugu gguugccguu gguggccuug 3900
ugcagguaca gcugguagcc gcuugggucg aagggcuccu ggcugaugcc gaucucgaag 3960
cccuggccgg cgucgaugua gcucaggaag augccgugca cgccggaggc ggucuccagg 4020
ccggugccgc aguaccagga gcuggaguuc augcuuggca gguagccgcc cagcaccacc 4080
acggcggggg ccugcacguu gaacuuggag aagaaccguc ugaaguugau uguggacugg 4140
caucuuguga cauccugagg gaggcugagg guggagagca cggggaggaa gagccagaag 4200
uaguugaggg auuucauggu gcugcuggac uaccugaguc cuaag 4245
<210> 39
<211> 1386
<212> PRT
<213> 猪流行性腹泻病毒
<400> 39
Met Lys Ser Leu Thr Tyr Phe Trp Leu Phe Leu Pro Val Leu Ser Thr
1 5 10 15
Leu Ser Leu Pro Gln Asp Val Thr Arg Cys Ser Ala Asn Thr Asn Phe
20 25 30
Arg Arg Phe Phe Ser Lys Phe Asn Val Gln Ala Pro Ala Val Val Val
35 40 45
Leu Gly Gly Tyr Leu Pro Ile Gly Glu Asn Gln Gly Val Asn Ser Thr
50 55 60
Trp Tyr Cys Ala Gly Gln His Pro Thr Ala Ser Gly Val His Gly Ile
65 70 75 80
Phe Val Ser His Ile Arg Gly Gly His Gly Phe Glu Ile Gly Ile Ser
85 90 95
Gln Glu Pro Phe Asp Pro Ser Gly Tyr Gln Leu Tyr Leu His Lys Ala
100 105 110
Thr Asn Gly Asn Thr Asn Ala Thr Ala Arg Leu Arg Ile Cys Gln Phe
115 120 125
Pro Ser Ile Lys Thr Leu Gly Pro Thr Ala Asn Asn Asp Val Thr Thr
130 135 140
Gly Arg Asn Cys Leu Phe Asn Lys Ala Ile Pro Ala Tyr Met Ser Glu
145 150 155 160
His Ser Val Val Gly Ile Thr Trp Asp Asn Asp Arg Val Thr Val Phe
165 170 175
Ser Asp Lys Ile Tyr Tyr Phe Tyr Phe Lys Asn Asp Trp Ser Arg Val
180 185 190
Ala Thr Lys Cys Tyr Asn Ser Gly Gly Cys Ala Met Gln Tyr Val Tyr
195 200 205
Glu Pro Thr Tyr Tyr Met Leu Asn Val Thr Ser Ala Gly Glu Asp Gly
210 215 220
Ile Ser Tyr Gln Pro Cys Thr Ala Asn Cys Ile Gly Tyr Ala Ala Asn
225 230 235 240
Val Phe Ala Thr Glu Pro Asn Gly His Ile Pro Glu Gly Phe Ser Phe
245 250 255
Asn Asn Trp Phe Leu Leu Ser Asn Asp Ser Thr Leu Val His Gly Lys
260 265 270
Val Val Ser Asn Gln Pro Leu Leu Val Asn Cys Leu Leu Ala Ile Pro
275 280 285
Lys Ile Tyr Gly Leu Gly Gln Phe Phe Ser Phe Asn Gln Thr Ile Asp
290 295 300
Gly Val Cys Asn Gly Ala Ala Val Gln Arg Ala Pro Glu Ala Leu Arg
305 310 315 320
Phe Asn Ile Asn Asp Thr Ser Val Ile Leu Ala Glu Gly Ser Ile Val
325 330 335
Leu His Thr Ala Leu Gly Thr Asn Phe Ser Phe Val Cys Ser Asn Ser
340 345 350
Ser Gly Pro His Leu Ala Thr Phe Ala Ile Pro Leu Gly Ala Thr Gln
355 360 365
Val Pro Tyr Tyr Cys Phe Leu Lys Val Asp Thr Tyr Asn Ser Thr Val
370 375 380
Tyr Lys Phe Leu Ala Val Leu Pro Pro Thr Val Arg Glu Ile Val Ile
385 390 395 400
Thr Lys Tyr Gly Asp Val Tyr Val Asn Gly Phe Gly Tyr Leu His Leu
405 410 415
Gly Leu Leu Asp Ala Val Thr Ile Asn Phe Thr Gly His Gly Thr Asp
420 425 430
Gly Asp Val Ser Gly Phe Trp Thr Ile Ala Ser Thr Asn Phe Val Asp
435 440 445
Ala Leu Ile Glu Val Gln Gly Thr Ala Ile Gln Arg Ile Leu Tyr Cys
450 455 460
Asp Asp Pro Val Ser Gln Leu Lys Cys Ser Gln Val Ala Phe Asp Leu
465 470 475 480
Asp Asp Gly Phe Tyr Pro Ile Ser Ser Arg Asn Leu Leu Ser His Glu
485 490 495
Gln Pro Ile Ser Phe Val Thr Leu Pro Ser Phe Asn Asp His Ser Phe
500 505 510
Val Asn Ile Thr Val Ser Ala Ser Phe Gly Gly His Ser Gly Ala Asn
515 520 525
Leu Ile Ala Ser Asp Thr Thr Ile Asn Gly Phe Ser Ser Phe Cys Val
530 535 540
Asp Thr Arg Gln Phe Thr Ile Ser Leu Phe Tyr Asn Val Thr Asn Ser
545 550 555 560
Tyr Gly Tyr Val Ser Asn Ser Gln Asp Ser Asn Cys Pro Phe Thr Leu
565 570 575
Gln Ser Val Asn Asp Tyr Leu Ser Phe Ser Lys Phe Cys Val Ser Thr
580 585 590
Ser Leu Leu Ala Ser Ala Cys Thr Ile Asp Leu Phe Gly Tyr Pro Glu
595 600 605
Phe Gly Ser Gly Val Lys Phe Thr Ser Leu Tyr Phe Gln Phe Thr Lys
610 615 620
Gly Glu Leu Ile Thr Gly Thr Pro Lys Pro Leu Glu Gly Val Thr Asp
625 630 635 640
Val Ser Phe Met Thr Leu Asp Val Cys Thr Lys Tyr Thr Ile Tyr Gly
645 650 655
Phe Lys Gly Glu Gly Ile Ile Thr Leu Thr Asn Ser Ser Phe Leu Ala
660 665 670
Gly Phe Tyr Tyr Thr Ser Asp Ser Gly Gln Leu Leu Ala Phe Lys Asn
675 680 685
Val Thr Ser Gly Ala Val Tyr Ser Val Thr Pro Cys Ser Phe Ser Glu
690 695 700
Gln Ala Ala Tyr Val Asp Asp Asp Ile Val Gly Val Ile Ser Ser Leu
705 710 715 720
Ser Ser Ser Thr Phe Asn Ser Thr Arg Glu Leu Pro Gly Phe Phe Tyr
725 730 735
His Ser Asn Asp Gly Ser Asn Cys Thr Glu Pro Val Leu Val Tyr Ser
740 745 750
Asn Ile Gly Val Cys Lys Ser Gly Ser Ile Gly Tyr Val Pro Ser Gln
755 760 765
Ser Gly Gln Val Lys Ile Ala Pro Thr Val Thr Gly Asn Ile Ser Ile
770 775 780
Pro Thr Asn Phe Ser Met Ser Ile Arg Thr Glu Tyr Leu Gln Leu Tyr
785 790 795 800
Asn Thr Pro Val Ser Val Asp Cys Ala Thr Tyr Val Cys Asn Gly Asn
805 810 815
Ser Arg Cys Lys Gln Leu Leu Thr Gln Tyr Thr Ala Ala Cys Lys Thr
820 825 830
Ile Glu Ser Ala Leu Gln Leu Ser Ala Arg Leu Glu Ser Val Glu Val
835 840 845
Asn Ser Met Leu Thr Ile Ser Glu Glu Ala Leu Gln Leu Ala Thr Ile
850 855 860
Ser Ser Phe Asn Gly Asp Gly Tyr Asn Phe Thr Asn Val Leu Gly Val
865 870 875 880
Ser Val Tyr Asp Pro Ala Ser Gly Arg Val Val Gln Lys Arg Ser Phe
885 890 895
Ile Glu Asp Leu Leu Phe Asn Lys Val Val Thr Asn Gly Leu Gly Thr
900 905 910
Val Asp Glu Asp Tyr Lys Arg Cys Ser Asn Gly Arg Ser Val Ala Asp
915 920 925
Leu Val Cys Ala Gln Tyr Tyr Ser Gly Val Met Val Leu Pro Gly Val
930 935 940
Val Asp Ala Glu Lys Leu His Met Tyr Ser Ala Ser Leu Ile Gly Gly
945 950 955 960
Met Val Leu Gly Gly Phe Thr Ser Ala Ala Ala Leu Pro Phe Ser Tyr
965 970 975
Ala Val Gln Ala Arg Leu Asn Tyr Leu Ala Leu Gln Thr Asp Val Leu
980 985 990
Gln Arg Asn Gln Gln Leu Leu Ala Glu Ser Phe Asn Ser Ala Ile Gly
995 1000 1005
Asn Ile Thr Ser Ala Phe Glu Ser Val Lys Glu Ala Ile Ser Gln
1010 1015 1020
Thr Ser Lys Gly Leu Asn Thr Val Ala His Ala Leu Thr Lys Val
1025 1030 1035
Gln Glu Val Val Asn Ser Gln Gly Ala Ala Leu Thr Gln Leu Thr
1040 1045 1050
Val Gln Leu Gln His Asn Phe Gln Ala Ile Ser Ser Ser Ile Asp
1055 1060 1065
Asp Ile Tyr Ser Arg Leu Asp Ile Leu Ser Ala Asp Val Gln Val
1070 1075 1080
Asp Arg Leu Ile Thr Gly Arg Leu Ser Ala Leu Asn Ala Phe Val
1085 1090 1095
Ala Gln Thr Leu Thr Lys Tyr Thr Glu Val Gln Ala Ser Arg Lys
1100 1105 1110
Leu Ala Gln Gln Lys Val Asn Glu Cys Val Lys Ser Gln Ser Gln
1115 1120 1125
Arg Tyr Gly Phe Cys Gly Gly Asp Gly Glu His Ile Phe Ser Leu
1130 1135 1140
Val Gln Ala Ala Pro Gln Gly Leu Leu Phe Leu His Thr Val Leu
1145 1150 1155
Val Pro Gly Asp Phe Val Asp Val Ile Ala Ile Ala Gly Leu Cys
1160 1165 1170
Val Asn Asp Glu Ile Ala Leu Thr Leu Arg Glu Pro Gly Leu Val
1175 1180 1185
Leu Phe Thr His Glu Leu Gln Asn His Thr Ala Thr Glu Tyr Phe
1190 1195 1200
Val Ser Ser Arg Arg Met Phe Glu Pro Arg Lys Pro Thr Val Ser
1205 1210 1215
Asp Phe Val Gln Ile Glu Ser Cys Val Val Thr Tyr Val Asn Leu
1220 1225 1230
Thr Arg Asp Gln Leu Pro Asp Val Ile Pro Asp Tyr Ile Asp Val
1235 1240 1245
Asn Lys Thr Leu Asp Glu Ile Leu Ala Ser Leu Pro Asn Arg Thr
1250 1255 1260
Gly Pro Ser Leu Pro Leu Asp Val Phe Asn Ala Thr Tyr Leu Asn
1265 1270 1275
Leu Thr Gly Glu Ile Ala Asp Leu Glu Gln Arg Ser Glu Ser Leu
1280 1285 1290
Arg Asn Thr Thr Glu Glu Leu Gln Ser Leu Ile Tyr Asn Ile Asn
1295 1300 1305
Asn Thr Leu Val Asp Leu Glu Trp Leu Asn Arg Val Glu Thr Tyr
1310 1315 1320
Ile Lys Trp Pro Trp Trp Val Trp Leu Ile Ile Phe Ile Val Leu
1325 1330 1335
Ile Phe Val Val Ser Leu Leu Val Phe Cys Cys Ile Ser Thr Gly
1340 1345 1350
Cys Cys Gly Cys Cys Gly Cys Cys Cys Ala Cys Phe Ser Gly Cys
1355 1360 1365
Cys Arg Gly Pro Arg Leu Gln Pro Tyr Glu Ala Phe Glu Lys Val
1370 1375 1380
His Val Gln
1385
<210> 40
<211> 1386
<212> PRT
<213> 猪流行性腹泻病毒
<400> 40
Met Lys Ser Leu Thr Tyr Phe Trp Leu Phe Leu Pro Val Leu Ser Thr
1 5 10 15
Leu Ser Leu Pro Gln Asp Val Thr Arg Cys Ser Ala Asn Thr Asn Phe
20 25 30
Arg Arg Phe Phe Ser Lys Phe Asn Val Gln Ala Pro Ala Val Val Val
35 40 45
Leu Gly Gly Tyr Leu Pro Ile Gly Glu Asn Gln Gly Val Asn Ser Thr
50 55 60
Trp Tyr Cys Ala Gly Gln His Pro Thr Ala Ser Gly Val His Gly Ile
65 70 75 80
Phe Val Ser His Ile Arg Gly Gly His Gly Phe Glu Ile Gly Ile Ser
85 90 95
Gln Glu Pro Phe Asp Pro Ser Gly Tyr Gln Leu Tyr Leu His Lys Ala
100 105 110
Thr Asn Gly Asn Thr Asn Ala Thr Ala Arg Leu Arg Ile Cys Gln Phe
115 120 125
Pro Ser Ile Lys Thr Leu Gly Pro Thr Ala Asn Asn Asp Val Thr Thr
130 135 140
Gly Arg Asn Cys Leu Phe Asn Lys Ala Ile Pro Ala Tyr Met Ser Glu
145 150 155 160
His Ser Val Val Gly Ile Thr Trp Asp Asn Asp Arg Val Thr Val Phe
165 170 175
Ser Asp Lys Ile Tyr Tyr Phe Tyr Phe Lys Asn Asp Trp Ser Arg Val
180 185 190
Ala Thr Lys Cys Tyr Asn Ser Gly Gly Cys Ala Met Gln Tyr Val Tyr
195 200 205
Glu Pro Thr Tyr Tyr Met Leu Asn Val Thr Ser Ala Gly Glu Asp Gly
210 215 220
Ile Ser Tyr Gln Pro Cys Thr Ala Asn Cys Ile Gly Tyr Ala Ala Asn
225 230 235 240
Val Phe Ala Thr Glu Pro Asn Gly His Ile Pro Glu Gly Phe Ser Phe
245 250 255
Asn Asn Trp Phe Leu Leu Ser Asn Asp Ser Thr Leu Val His Gly Lys
260 265 270
Val Val Ser Asn Gln Pro Leu Leu Val Asn Cys Leu Leu Ala Ile Pro
275 280 285
Lys Ile Tyr Gly Leu Gly Gln Phe Phe Ser Phe Asn Gln Thr Ile Asp
290 295 300
Gly Val Cys Asn Gly Ala Ala Val Gln Arg Ala Pro Glu Ala Leu Arg
305 310 315 320
Phe Asn Ile Asn Asp Thr Ser Val Ile Leu Ala Glu Gly Ser Ile Val
325 330 335
Leu His Thr Ala Leu Gly Thr Asn Phe Ser Phe Val Cys Ser Asn Ser
340 345 350
Ser Gly Pro His Leu Ala Thr Phe Ala Ile Pro Leu Gly Ala Thr Gln
355 360 365
Val Pro Tyr Tyr Cys Phe Leu Lys Val Asp Thr Tyr Asn Ser Thr Val
370 375 380
Tyr Lys Phe Leu Ala Val Leu Pro Pro Thr Val Arg Glu Ile Val Ile
385 390 395 400
Thr Lys Tyr Gly Asp Val Tyr Val Asn Gly Phe Gly Tyr Leu His Leu
405 410 415
Gly Leu Leu Asp Ala Val Thr Ile Asn Phe Thr Gly His Gly Thr Asp
420 425 430
Gly Asp Val Ser Gly Phe Trp Thr Ile Ala Ser Thr Asn Phe Val Asp
435 440 445
Ala Leu Ile Glu Val Gln Gly Thr Ala Ile Gln Arg Ile Leu Tyr Cys
450 455 460
Asp Asp Pro Val Ser Gln Leu Lys Cys Ser Gln Val Ala Phe Asp Leu
465 470 475 480
Asp Asp Gly Phe Tyr Pro Ile Ser Ser Arg Asn Leu Leu Ser His Glu
485 490 495
Gln Pro Ile Ser Phe Val Thr Leu Pro Ser Phe Asn Asp His Ser Phe
500 505 510
Val Asn Ile Thr Val Ser Ala Ser Phe Gly Gly His Ser Gly Ala Asn
515 520 525
Leu Ile Ala Ser Asp Thr Thr Ile Asn Gly Phe Ser Ser Phe Cys Val
530 535 540
Asp Thr Arg Gln Phe Thr Ile Ser Leu Phe Tyr Asn Val Thr Asn Ser
545 550 555 560
Tyr Gly Tyr Val Ser Asn Ser Gln Asp Ser Asn Cys Pro Phe Thr Leu
565 570 575
Gln Ser Val Asn Asp Tyr Leu Ser Phe Ser Lys Phe Cys Val Ser Thr
580 585 590
Ser Leu Leu Ala Ser Ala Cys Thr Ile Asp Leu Phe Gly Tyr Pro Glu
595 600 605
Phe Gly Ser Gly Val Lys Phe Thr Ser Leu Tyr Phe Gln Phe Thr Lys
610 615 620
Gly Glu Leu Ile Thr Gly Thr Pro Lys Pro Leu Glu Gly Val Thr Asp
625 630 635 640
Val Ser Phe Met Thr Leu Asp Val Cys Thr Lys Tyr Thr Ile Tyr Gly
645 650 655
Phe Lys Gly Glu Gly Ile Ile Thr Leu Thr Asn Ser Ser Phe Leu Ala
660 665 670
Gly Phe Tyr Tyr Thr Ser Asp Ser Gly Gln Leu Leu Ala Phe Lys Asn
675 680 685
Val Thr Ser Gly Ala Val Tyr Ser Val Thr Pro Cys Ser Phe Ser Glu
690 695 700
Gln Ala Ala Tyr Val Asp Asp Asp Ile Val Gly Val Ile Ser Ser Leu
705 710 715 720
Ser Ser Ser Thr Phe Asn Ser Thr Arg Glu Leu Pro Gly Phe Phe Tyr
725 730 735
His Ser Asn Asp Gly Ser Asn Cys Thr Glu Pro Val Leu Val Tyr Ser
740 745 750
Asn Ile Gly Val Cys Lys Ser Gly Ser Ile Gly Tyr Val Pro Ser Gln
755 760 765
Ser Gly Gln Val Lys Ile Ala Pro Thr Val Thr Gly Asn Ile Ser Ile
770 775 780
Pro Thr Asn Phe Ser Met Ser Ile Arg Thr Glu Tyr Leu Gln Leu Tyr
785 790 795 800
Asn Thr Pro Val Ser Val Asp Cys Ala Thr Tyr Val Cys Asn Gly Asn
805 810 815
Ser Arg Cys Lys Gln Leu Leu Thr Gln Tyr Thr Ala Ala Cys Lys Thr
820 825 830
Ile Glu Ser Ala Leu Gln Leu Ser Ala Arg Leu Glu Ser Val Glu Val
835 840 845
Asn Ser Met Leu Thr Ile Ser Glu Glu Ala Leu Gln Leu Ala Thr Ile
850 855 860
Ser Ser Phe Asn Gly Asp Gly Tyr Asn Phe Thr Asn Val Leu Gly Val
865 870 875 880
Ser Val Tyr Asp Pro Ala Ser Gly Arg Val Val Gln Lys Arg Ser Phe
885 890 895
Ile Glu Asp Ala Ala Phe Asn Lys Val Val Thr Asn Gly Leu Gly Thr
900 905 910
Val Asp Glu Asp Tyr Lys Arg Cys Ser Asn Gly Arg Ser Val Ala Asp
915 920 925
Leu Val Cys Ala Gln Tyr Tyr Ser Gly Val Met Val Leu Pro Gly Val
930 935 940
Val Asp Ala Glu Lys Leu His Met Tyr Ser Ala Ser Leu Ile Gly Gly
945 950 955 960
Met Val Leu Gly Gly Phe Thr Ser Ala Ala Ala Leu Pro Phe Ser Tyr
965 970 975
Ala Val Gln Ala Arg Leu Asn Tyr Leu Ala Leu Gln Thr Asp Val Leu
980 985 990
Gln Arg Asn Gln Gln Leu Leu Ala Glu Ser Phe Asn Ser Ala Ile Gly
995 1000 1005
Asn Ile Thr Ser Ala Phe Glu Ser Val Lys Glu Ala Ile Ser Gln
1010 1015 1020
Thr Ser Lys Gly Leu Asn Thr Val Ala His Ala Leu Thr Lys Val
1025 1030 1035
Gln Glu Val Val Asn Ser Gln Gly Ala Ala Leu Thr Gln Leu Thr
1040 1045 1050
Val Gln Leu Gln His Asn Phe Gln Ala Ile Ser Ser Ser Ile Asp
1055 1060 1065
Asp Ile Tyr Ser Arg Leu Asp Ile Leu Ser Ala Asp Val Gln Val
1070 1075 1080
Asp Arg Leu Ile Thr Gly Arg Leu Ser Ala Leu Asn Ala Phe Val
1085 1090 1095
Ala Gln Thr Leu Thr Lys Tyr Thr Glu Val Gln Ala Ser Arg Lys
1100 1105 1110
Leu Ala Gln Gln Lys Val Asn Glu Cys Val Lys Ser Gln Ser Gln
1115 1120 1125
Arg Tyr Gly Phe Cys Gly Gly Asp Gly Glu His Ile Phe Ser Leu
1130 1135 1140
Val Gln Ala Ala Pro Gln Gly Leu Leu Phe Leu His Thr Val Leu
1145 1150 1155
Val Pro Gly Asp Phe Val Asp Val Ile Ala Ile Ala Gly Leu Cys
1160 1165 1170
Val Asn Asp Glu Ile Ala Leu Thr Leu Arg Glu Pro Gly Leu Val
1175 1180 1185
Leu Phe Thr His Glu Leu Gln Asn His Thr Ala Thr Glu Tyr Phe
1190 1195 1200
Val Ser Ser Arg Arg Met Phe Glu Pro Arg Lys Pro Thr Val Ser
1205 1210 1215
Asp Phe Val Gln Ile Glu Ser Cys Val Val Thr Tyr Val Asn Leu
1220 1225 1230
Thr Arg Asp Gln Leu Pro Asp Val Ile Pro Asp Tyr Ile Asp Val
1235 1240 1245
Asn Lys Thr Leu Asp Glu Ile Leu Ala Ser Leu Pro Asn Arg Thr
1250 1255 1260
Gly Pro Ser Leu Pro Leu Asp Val Phe Asn Ala Thr Tyr Leu Asn
1265 1270 1275
Leu Thr Gly Glu Ile Ala Asp Leu Glu Gln Arg Ser Glu Ser Leu
1280 1285 1290
Arg Asn Thr Thr Glu Glu Leu Gln Ser Leu Ile Tyr Asn Ile Asn
1295 1300 1305
Asn Thr Leu Val Asp Leu Glu Trp Leu Asn Arg Val Glu Thr Tyr
1310 1315 1320
Ile Lys Trp Pro Trp Trp Val Trp Leu Ile Ile Phe Ile Val Leu
1325 1330 1335
Ile Phe Val Val Ser Leu Leu Val Phe Cys Cys Ile Ser Thr Gly
1340 1345 1350
Cys Cys Gly Cys Cys Gly Cys Cys Cys Ala Cys Phe Ser Gly Cys
1355 1360 1365
Cys Arg Gly Pro Arg Leu Gln Pro Ala Glu Ala Phe Glu Lys Val
1370 1375 1380
Arg Val Gln
1385
<210> 41
<211> 29
<212> DNA
<213> 人工序列
<220>
<223> 探针序列
<400> 41
acagagcctg tgttggtgta tagtaacat 29
<210> 42
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> 引物序列
<400> 42
tatagtgggt gttatttcta gtt 23
<210> 43
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 引物序列
<400> 43
gccaatactg ccagatttac a 21
<210> 44
<211> 170
<212> DNA
<213> 人工序列
<220>
<223> ultramer序列
<400> 44
tgatgatata gtgggtgtta tttctagttt gtctagctcc acttttaaca gtactaggga 60
gttgcctggt ttcttctacc attctaatga tggctctaat tgtacagagc ctgtgttggt 120
gtatagtaac ataggtgttt gtaaatctgg cagtattggc tatgtcccat 170
Claims (17)
1.一种核酸分子，其编码选自由以下(a)及(b)组成的组的猪流行性腹泻病毒(PEDV)刺突(S)蛋白：
(a)具有至少一个突变的基因型2a(G2a)PEDV S蛋白，其中
氨基酸位置900处的亮氨酸残基被亮氨酸残基以外的氨基酸残基取代，和/或
氨基酸位置901处的亮氨酸残基被亮氨酸残基以外的氨基酸残基取代，
其中氨基酸位置的编号参考SEQ ID NO:2或SEQ ID NO:39的野生型G2a PEDV S蛋白的氨基酸序列；
(b)具有至少一个突变的基因型2b(G2b)PEDV S蛋白，其中
氨基酸位置897处的亮氨酸残基被亮氨酸残基以外的氨基酸残基取代，和/或
氨基酸位置898处的亮氨酸残基被亮氨酸残基以外的氨基酸残基取代，
其中氨基酸位置的编号参考SEQ ID NO:3的野生型G2b PEDV S蛋白的氨基酸序列。
2.如权利要求1的核酸分子，其中除亮氨酸残基以外的所述氨基酸残基选自以下组成的组：丙氨酸残基、甘氨酸残基、异亮氨酸残基、甲硫氨酸残基及缬氨酸残基。
3.如权利要求1或2的核酸分子，其中氨基酸位置的编号参考野生型G PEDV S蛋白的氨基酸序列RSXIEDLLF(SEQ ID NO:4)，其中R是S1/S2裂解位点的保守精氨酸残基，且LL是在基因型2a(G2a)PEDV S蛋白内的氨基酸位置900及901或LL是在基因型2b(G2b)PEDV S蛋白内的氨基酸位置897及898。
4.一种核酸分子，其编码包含氨基酸序列RSX1IEDX2X3(SEQ ID NO:1)的猪流行性腹泻病毒(PEDV)刺突(S)蛋白，
其中R是所述PEDV S蛋白的S1/S2裂解位点的保守精氨酸残基，X1可为任一氨基酸残基，且其中
(I)X2是除亮氨酸残基以外的氨基酸残基，且X3是亮氨酸残基，或
(II)X2是亮氨酸残基，且X3是除亮氨酸残基以外的氨基酸残基，或
(III)X2是除亮氨酸残基以外的氨基酸残基，且X3是除亮氨酸残基以外的氨基酸残基。
5.如权利要求1-4中任一项的核酸分子，其中所述PEDV S蛋白包含氨基酸序列RSXIEDAAF(SEQ ID NO:5)，其中R是所述PEDV S蛋白的S1/S2裂解位点的保守精氨酸残基，且AA是在基因型2a(G2a)PEDV S蛋白内的氨基酸位置900及901或AA是在基因型2b(G2b)PEDV S蛋白内的氨基酸位置897及898。
6.如权利要求1-5中任一项的核酸分子，其中所述PEDV S蛋白进一步包含氨基酸序列X1X2X3FX4KX5X6X7X8(SEQ ID NO:6)，
其中X8是所述PEDV S蛋白的C末端氨基酸残基或是相对于所述PEDV S蛋白的C末端氨基酸位置-2位置处的氨基酸残基，
X2至X5、X7及X8可为任一氨基酸残基，且其中
(i)X1是除酪氨酸残基以外的氨基酸残基，且X6是组氨酸残基，或
(ii)X1是酪氨酸残基，且X6是除组氨酸残基以外的氨基酸残基，或
(iii)X1是除酪氨酸残基以外的氨基酸残基，且X6是除组氨酸残基以外的氨基酸残基。
7.如权利要求1-3、5或6中任一项的核酸分子，其中
(a)在所述G2a PEDV S蛋白中，进一步
氨基酸位置1377处的酪氨酸残基被酪氨酸残基以外的氨基酸残基取代，和/或
氨基酸位置1384处的组氨酸残基被组氨酸残基以外的氨基酸残基取代，
或
(b)在所述G2b PEDV S蛋白中，进一步
氨基酸位置1374处的酪氨酸残基被酪氨酸残基以外的氨基酸残基取代，和/或
氨基酸位置1381处的组氨酸残基被组氨酸残基以外的氨基酸残基取代。
8.如权利要求6或7的核酸分子，其中
-除酪氨酸残基以外的所述氨基酸残基选自以下组成的组：丙氨酸残基、甘氨酸残基、亮氨酸残基、异亮氨酸残基、甲硫氨酸残基及缬氨酸残基，和/或
-除组氨酸残基以外的所述氨基酸残基是精氨酸残基。
9.如权利要求1-8中任一项的核酸分子，其中所述PEDV S蛋白：
i)(a)包含与SEQ ID NO:15、16、17、18、19、20、40中任一者的氨基酸序列具有至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、至少99％、至少99.1％、至少99.2％、至少99.3％、至少99.4％、至少99.5％、至少99.6％、至少99.7％、至少99.8％或至少99.9％序列相同性的氨基酸序列或由其组成，或
(b)包含与SEQ ID NO:9、10、11、12、13、14中任一者的氨基酸序列具有至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、至少99％、至少99.1％、至少99.2％、至少99.3％、至少99.4％、至少99.5％、至少99.6％、至少99.7％、至少99.8％或至少99.9％序列相同性的氨基酸序列或由其组成；和/或
ii)(a)由编码与SEQ ID NO:15、16、17、18、19、20、40中任一者的氨基酸序列具有至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、至少99％、至少99.1％、至少99.2％、至少99.3％、至少99,4％、至少99.5％、至少99.6％、至少99.7％、至少99.8％或至少99.9％序列相同性的氨基酸序列的核苷酸序列编码，或
(b)由编码与SEQ ID NO:9、10、11、12、13、14中任一者的氨基酸序列具有至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、至少99％、至少99.1％、至少99.2％、至少99.3％、至少99.4％、至少99.5％、至少99.6％、至少99.7％、至少99.8％或至少99.9％序列相同性的氨基酸序列的核苷酸序列编码。
10.一种PEDV(S)蛋白，由如权利要求1-9中任一项的核酸分子所编码。
11.如权利要求1-9中任一项的核酸分子或如权利要求10的PEDV S蛋白，其中所述编码PEDV S蛋白的核酸分子或所述PEDV S蛋白是重组的。
12.一种载体，其包含如权利要求1-9中任一项的核酸分子。
13.一种免疫原性组合物，其包含如权利要求1-9中任一项的编码PEDV S蛋白的核酸分子和/或如权利要求10的PEDV S蛋白和/或如权利要求12的载体。
14.一种免疫个体的方法，包括向所述个体施用如权利要求13的免疫原性组合物。
15.一种减少或预防仔猪中因感染PEDV所引起的临床征象或疾病的方法，其中所述仔猪是由经施用如权利要求13的免疫原性组合物的母猪进行哺乳。
16.一种降低仔猪中因感染PEDV所引起的死亡率的方法，其中所述仔猪是由经施用如权利要求12的免疫原性组合物的母猪进行哺乳。
17.如权利要求14-16中任一项的方法，其中所述免疫原性组合物用于经鼻内、经黏膜、经口、经皮内或肌内施用。
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| KR20210062015A (ko) | 2021-05-28 |
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