CN101969993B - 对抗水产养殖中无脊椎动物的病原体感染的合成Replikin肽 - Google Patents
对抗水产养殖中无脊椎动物的病原体感染的合成Replikin肽 Download PDFInfo
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Abstract
本发明提供在水产养殖的无脊椎动物的病原体基因组中鉴定的含有约7至约50个氨基酸的分离的或被合成的肽,其用来预防和治疗水产养殖中这些病原体的爆发,以及使用被鉴定的肽预防和治疗病原体爆发的方法。
Description
本申请要求2008年1月18日提交的序列号为12/010,027的美国申请、2007年11月30日提交的序列号为60/991,676的美国临时申请、2007年10月24日提交的序列号为11/923,559的美国申请、2007年10月24日提交的序列号为60/982,336的美国临时申请、2007年10月24日提交的序列号为60/982,333的美国临时申请、2007年10月24日提交的序列号为60/982,338的美国临时申请、2007年8月31日提交的序列号为60/935,816的美国临时申请、2007年8月16日提交的序列号为60/935,499的美国临时申请、2007年8月8日提交的序列号为60/954,743的美国临时申请和2007年5月30日提交的序列号为11/755,597的美国申请的优先权,其中每一个申请的整体通过引用被并入本文。另外,本申请通过引用将如下每一个申请的整体并入本文:2007年1月30日提交的序列号为60/898,097的美国临时申请、2007年1月18日提交的序列号为60/880,966的美国临时申请、2006年10月24日提交的序列号为60/853,744的美国临时申请、2006年2月16日提交的序列号为11/355,120的美国申请、2005年4月28日提交的序列号为11/116,203的美国申请、2004年6月4日提交的序列号为10/860,050的美国申请、2002年7月8日提交的序列号为10/189,437的美国申请、2002年3月26日提交的序列号为10/105,232的美国申请、现在的序列号为7,189,800的美国专利、2001年10月26日提交的序列号为09/984,057的美国申请和2001年10月26日提交的序列号为09/984,056的美国申请、现在的序列号为7,176,275的美国专利。
水产养殖一般指对食用水生动物的繁殖和养殖。水产养殖是21世纪快速发展的全球性行业。造成该行业经济损失的最重要原因是疾病。Meyer,F.P.,J Anim Sci 1991.69:4201-4208。水产养殖,特别是无脊椎动物水产养殖,常常包括在销售或诱发蜕皮之前在围栏或储罐中短期保存高密度数量的动物。同前。这些浓度对于无脊椎动物例如虾、蛤蚌、牡蛎、龙虾、扇贝、鲍鱼等是有压力的。有压力的条件对于病原体的传播是理想的,其中所述病原体包括细菌例如弧菌(Vibrio)、衣原体(Chlamydia)样和立克次氏体(Richettsia)样的物种,病毒例如桃拉综合征病毒和白斑综合征病毒,以及其他微生物病原体。
在水产养殖中一个特别严重的病毒性疾病是桃拉综合征,其显著地影响全世界的虾养殖业。桃拉综合征由桃拉综合征病毒(TSV)所致,桃拉综合征病毒(TSV)是蟋蟀麻痹病毒(Cripavirus)属中二顺反子病毒(Discistroviridae)家族的成员并且具有约10,000个核苷酸的单个正链基因组。所述基因组含有两个开放的读码框(ORF)。据报道,ORF1含有解旋酶、蛋白酶和依赖于RNA的RNA聚合酶的编码。据报道,ORF2含有三种衣壳蛋白的编码。
桃拉综合征现在被认为是美洲地方性的,而且也观察到在亚洲的爆发。受感染的虾通常具有红色尾巴,厌食且行为反复无常,尾部肌肉可变得不透明,并且角质层可变软。在该疾病的急性阶段观察到5%和95%之间的死亡率。从TSV爆发中幸存的虾看上去在保持传染性的同时对再感染具有抵抗力。
快速复制是某些细菌、病毒和恶性肿瘤的毒力特征,其中所述细菌、病毒和恶性肿瘤包括TSV和水产养殖中的其他病毒和细菌疾病,例如衣原体样疾病和白斑综合征(一种病毒性疾病)。本发明人已经发现一类与快速复制有关的保守肽序列,其被命名为Replikin。本发明人已经把流感和其它病毒种株中Replikin肽的浓度增加同增加的病毒毒力联系起来。本领域中需要通过操控Replikin序列的复制功能而预防和治疗病原体感染的方法,而且需要鉴定与Replikin序列的复制功能相关的分子靶标以治疗毒性感染,其包括疫苗和其他疗法。此外,本领域中需要减少针对新出现的病原体的疫苗和其他疗法的开发所需时间,其中所述新出现的病原体在种群中快速扩张或高度可变或二者。目前用于疫苗开发的三至十二个月的时间范围常常将疫苗提供在流行病早已经结束之后,或在流行病依然活跃但病原体变异已经使疫苗不太有效或无效之后。本领域这些问题对于人类和动物健康专业人员和政府是很大的烦恼。
发明概述
本发明提供合成的肽序列以及分离的、合成的或被合成的Replikin肽序列以预防和治疗病原体在水产养殖中的无脊椎动物中的爆发,以及向水产养殖中的无脊椎动物施用一种或多种物质以预防和/或治疗病原体在无脊椎动物中的爆发的方法,其中所述物质包括一个或多个所述分离的、合成的或被合成的Replikin肽序列或由一个或多个所述分离的、合成的或被合成的Replikin肽序列组成。
本发明第一个非限制性的方面提供一种用于水产养殖的物质,其包括至少一种含有约七至约五十个氨基酸的合成肽,其中所述至少一种合成肽当被施用于至少一种能够在水中养殖的无脊椎动物时增加该无脊椎动物对至少一种病原体的抵抗力。在一个非限制性的实施方案中,所述至少一种无脊椎动物是甲壳纲动物。在一个进一步的非限制性的实施方案中,所述至少一种甲壳纲动物是虾。
本发明第一个方面的一个进一步的非限制性的实施方案提供一种提高水产养殖的无脊椎动物抵抗力的物质,其包括至少一种分离的或合成的肽,所述肽是来自所述无脊椎动物的病原体的至少一种肽的至少一种分离的或合成的形式,其中所述至少一种分离的或合成的肽是至少一种由7至约50个氨基酸组成的分离的或合成的Replikin肽,其包括Replikin模体,所述replikin模体包括:
(1)位于所述模体的第一个末端的至少一个赖氨酸残基和位于所述模体的第二个末端的至少一个赖氨酸残基或至少一个组氨酸残基;
(2)位于距离第二个赖氨酸残基六至十个残基处的至少一个赖氨酸残基;
(3)至少一个组氨酸残基;和
(4)至少百分之六的赖氨酸残基。
在一个进一步的非限制性的实施方案中,所述的至少一种分离的或合成的Replikin肽由Replikin模体组成。在一个进一步的非限制性的实施方案中,所述Replikin模体由约7至约10个、约10至约15个氨基酸、约15至约20个氨基酸、约20至约25个氨基酸、约25至约30个氨基酸、约30至约35个氨基酸、约35至约40个氨基酸、约40至约45个氨基酸或约45至约50个氨基酸组成。
在本发明的一个进一步的非限制性的实施方案中,所述的至少一种分离的或合成的Replikin肽包括SEQ ID NO.1-11、86、87、103-112和114-198中的任一种。在一个进一步的非限制性的实施方案中,所述物质包括SEQ ID NO.1-11、86、87、103-112和114-198的分离的或合成的Replikin肽中的一种或多种的混合物。在一个进一步的非限制性的实施方案中,所述的至少一种分离的或合成的Replikin肽包括KVGSRRYKSH(SEQ ID NO.1)、HFATKCFGEVPKK(SEQ ID NO.2)、KAENEFWDGVKQSH(SEQ ID NO.3)、KGHRKVPCEQK(SEQ ID NO.4)、HRKVPCEQK(SEQ ID NO.5)、KVPCEQKIWLH(SEQ ID NO.6)、KIWLHQNPGK(SEQ ID NO.7)、HQNPGKTQQDMK(SEQ ID NO.8)、KGNTRVHVK(SEQ ID NO.9)、KEHVEKIVDK(SEQ ID NO.10)或HVEKIVDKAK(SEQ ID NO.11)。在一个进一步的非限制性的实施方案中,本发明第一个方面的物质包括任意两种或多种合成的Replikin肽的混合物。在一个进一步的非限制性的实施方案中,所述物质包括合成的Replikin肽的等重混合物。
本发明的第二个非限制性的方面提供一种包括用于水产养殖的物质的疫苗,其中所述物质包括至少一种含有约7至约50个氨基酸的分离的或合成的肽,其中所述至少一种分离的或合成的肽当被施用于至少一种能够在水中养殖的无脊椎动物时增加该无脊椎动物对至少一种病原体的抵抗力。
在本发明的第二个方面的一个非限制性的实施方案中,所述疫苗的物质的至少一种分离的或合成的肽是至少一种Replikin肽,其中所述Replikin肽由7至约50个氨基酸组成并包括Replikin模体,所述replikin模体包括:
(1)位于所述模体的第一个末端的至少一个赖氨酸残基和位于所述模体的第二个末端的至少一个赖氨酸残基或至少一个组氨酸残基;
(2)位于距离第二个赖氨酸残基六至十个残基处的至少一个赖氨酸残基;
(3)至少一个组氨酸残基;和
(4)至少百分之六的赖氨酸残基。
在一个进一步的实施方案中,所述疫苗还包括一种药学上可接受的载体。
在本发明第二个方面的一个进一步的非限制性的实施方案中,所述疫苗提供针对无脊椎动物中至少一种病原体的保护,所述无脊椎动物例如是甲壳纲动物或软体动物。在一个进一步的非限制性的实施方案中,所述疫苗提供针对虾中至少一种病原体的保护。在一个进一步的非限制性的实施方案中,为了施用于虾,将所述疫苗与虾饲料混合。在一个进一步的非限制性的实施方案中,将所述疫苗与每日定量的虾饲料混合。在一个进一步的非限制性的实施方案中,所述病原体是病毒。在一个进一步的非限制性的实施方案中,所述病原体是桃拉综合征病毒。
在本发明第二个方面的一个进一步的非限制性的实施方案中,所述疫苗的至少一种分离的或合成的肽是SEQ ID NO.1-11、86、87、103-112和114-198中的任一种。在一个进一步的非限制性的实施方案中,所述疫苗包括SEQ ID NO.1-11、86、87、103-112和114-198的分离的或合成的Replikin肽中一种或多种的混合物。
在本发明第二个方面的一个进一步的非限制性的实施方案中,所述疫苗的至少一种合成肽是KVGSRRYKSH(SEQ ID NO.1)、HFATKCFGEVPKK(SEQ ID NO.2)、KAENEFWDGVKQSH(SEQ ID NO.3)、KGHRKVPCEQK(SEQ ID NO.4)、HRKVPCEQK(SEQ ID NO.5)、KVPCEQKIWLH(SEQ ID NO.6)、KIWLHQNPGK(SEQ ID NO.7)、HQNPGKTQQDMK(SEQ ID NO.8)、KGNTRVHVK(SEQ ID NO.9)、KEHVEKIVDK(SEQ ID NO.10)或HVEKIVDKAK(SEQ ID NO.11)。在一个进一步的非限制性的实施方案中,所述疫苗包括任意两种或多种合成肽的混合物。在一个进一步的非限制性的实施方案中,所述疫苗包括每一种合成肽的混合物。在一个进一步的非限制性的实施方案中,所述疫苗包括每一种合成肽的等重混合物。
在本发明第二个方面的一个进一步的非限制性的实施方案中,所述疫苗以每天每只受治疗的虾的每克体重约0.001mg至约10mg疫苗的量被施用于至少一只虾。在一个进一步的非限制性的实施方案中,所述疫苗以每天每只受治疗的虾的每克体重约0.005mg至约5mg疫苗的量被施用于至少一只虾。在一个进一步的非限制性的实施方案中,所述疫苗以每天每只受治疗的虾的每克体重约0.01mg至约2mg疫苗的量被施用于至少一只虾。在一个进一步的非限制性的实施方案中,所述疫苗以每天每只受治疗的虾的每克体重约0.02mg至约1.5mg疫苗的量被施用于至少一只虾。在一个进一步的非限制性的实施方案中,所述疫苗以每天每只受治疗的虾的每克体重约0.08mg至约1.0mg疫苗的量被施用于至少一只虾。在一个进一步的非限制性的实施方案中,所述疫苗以每天每只受治疗的虾的每克体重约0.1mg至约0.9mg疫苗的量被施用于至少一只虾。在一个进一步的非限制性的实施方案中,所述疫苗以每天每只受治疗的虾的每克体重约0.2mg至约0.8mg疫苗的量被施用于至少一只虾。在一个进一步的非限制性的实施方案中,所述疫苗以每天每只受治疗的虾的每克体重约0.5mg疫苗的量被施用于至少一只虾。
在本发明第二个方面的一个进一步的非限制性的实施方案中,本发明的疫苗的至少一种分离的、被合成的或合成的Replikin肽是存在于桃拉综合征病毒新出现的种株中的至少一种Replikin肽的至少一种分离的、被合成的或合成的形式。
在本发明第二个方面的一个进一步的非限制性的实施方案中,本发明所述疫苗作为预防性疗法在桃拉综合征病毒的症状发作前被施用于虾。在一个进一步的非限制性的实施方案中,本发明疫苗作为预防性疗法在桃拉综合征病毒的症状发作后被施用于虾。在一个进一步的非限制性的实施方案中,所述疫苗以亚治疗浓度被施用。在一个进一步的非限制性的实施方案中,所述疫苗在至少一只虾的基本上全部的生命周期中被施用。
本发明第三个非限制性的方面提供一种为水产养殖中的无脊椎动物提供抵抗力的方法,其包括施用一种包括至少一种合成肽的物质,其中所述至少一种合成肽当被施用于至少一种能够在水中养殖的无脊椎动物时能够增加对至少一种病原体的抵抗力。在一个非限制性的实施方案中,所述物质通过口服、通过将无脊椎动物浸没在含有此物质的水介质中或通过注射被施用。在一个进一步的非限制性的实施方案中,所述物质被口服施用。在一个非限制性的实施方案中,所述无脊椎动物是甲壳纲动物。在一个进一步的非限制性的实施方案中,所述甲壳纲动物是虾。
本发明第四个非限制性的方面提供一种由7至约50个氨基酸组成的分离的、合成的或被合成的桃拉综合征病毒Replikin肽,其中所述Replikin肽包括Replikin模体,所述replikin模体包括:
(1)位于所述模体的第一个末端的至少一个赖氨酸残基和位于所述模体的第二个末端的至少一个赖氨酸残基或至少一个组氨酸残基;
(2)位于距离第二个赖氨酸残基六至十个残基处的至少一个赖氨酸残基;
(3)至少一个组氨酸残基;和
(4)至少百分之六的赖氨酸残基。
在本发明一个进一步的非限制性的实施方案中,分离的、合成的或被合成的桃拉综合征病毒Replikin肽由Replikin模体组成。一个进一步的非限制性的实施方案提供编码桃拉综合征病毒Replikin肽的核酸序列。
本发明第五个非限制性的方面提供一种由约16至约34个氨基酸组成的分离的、合成的或被合成的桃拉综合征病毒Replikin支架肽,其中所述Replikin支架肽包括:
(1)一个末端赖氨酸和任选地紧邻所述末端赖氨酸的一个赖氨酸;
(2)一个末端组氨酸和任选地紧邻所述末端组氨酸的一个组氨酸;
(3)距离另一个赖氨酸约6至约10个氨基酸以内的一个赖氨酸;和
(4)至少6%的赖氨酸。
在一个进一步的非限制性的实施方案中,分离的、合成的或被合成的桃拉综合征病毒Replikin支架肽由约28至约33个氨基酸组成。在一个进一步的非限制性的实施方案中,所述肽包括KKVQANKTRVFAASNQGLALALRRYYLSFLDH(SEQ ID NO.197)或KKACRNAGYKEACLHELDCKSFLLAQQGRAGAH(SEQ ID NO.198)。
本发明第六个非限制性的方面提供一种增加无脊椎动物对病原体的抵抗力的方法,其包括:
(1)使用所述病原体攻击与所述无脊椎动物同种的多个无脊椎动物,所述病原体的水平足以使所述多个无脊椎动物的至少一个个体致病;
(2)将患病的或死亡的所述多个无脊椎动物的至少一个个体丢弃;
(3)重复步骤1和2至少一次;并且
(4)至少一次地在步骤(1)、(2)和/或(3)中对所述多个无脊椎动物施用权利要求1的物质,其增加所述无脊椎动物对病原体的抵抗力。
在本发明第六个方面的一个非限制性的实施方案中,所述至少一种分离的或合成的肽是至少一种Replikin肽,其中所述Replikin肽由7至约50个氨基酸组成并包括Replikin模体,所述replikin模体包括:
(1)位于所述模体的第一个末端的至少一个赖氨酸残基和位于所述模体的第二个末端的至少一个赖氨酸残基或至少一个组氨酸残基;
(2)位于距离第二个赖氨酸残基六至十个残基处的至少一个赖氨酸残基;
(3)至少一个组氨酸残基;和
(4)至少百分之六的赖氨酸残基。
在一个进一步的非限制性的实施方案中,所述无脊椎动物是虾。在一个进一步的非限制性的实施方案中,所述病原体是桃拉综合征病毒。
本发明第七个非限制性的方面提供一种生产疫苗的方法,其包括:(1)从一种能够在水介质中养殖的无脊椎动物的病原体中鉴定至少一种Replikin序列,和(2)化学合成至少一种被鉴定的Replikin序列作为所述疫苗的活性剂。在一个非限制性的实施方案中,所述疫苗从在病原体内至少一种Replikin序列被鉴定时起的七天或更少的时间内被生产。
本发明第八个非限制性的方面提供一种包括用于水产养殖的物质的动物饲料,其包括至少一种含约七至约五十个氨基酸的合成肽,其中所述至少一种合成肽当被施用于至少一种能够在水介质中养殖的无脊椎动物时增加该无脊椎动物对至少一种病原体的抵抗力。在一个非限制性的实施方案中,所述动物饲料是甲壳纲动物的饲料。在一个进一步的非限制性的实施方案中,所述动物饲料是虾饲料。在一个进一步的实施方案中,所述动物饲料中的物质中的合成肽是合成的Replikin肽。在一个进一步的实施方案中,所述动物饲料包括虾生产Rangen 35麦芽浆、1%的海藻酸钠、1%的六偏磷酸钠和至少一种合成的Replikin肽,其中所述合成的Replikin肽是KVGSRRYKSH(SEQ ID NO.1)、HFATKCFGEVPKK(SEQ ID NO.2)、KAENEFWDGVKQ SH(SEQ ID NO.3)、KGHRKVPCEQK(SEQ ID NO.4)、HRKVPCEQK(SEQ ID NO.5)、KVPCEQKIWLH(SEQ ID NO.6)、KIWLHQNPGK(SEQ ID NO.7)、HQNPGKTQQDMK(SEQ ID NO.8)、KGNTRVHVK(SEQ ID NO.9)、KEHVEKIVDK(SEQ ID NO.10)或HVEKIVDKAK(SEQ ID NO.11)。
本发明第九个非限制性的方面提供一种虾,其中所述虾被包括至少一种Replikin肽的疫苗处理,其中所述至少一种Replikin肽由7至约50个氨基酸组成并包括Replikin模体,所述replikin模体包括:
(1)位于所述模体的第一个末端的至少一个赖氨酸残基和位于所述模体的第二个末端的至少一个赖氨酸残基或至少一个组氨酸残基;
(2)位于距离第二个赖氨酸残基六至十个残基处的至少一个赖氨酸残基;
(3)至少一个组氨酸残基;和
(4)至少百分之六的赖氨酸残基。
在一个进一步的实施方案中,所述Replikin肽是桃拉综合征病毒Replikin肽。在本发明第九个方面的一个进一步的实施方案中,所述虾(1)与多个其他虾一起被桃拉综合征病毒攻击,所述桃拉综合征病毒的水平足以使所述多个虾中的至少一个致病;(2)将所述多个虾中患病的虾或死亡的虾或二者丢弃;(3)重复步骤1和2至少一次;并且(4)至少一次地在步骤(1)、(2)和/或(3)中对所述多个虾施用一种疫苗,其中所述疫苗包括至少一种分离的或合成的桃拉综合征病毒Replikin肽。
附图简述
图1举例说明在用桃拉综合征病毒攻击的虾(南美白对虾(Penaeusvannamei))15天试验期内的存活率。图1A举例说明用T1疫苗接种的虾,其中所述T1疫苗含有来自桃拉综合征病毒(TSV)的Replikin序列。图1B举例说明未被接种的虾(对照)。图1中的数据反映下面实施例2中阐述的试验。图1A举例说明5个试验,其中每个试验与对照一起进行了相同的15天时间。图1B举例说明在相同的15天期间的三个对照试验。在从总共六个试验(如下面实施例2中所述)中去掉一个异常值后,被接种的虾具有59%的累计存活率(图1A)。未被接种的虾具有25%的累计存活率(图1B)。被接种的虾的累计存活率比未被接种的虾的累计存活率高。这些数据表明,使用Replikin序列接种提供了免受TSV感染的保护。接种后对抗TSV的相对存活率是45%。
图2举例说明被桃拉综合征病毒(TSV)预先攻击的(慢性感染的)并且接着在用T1疫苗、T2抑制的或“阻断的”疫苗或不用疫苗(对照)处理后被TSV再一次攻击的虾(南美白对虾)的15天累计存活率。使用未被TSV预先攻击(未慢性感染的)的虾举例说明了另一个对照研究。这另一个对照未被疫苗处理。对于T1接种的虾,一直到第13天未出现死亡。在暴露于TSV之后第15天,这组具有91%的存活率。对于喂有抑制的疫苗T2的虾,在第2天观察到第一例死亡。此组具有60%的存活率。对于经受了之前TSV攻击的未被接种的对照组,在第10天发生第一例死亡,并且该组具有75%的存活率。对于之前未被桃拉综合征病毒攻击的另一个对照组(SPF虾),累计存活率是25%。这些结果显示,TSV慢性感染的虾当被TSV再次攻击时具有更高的存活率(60-91%)。特别地,T1接种的南美白对虾具有最高的存活率和最低的病毒载量。用TSV攻击的SPF南美白对虾的存活率是25%。图2中举例说明的试验被描述在下面的实施例3中。
图3举例说明分别从伯利兹、泰国、夏威夷和委内瑞拉采集的桃拉综合征病毒(TSV)的分离物中的Replikin浓度与被相应TSV分离物在第1、2和3天攻击的凡纳滨对虾(Litopenaeus vannamei)达到50%死亡率所用的平均天数之间的直接顺序相关性(direct sequentialcorrelation)。每种分离物的Replikin浓度之间的统计学差异是显著的,在p<0.001的水平上。图3中所举例说明的数据在下面的实施例1中被描述。
图4举例说明分别从伯利兹、泰国、夏威夷和委内瑞拉采集的桃拉综合征病毒(TSV)的分离物中的Replikin浓度与被相应的TSV分离物攻击后15天的凡纳滨对虾的平均累计存活率之间的直接相关性。每种分离物的Replikin浓度之间的统计学差异是显著的,在p<0.001的水平上。图4中所举例说明的数据被描述在下面的实施例1中。
图5举例说明被四种不同的桃拉综合征病毒分离物攻击的凡纳滨对虾的15天累计存活率(除非在15天之前发生100%的死亡)与每种分离物的开放读码框1(ORF1)的Replikin浓度之间的相关性。针对Replikin浓度分析了来自伯利兹、泰国、夏威夷和委内瑞拉的TSV的个体分离物的基因组的ORF1的被翻译的氨基酸序列。对于伯利兹分离物Replikin浓度被确定为3.5,对于泰国分离物其为3.4,对于夏威夷分离物其为3.3,而对于委内瑞拉分离物其为3.0。图A举例说明用TSV的伯利兹分离物攻击的虾在三个试验中观察到的存活率。在一个试验中,在第6天观察到全部死亡。在其他试验中,在第11天观察到全部死亡。图B、C和D举例说明用泰国分离物、夏威夷分离物和委内瑞拉分离物分别攻击的虾在为期15天的三个试验中观察到的存活率。在泰国分离物中,在第15天观察到平均80%的死亡率。在夏威夷分离物中,在第15天观察到平均78.3%的死亡率。在委内瑞拉分离物中,在第15天观察到平均58.3%的死亡率。图5中所举例说明的数据在下面的实施例1中被描述。
图6举例说明桃拉综合征病毒基因组中增加的Replikin浓度与在2000年和2007年中此病毒在虾中的爆发之间的相关性。本发明人分析了可得自www.pubmed.com的桃拉综合征病毒肽序列的公开可得的序列的平均Replikin浓度。图6是比较2000年和2005年之间肽序列可公开获得的每年平均Replikin浓度(带有标准偏差)和桃拉综合征病毒严重爆发日期的图。此图中所反映的Replikin浓度数据可在下面的表13中找到。在2000年和2007年记录了此病的严重爆发。可以从此图观察到的是,此病毒的爆发发生在Replikin浓度增加之后。在2000年,TSV具有2.7的Replikin浓度。在2001和2004年之间,TSV具有低至0.6的较低平均Replikin浓度,而且被鉴定的Replikin支架消失了。在2005年Replikin支架再现,赖氨酸和组氨酸增加,并且Replikin浓度相应增加到1.8,接着是在2006-2007年期间TSV爆发的增加。参见实施例5中的2000和2005年TSV的Replikin支架。
图7举例说明西尼罗河病毒Replikin的周期产生和每年的人类发病率,通过证明每年西尼罗河病毒的包膜蛋白的每100个氨基酸的Replikin浓度(Replikin计数)(Replikin计数平均值被带有所绘标准偏差的黑色柱所举例说明)与疾病控制中心(CDC)报道的基于全国范围的美国每年的人类病例数之间的相关性。浏览此数据发现,包膜蛋白的Replikin计数平均值的标准偏差在2000和2001年之间显著增加(p<0.001的统计学显著性)。观察病毒种群的Replikin计数平均值的标准偏差的此种变化传达了所有常见流感病毒种株的快速复制和Replikin计数范围的扩大(流感病毒被归类在显著不同于西尼罗河病毒的病毒家族中)的信号。在流感中,在病毒爆发前观察到Replikin计数上的显著统计变化。
从2000至2003年在西尼罗河病毒中观察到的平均Replikin计数的增加发生在被CDC独立记录并公布的人类西尼罗河病毒(WNV)病例的数量增加之前。同样详细的Replikin计数与发病率关系已被显示在流感种株中,例如H5N1与人的死亡率(参见图8),和H3N8马脑炎与马的发病率(参见图12),和锥虫属恶性疟原虫(Plasmodium falciparum)(疟疾)与人的死亡率(参见图9),和桃拉综合征病毒与虾的死亡率(参见图3-5)。因为所述关系已经在若干物种即甲壳纲动物、马和人中被证明,而且因为Replikin序列已经与植物、无脊椎动物、脊椎动物、原生动物(例如恶性疟原虫)、细菌(例如炭疽)和病毒(参见例如编号为7,176,275和7,189,800的美国专利)的快速复制联系在一起,所以使Replikin计数与发病率关联看上去是广泛分布的一般原则。
图7中的数据另外举例说明,在2004年和又一次在2005年出现Replikin计数和WNV人类病例数量二者的降低。在2006年,在Replikin计数增加之后在2007年人类病例数量(发病率)增加。因此,图7举例说明Replikin浓度(Replikin计数)的两个周期和变化的WNV人类发病率的两个周期。在图7中观察到2000-2003年和2004-2008年之间的两个周期(病毒Replikin周期)互相关联。在之前H1N1和H3N2流感病毒数据中已经观察到Replikin计数的周期(参见例如图11)。所述关系在WNV数据中比它在流感数据中更清楚地被证明,因为由H1N1或H3N2流感病毒所致的实际病例数在历史上对特定种株的记录不像现在对西尼罗河病毒所记录的这样准确。相反地,H1N1和H3N2被记作爆发、流行或大流行。在重复的周期中Replikin浓度(Replikin计数)的逐步增加可用作预测病毒扩张的方法。对Replikin计数的逐步增加的监测为技术人员提供了预测病毒种群扩张和造成的包括病毒性疾病的爆发、流行或大流行的发病率的数据。这些事件实际的发病率未被记录。应该注意的是,2007和2008年的Replikin计数的数据被排除在图7外,因为到本申请撰写时为止,WNV序列的CDC报告被推迟了。
图7中的数据也是重要的,因为图7描述了一种在1999年第一次到达纽约市并在之后蔓延到全美国的病毒的进展,而不是在许多先前的流行之后重返一个国家的病毒,例如H1N1或H3N2的情况。从所述病毒的新发现的Replikin结构和CDC提供的很好的流行病学数据方面来看,存在着检查此种蔓延步骤的机会。
图8举例说明在人H5N1中Replikin峰基因pB1基因区域的Replikin计数与H5N1感染的人类病例中2003和2007年之间的人类死亡率百分数的关系。观察到H5N1的pB1基因区域中Replikin计数的增加与宿主的更高死亡率在数量上是相关的。在图中,(1)浅灰色表示在指定年份全部病毒分离物的平均Replikin计数,(2)深灰色表示在指定年份人H5N1分离物的公开可得的序列的pB1区域中的平均Replikin计数,(3)白色柱表示在指定年份Replikin计数平均值的标准偏差,以及(4)黑色柱表示在指定年份被鉴定的H5N1感染的人病例的10%的死亡率百分数,其最终达到86%的死亡率(在图8中显示为8.6)。
图9举例说明来自恶性疟原虫的每1000个临床人类病例的死亡率与恶性疟原虫的ATP酶中的Replikin计数相关联。疟疾的高发病率和死亡率发生在20世纪90年代晚期,而且这些率被认为是由于微生物的适应和抗疟疾药效果的降低所致。ATP酶是青蒿素(arteminisin)治疗疟疾的首要靶。随着青蒿素使用的增加和公共健康措施的改善,从1999年至2006年发病率和死亡率下降了。从1997年至1998年,恶性疟原虫的ATP酶的Replikin计数和每个疟疾病例死亡率的增加一起增加了。从1998年至2006年,恶性疟原虫的ATP酶的Replikin计数和死亡率一起减少了(目前可得的只贯穿于2005年的一致死亡率)。1997至2005年的每1000个人类疟疾病例的死亡率如下:1997年的死亡率是17;1998年的死亡率是17;1999年的死亡率是19;2000年的死亡率是16;2001年的死亡率是13;2002年的死亡率是10;2003年的死亡率是10;2004年的死亡率是9;而且2005年的死亡率是9。死亡率如世界卫生组织所宣布的那样被记录。参见www.who.int。
图10举例说明在分离于1995和2007年之间的白斑综合征病毒(WSSV)的公开可得的氨基酸序列中观察到的Replikin序列的平均Replikin计数和标准偏差与WSSV于2001年在虾中的严重爆发之间的相关性。在2000年的Replikin浓度97.6预言2001年的爆发。此外,在来自2000年的WSSV分离物的核糖核苷酸还原酶蛋白序列中观察到Replikin浓度为103.8,其中Replikin峰基因被鉴定具有甚至更高的Replikin浓度110.7。
图11举例说明在上世纪三次流感大流行中的总的血凝素Replikin计数。种株特异性的高Replikin计数伴随着三次大流行中的每一次:1918、1957和1968。在所有情况下,此峰之后是减退(很可能是由于宿主的免疫力所致),然后是恢复的以及“反弹的”流行。这些相关是由于偶然性的概率非常低所致,因为它们对每个种株是特定的,对该世纪三个大流行年份中的每一个是特定的,对每次大流行后的减退是特定的,并且对每次反弹流行是特定的。
图12显示1977-2007年间在马流感的pB1、pB2和pA基因组区域内被鉴定的Replikin峰基因的Replikin计数与H3N8马流感所致的马脑炎流行病之间的关系。系列1反映在所述基因组的pB1区域的Replikin峰基因中被鉴定的平均Replikin计数。系列2反映pB1基因区域中的平均Replikin计数的标准偏差。系列3反映在所述基因组的pA基因区域的Replikin峰基因中被鉴定的Replikin计数,其中所述pA基因区域与pB1基因区域相邻。系列4反映在所述基因组的pB2基因区域的Replikin峰基因中被鉴定的Replikin计数,其中所述pB2基因区域也与pB1基因区域相邻。据观察,pB1基因区域中的Replikin计数的增加在流行病爆发前一至三年发生,而没有观察到pB2和pA基因区域中Replikin计数的增加。
发明详述
定义
如本文所用,“合成肽”指的是通过一种过程产生的肽,其中所述过程的至少一个步骤是在活细胞外进行的,而且此过程是被人直接地或间接地启动或指挥的。
如本文所用,“水产养殖”指的是天然水产物的养殖,例如有壳的水生动物的养殖。
如本文所用,“施用(administer)”、“施用(administration)”或相关术语指的是为了治疗目的而将一种化合物引入动物或其他受治疗者,其中所述引入可以由通过口的应用、在皮肤上的应用、穿过皮肤的应用、穿过鳃的应用、经皮注射的应用或使用本领域技术人员现在和以后知道的任何其他方法的应用而完成,由此所述化合物被直接或间接地引入动物或其他受治疗者体内。
如本文所用,一种肽或其他化合物是“免疫原性的”,如果它能够独立地或与其他化合物一起刺激活动物中的免疫应答或抵抗力应答。
如本文所用,刺激“抵抗力”或刺激发展“有抵抗力的”无脊椎动物或其他动物的化合物、治疗或疗法是能够独立地或与其他化合物、治疗或疗法一起刺激活动物包括例如无脊椎动物中的免疫应答或抵抗力应答的化合物、处理或治疗。
如本文所用,“治疗浓度”指的是病原体疾病在所述疾病至少一个生命周期中在统计学可测量的水平上被抑制的治疗剂浓度。
如本文所用,“亚治疗浓度”指的是病原体疾病在所述疾病至少一个生命周期中在统计学可测量的水平上没有被抑制的治疗剂浓度。
如本文所用,“疫苗”指的是一种能够刺激针对病原体的抵抗力或免疫应答的化合物对动物或人体的施用。施用可以是通过口、鳃、经皮注射、浸没在一种浓度的疫苗中或本领域技术人员现在和以后知道的任何其他施用方法。无脊椎动物例如虾、蛤蚌、扇贝等的免疫系统的详情未被完全理解。例如,虾表面上可能不产生抗体。然而,本文的数据证实了对于感染的抵抗现象。这种抵抗可以是基于“原始的免疫系统”。虽然不被理论所限制,但是虾和一些其他无脊椎动物的“原始的免疫系统”被推理为与其他动物中的“Toll受体”和相关系统类似。
如本文所用,“动物”包括虾和任何其他动物。
如本文所用,“无脊椎动物”指的是缺少脊柱的任何动物。容易水产养殖的无脊椎动物包括但不限于软体动物、甲壳纲动物和棘皮动物。软体动物包括但不限于蛤、贻贝、牡蛎、螺、扇贝和头足类动物如乌贼、章鱼、墨鱼和陆栖蜗牛。甲壳纲动物包括但不限于虾、蟹、龙虾、对虾和螯虾。棘皮动物包括但不限于海参和海胆。
如本文所用,“甲壳纲动物”根据本领域技术人员的理解是一组通常为水生的节肢动物,并且包括但不限于虾、蟹、龙虾、对虾和螯虾。
如本文所用,术语“肽”或“蛋白”指的是含有两个或多个氨基酸的化合物,其中一个氨基酸的羧基通过肽键被连到另一个氨基酸的氨基。如本文所用,一种“分离的”或“纯化的”肽或其生物活性部分指的是纯化后基本上不含来自衍生所述肽的细胞或组织来源的细胞物质或其他污染蛋白或肽的一种肽。一种“合成的”或“被合成的”肽或其生物活性部分指的是合成后基本时不含使用任何方法化学合成时的化学前体或其他化学药品,或基本不含使用重组基因技术合成时的污染肽的一种肽。
“被编码的”蛋白、蛋白序列、蛋白片段序列或肽序列是由编码所述蛋白或肽序列的氨基酸的核酸序列所编码的肽序列,其中所述核酸使用本领域技术人员现在或以后知道的任何密码子编码氨基酸。应该注意,本领域众所周知的是,由于遗传密码的冗余性,密码子中单个核苷酸可容易地变换并仍然产生相同的氨基酸序列。将被本领域技术人员所理解的是,鉴定Replikin氨基酸序列的方法还包括鉴定编码Replikin氨基酸序列的核酸序列的方法,其中所述Replikin氨基酸序列由被鉴定的核酸序列所编码。
如本文所用,Replikin序列是含有7至约50个氨基酸的氨基酸序列,其包括:
(1)位于距离第二个赖氨酸残基六至十个氨基酸残基处的至少一个赖氨酸残基;
(2)至少一个组氨酸残基;和
(3)至少6%的赖氨酸残基。
Replikin序列可包括一个末端赖氨酸并还可包括一个末端赖氨酸或末端组氨酸。Replikin肽或Replikin蛋白是由Replikin序列组成的肽或蛋白。Replikin序列还可被描述为7至约50个氨基酸的Replikin序列,其包括Replikin模体或由Replikin模体组成,其中所述replikin模体包括(1)位于所述分离的肽的第一个末端的至少一个赖氨酸残基和位于所述分离的肽的第二个末端的至少一个赖氨酸残基或至少一个组氨酸残基;(2)位于距离第二个赖氨酸残基六至十个残基处的第一个赖氨酸残基;(3)至少一个组氨酸残基;和(4)至少6%的赖氨酸残基。为了确定Replikin浓度,Replikin序列必须在一个末端处具有赖氨酸残基和在另一个末端出具有赖氨酸残基或组氨酸残基。
术语“Replikin序列”也可以指编码具有7至约50个氨基酸的氨基酸序列的核酸序列,其中所述氨基酸序列包括:
(1)位于距离第二个赖氨酸残基六至十个氨基酸残基处的至少一个赖氨酸残基;
(2)至少一个组氨酸残基;和
(3)至少6%的赖氨酸残基,
其中所述氨基酸序列可包括一个末端赖氨酸并还可包括一个末端赖氨酸或末端组氨酸。
如本文所用,Replikin峰基因(RPG)或Replikin峰基因区域(RPGA)可互换地被用来指基因组区段、蛋白、蛋白区段或蛋白片段,其中被表达的基因或基因区段当与所述基因组的其他区段或命名的基因相比时具有最高浓度的Replikin(每100个氨基酸中的Replikin序列个数),所述基因组具有连续的、不间断的和重叠的Replikin序列。一般地,与全蛋白相关的基因或基因区段或表达蛋白的基因被称为Replikin峰基因,而与蛋白片段相关的基因或基因区段被称为Replikin峰基因区域。在基因、基因区段、蛋白或蛋白片段中可以鉴定不止一个RPG或RPGA。RPG或RPGA可具有一个末端赖氨酸或一个末端组氨酸、两个末端赖氨酸、或一个末端赖氨酸和一个末端组氨酸。RPG或RPGA可同样地既不具有末端赖氨酸也不具有末端组氨酸,只要它含有由Replikin序列的定义所定义的Replikin序列,即,具有7至约50个氨基酸的氨基酸序列,其包括:
(1)位于距离第二个赖氨酸残基六至十个氨基酸残基处的至少一个赖氨酸残基;
(2)至少一个组氨酸残基;和
(3)至少6%的赖氨酸残基。
如本文所用,“新出现的种株”指的是被鉴定为相对于这种有机体的其他种株中Replikin的浓度具有被提高的或正在提高的浓度的它的一个或多个蛋白序列中的Replikin序列的病毒或其他病原体的种株。病毒的新出现的种株指示毒性或复制的提高。
如本文所用,“爆发”是在与相同病毒性疾病中较早出现的感染的流行病学模式相比之下病毒性疾病的毒力、发病率或死亡率的增加。
如本文所用,“Replikin计数”或“Replikin浓度”指的是在蛋白、蛋白片段、病毒或生物体中每100个氨基酸中Replikin的数量。已经发现,在病毒或生物体的第一个种株中的较高Replikin浓度与第一种病毒或生物体的更快速的复制相关,相比之下所述病毒或生物体的第二个较早或较晚出现的种株具有较低的Replikin浓度。
如本文所用,“Replikin支架”指的是一系列保守的Replikin肽,其中每个所述Replikin肽序列包括约16至约34个氨基酸以及优选地约28至约33个氨基酸,并且还包括:(1)一个末端赖氨酸和任选地紧邻所述末端赖氨酸的一个赖氨酸;(2)一个末端组氨酸和任选地紧邻所述末端组氨酸的一个组氨酸;(3)距离另一个赖氨酸6至10个氨基酸残基以内的一个赖氨酸;和(4)约6%的赖氨酸。“Replikin支架”还指一系列Replikin支架的单个成员或多个成员。
在桃拉综合征病毒中,Replikin支架可指包括约16至约34个氨基酸残基、优选地约27至约33个氨基酸残基和更优选地约30至33个氨基酸残基的Replikin肽序列。在流感病毒中,Replikin支架可指包括约16至约34个氨基酸残基和更优选地约28至30个氨基酸残基的Replikin肽序列。在白斑综合征病毒中,Replikin支架可指包括约16至约34个氨基酸残基和更优选地约27至29个氨基酸残基的Replikin肽序列。
如本文所用,虾的“生命周期”基本上从虾能用口进食之时延伸直到虾被收获。
如本文所用,“时间段”或“时间点”是可以彼此区分开的任两个时间段或点。例如,2004年分离的病毒分离物在与2005年分离的相同病毒分离物的不同时间段被分离。同样地,2004年5月分离的病毒分离物在与2004年六月分离的相同病毒分离物的不同时间段被分离。作为包括虾在内的无脊椎动物中的治疗化合物的Replikin序列
本发明人已经将水产养殖的无脊椎动物的病原体基因组中的Replikin序列(其包括在桃拉综合征病毒(TSV)基因组中的Replikin序列)鉴定为针对例如虾、扇贝、牡蛎、龙虾等无脊椎动物中病毒、细菌和原生动物疾病的治疗化合物。被鉴定的治疗化合物激发被病原体攻击的无脊椎动物的抵抗力,其中所述病原体例如是衣原体样、立克次氏体样、弧菌、桃拉综合征病毒、白斑综合征病毒和其他病原体。被鉴定的序列是分离的或被合成的由7至约50个氨基酸组成的Replikin肽,其包括Replikin模体,所述Replikin模体包括(1)位于所述模体的第一个末端的至少一个赖氨酸残基和位于所述模体的第二个末端的至少一个赖氨酸残基或至少一个组氨酸残基、(2)位于距离第二个赖氨酸残基六至十个残基处的第一个赖氨酸残基、(3)至少一个组氨酸残基和(4)至少6%的赖氨酸残基,其中所述分离的或被合成的肽是通过选择被鉴定的模体以及分离或合成包括所述模体的所述肽而被分离或合成的。在一个进一步的实施方案中,Replikin肽由所述Replikin模体组成。技术人员将理解如何使用上述方法分离和合成Replikin肽。可以使用生产已知结构的肽的任何方法。
Replikin肽已经与植物、动物、细菌、病毒、恶性疟原虫和其他生物中的快速复制相关联。参见序列号为7,176,275和7,189,800的美国专利。Replikin还已经与例如流感、西尼罗河病毒、疟疾、白斑综合征病毒和桃拉综合征病毒的病原体的毒力、发病率和死亡率相关联。参见图6-12。此外,迄今进行的包括鸡、兔、虾和人的所有测试或研究都显示,Replikin序列是免疫原性的和/或激发抵抗力的,或二者。参见2006年2月16日提交的序列号为11/355,120的美国申请(实施例6和7)、序列号为6,638,505的美国专利。此外,病原体基因组中Replikin序列(或病原体基因组中特别感兴趣的区域,其被称为Replikin峰基因)的浓度已经与病原性爆发、发病率和死亡率相关联。参见图3-12。特别地,Replikin浓度已经与桃拉综合征病毒中无脊椎动物(虾)的死亡率以及桃拉综合征病毒和白斑综合征病毒二者中无脊椎动物(虾)的病原性爆发相关联。参见图3-6和10。Replikin序列已经广泛地与毒力、发病率和死亡率相关,并且一致地与马、兔、鸡、人和虾的免疫原性和抵抗力相关。这些大范围的数据为含有Replikin序列的疫苗提供支持,其包括对含有来自水产养殖中的病原体的Replikin序列的疫苗的支持。
在水产养殖的无脊椎动物的病原体中鉴定的分离的或被合成的Replikin肽然后被喂、被注射或以其他方式被施用于例如虾、扇贝、牡蛎、龙虾等无脊椎动物,作为在病原体疾病包括TSV或其他病原体疾病的预测爆发之前或在所述疾病的爆发之中对抗所述疾病可能的爆发的预防药。所述肽可被单独地或与普通饲料或为了携带所述肽而配制的补充饲料一起被施用于无脊椎动物。技术人员将理解,可以使用配制饲料的任何方法,其中所述方法经口服为无脊椎动物提供Replikin序列。可以将稳定剂或防腐剂或两者加入Replikin序列的混合物或Replikin序列和无脊椎动物饲料的混合物中以在一段时间内维持治疗有效的定量喂食和治疗所养殖的包括虾、扇贝、牡蛎、蛤、蟹、鲍鱼、龙虾等的无脊椎动物。技术人员将理解对于使饲料和治疗混合物中短肽稳定的方法的广泛选择。
可以在感染发生之前或之后施用治疗或亚治疗水平的肽。还可对慢性感染的群体进行施用。
在病原体基因组中被鉴定的或被鉴定为由病原体所表达的任何Replikin可作为治疗化合物被施用以激发虾的抵抗力应答。下面的示范性序列可作为对抗桃拉综合征病毒的疫苗单独地或以任何组合被喂给虾:KVGSRRYKSH(SEQ ID NO.1)、HFATKCFGEVPKK(SEQ ID NO.2)、KAENEFWDGVKQSH(SEQ ID NO.3)、KGHRKVPCEQK(SEQID NO.4)、HRKVPCEQK(SEQ ID NO.5)、KVPCEQKIWLH(SEQ IDNO.6)、KIWLHQNPGK(SEQ ID NO.7)、HQNPGKTQQDMK(SEQID NO.8)、KGNTRVHVK(SEQ ID NO.9)、KEHVEKIVDK(SEQ IDNO.10)或HVEKIVDKAK(SEQ ID NO.11)。与所有桃拉综合征病毒Replikin序列一样,包括如下所讨论的Replikin序列和Replikin支架序列的示范性序列可以被喂,或以浸入施用方法被使用,或被注射。所述序列可被单独地或以任何组合被施用,其中所述组合包括肽的等重组合。含有约7至约50个氨基酸的任何Replikin序列或免疫原性序列可被用作施用于无脊椎动物的化合物,包括用作疫苗。例如,SEQ ID NO.1-11、86、87、103-112和114-198中的每一个可被单独地或以组合被用作施用于无脊椎动物以对抗TSV感染的化合物。
病毒载量的减少和剂量响应曲线
免疫原性的或激发抵抗力的合成肽可以以每天每只受治疗的无脊椎动物的每克体重约0.001mg至约10mg合成肽的量、以每天每只受治疗的无脊椎动物的每克体重约0.005mg至约5mg合成肽的量、以每天每只受治疗的无脊椎动物的每克体重约0.01mg至约2mg合成肽的量、以每天每只受治疗的无脊椎动物的每克体重约0.02mg至约1.5mg合成肽的量、以每天每只受治疗的无脊椎动物的每克体重约0.08mg至约1.0mg合成肽的量、以每天每只受治疗的无脊椎动物的每克体重约0.1mg至约0.9mg合成肽的量、以每天每只受治疗的无脊椎动物的每克体重约0.2mg至约0.8mg合成肽的量、以每天每只受治疗的无脊椎动物的每克体重约0.5mg合成肽的量施用于无脊椎动物。本领域技术人员将理解如何确定适合于治疗或亚治疗施用的合成肽剂量。
现在已经在虾中测试了含有等重肽的混合物的TSV疫苗剂量并显示其提供保护作用。已经测试了下面的肽:KVGSRRYKSH(SEQ ID NO.1)、HFATKCFGEVPKK(SEQ ID NO.2)、KAENEFWDGVKQSH(SEQID NO.3)、KGHRKVPCEQK(SEQ ID NO.4)、HRKVPCEQK(SEQ IDNO.5)、KVPCEQKIWLH(SEQ ID NO.6)、KIWLHQNPGK(SEQ IDNO.7)、HQNPGKTQQDMK(SEQ ID NO.8)、KGNTRVHVK(SEQ IDNO.9)、KEHVEKIVDK(SEQ ID NO.10)和HVEKIVDKAK(SEQ IDNO.11)。在不同实验中,所述疫苗以每天被测试虾的每克体重大约0.02、0.08和0.50mg Replikin疫苗的量被施用。所述剂量是近似的,由于个体虾消耗的个体差异。被重1g至4g的虾口服摄取后,所有三种剂量水平都被很好地耐受,而且与未被接种的对照相比,所有都在虾中产生统计学上显著的较低的病毒载量。0.08mg和0.5mg剂量提供了统计学上显著的保护。最低的剂量0.02mg在两个实验之一中提供了未达到统计学显著性的保护,然而如上面所证明,观察到统计学上显著的较低的病毒载量。每“克虾”0.50mg的剂量(迄今被测的最高剂量)提供了统计学上最显著的保护91%。因此,从迄今的结果来看,每“克虾”0.50mg的剂量和可能地更高一些,是本发明一个方面的优选的实施方案。
在约七天或更少时间以内的疫苗生产
本发明另一个非限制性的方面提供一种生产疫苗的方法,其中至少一种Replikin序列在病原体内被鉴定而且所述至少一种Replikin序列作为疫苗的活性剂被化学合成。本发明人已经在从病原体被鉴定之时开始七天或更少的时间内成功地生产了这样一种有效的疫苗。
一旦病原体被鉴定,其基因组就被确定。技术人员然后使用例如ReplikinsForecastTM(Replikins LLC,波士顿,马萨诸塞州)来调查基因组的Replikin序列。一旦Replikin序列被鉴定,任何一个或多个Replikin序列被选作化学合成。优选的Replikin序列可以是在Replikin峰基因中鉴定的Replikin序列。被鉴定的至少一种Replikin序列的化学合成是按本领域技术人员所理解的那样而进行。
所述合成肽然后被施用于病原体的宿主。疫苗的施用可以是口服,与食物源混合用于口服食用,通过鳃,在浓缩的浸液中使疫苗通过鳃、皮肤、口等被吸收入体内,通过注射或使用本领域技术人员现在和以后知道的任何其他方法。所述疫苗可与药学上可接受的载体、赋形剂、结合剂或本领域技术人员已知的其他有帮助的化合物、辅助剂、溶液或混合物组合。
所述方法可在七天或更少的时间内完成,这是基于在病原体基因组中鉴定Replikin序列的容易性和化学合成大量肽的容易性。在七天或更少的时间内为疫苗提供有效的活性成分的这个新方法解决了本领域一个关键问题,因为目前的疫苗生产方法通常需要三至十二个月。疫苗生产的这种耽搁可能在流行病早已经结束之后,或在流行病仍活跃但病原体的变异已经使疫苗不太有效或无效之后,才能供应疫苗。疫苗开发的长过程对于卫生专业人员和政府是很大的烦恼。本发明人现在已经提供一种方法以大大地减少疫苗开发的耽搁。
养殖的无脊椎动物的抵抗系的开发
本发明另一个非限制性的方面提供一种增加无脊椎动物对病原体的抵抗力的方法,其包括:
(1)使用所述病原体攻击与所述无脊椎动物同种的多个无脊椎动物,所述病原体的水平足以使所述多个无脊椎动物的至少一个个体致病;
(2)将患病的或死亡的所述多个无脊椎动物的至少一个个体丢弃;
(3)重复步骤(1)和(2)至少一次;并且
(4)至少一次地在步骤(1)、(2)和/或(3)中对所述多个无脊椎动物施用权利要求1的物质,其增加所述无脊椎动物对病原体的抵抗力。
所述过程可被重复若干次,直至在养殖的无脊椎动物中观察到期望水平的存活率,包括100%存活率。养殖的有抵抗力的无脊椎动物然后可被用作繁殖种以生产水产养殖的无脊椎动物的抵抗系。包括免疫原性肽的化合物可在每次重复步骤1和2时被施用,可在第二次重复步骤1和2时被施用,或可在之后某次重复步骤1和2时被施用。如下面的实施例3和图2所证明,在对每克虾体重施用约0.5mg的包括十一种等重的桃拉综合征病毒免疫原性肽的化合物之前被桃拉综合征病毒慢性感染的虾提供了91%的被TSV攻击的虾的存活率。相比之下,只有25%的之前未被TSV攻击且未被施用疫苗的虾在攻击中存活了下来。进一步地,75%的被TSV慢性感染且未被施用疫苗的虾另外在攻击中存活了下来。
实施例3和图2中报告的试验证明,与疫苗处理结合的耐受抵抗力迄今已经提供了所观察到的针对TSV攻击的最高度保护。像这样,本发明的一个方面提供了一种提高抵抗力的方法,其使用所选病原体对无脊椎动物的周期攻击并与疫苗的施用相结合。在一个优选的实施方案中,疫苗的至少一种分离的或合成的肽是Replikin肽。Replikin肽已被证明激发脊椎动物和无脊椎动物中的免疫原性和/或抵抗力应答。例如,针对SARS的Replikin序列和H5N1流感病毒Replikin支架的疫苗产品已经被证明,参见例如2006年2月16日提交的序列号为11/355,120的美国申请(实施例6和7),所有在兔或鸡上测试的Replikin序列诱导了免疫应答,而且神经胶质瘤Replikin序列已经在癌细胞中被鉴定且被分离或合成为肽,其中所述肽在兔中诱导免疫应答并与人的天然抗体应答发生反应。参见美国专利号6,638,505。
Replikin结构的保守性与毒力和致死性相关
任何结构的保守性对于此结构是否提供用来攻击和破坏或刺激的稳定不变的靶来说是重要的。已经显示,Replikin序列通常是保守的。当一个结构被以某种方式与该生物体的基本生存机制相关联时,所述结构往往是保守的。变化的结构提供不恒定的靶,这是避免袭击者的好策略,其中所述袭击者例如针对先前结构专门生成的并因此对修改形式无效的抗体。此策略被流感病毒所用,例如,以致先前疫苗在应对当前有毒性的病毒时可能是非常无效的。
然而,与存活功能太紧密联系的特定结构显然不能经常改变。Replikin结构的一个必需成分是组氨酸(h),已知其经常与氧化还原酶中的金属基团结合并且是复制所需的能量的可能来源。因为组氨酸结构保持不变,Replikin序列结构更保持为用于破坏或刺激的靶具有吸引力。此外,如下面表1和2中所证明,Replikin结构在有毒性的病原体中通常是保守的,其中所述病原体包括无脊椎动物的病原体。
鉴于Replikin结构在无脊椎动物病原体中的保守性,本发明的一个方面提供针对至少一种分离的或被合成的Replikin序列的抗体或抗体片段或抗Replikin的小分子,其中所述分离的或被合成的Replikin序列是在水产养殖病原体的蛋白或蛋白片段中或在Replikin峰基因中或在包括水产养殖病原体的Replikin峰基因的蛋白或基因区域中。Replikin的抗体和抗Replikin的小分子作为针对病原体爆发的疗法是有用的。在鉴定病原体中的Replikin序列后,本领域技术人员知道很多为了治疗和诊断的目的而开发抗体或抗体片段的途径。本领域技术人员同样知道如何生产用来结合被鉴定的Replikin序列的小分子。
作为治疗靶和预示器的Replikin支架
本发明人已经在流感、白斑综合征病毒和桃拉综合征病毒的种株中证实,Replikin支架的存在预示了流行病。像这样,除了病毒中Replikin的总数外,跨越时间的每个Replikin的结构是富含信息的,而且Replikin支架提供用来鉴定和控制快速复制的特别有用的靶,其中所述快速复制包括病原体疾病在水产养殖的无脊椎动物包括虾中的爆发。下面的表1显示1917年在被流感感染的鹅中第一次观察到的Replikin支架(鹅Replikin)。几十年来,恒定的长度、恒定的氨基末端的赖氨酸和羧基末端的组氨酸残基在不同种株中在固定的支架中是保守的。鹅Replikin的同系物从1917年直至2006年在包括对1918年、1957年和1968年三次大流行负责的每个种株H1N1、H2N2和H3N2的种株中出现。含有其他取代的同系物也在H1N2、H7N7、H5N2和H5N1中被观察到。
表1:在与快速复制相关的流感病毒Replikin肽的89年的保守性中显示有序取代的Replikin支架,从1917年鹅流感的Replikin和1918年人类大流行的Replikin到2006年H5N1“禽流感”的同系物。(SEQ ID NO.12-74,分别地,按出现顺序)
*与鹅Replikin氨基酸相同的残基是未画阴影的;氨基酸取代是画明暗阴影的以显示跨年份和种株的支架式样。在2004年和2006年的H5N1、1957年的H2N2、1968年的H3N2和H7N7中的位置24的取代被画在方框中。
表1通过年或更小的时间段举例说明鹅Replikin的蛋白结构和它在其他流感Replikin中的同系物的存在史。表1还举例说明在那些同系物中的氨基酸取代史和Replikin结构某些氨基酸的保守性,其中所述Replikin结构对于Replikin的定义和由Replikin提供的快速复制功能是必需的。
对表1的综述举例说明,如果氨基酸的随机取代是发生在1917年至今的流感的毒性种株上,鹅Replikin的某些骨架氨基酸在发生流行病的种株中将不是逐年保守的。然而,与随机取代导致的相反,流感的毒性种株逐年一致地在定义Replikin的那些位置含有保守的氨基酸。就是说,如果取代发生在定义Replikin的氨基酸之一,例如赖氨酸或组氨酸,Replikin的所述定义将失去。然而,所述Replikin序列在超过89年中都是保守的。因此,既然几十年来某些氨基酸具有保守性,就不能说取代是完全随机的。取代的确发生在对Replikin的定义不必要的氨基酸中(即除了赖氨酸或组氨酸之外的氨基酸)的事实证明Replikin和Replikin支架在种株病原性上的重要性。
从表1还可以注意到,当取代发生时,发现它们发生在Replikin支架的某些明显优选的位置上。表1显示在位置1、3-24和26-27上重复出现的取代。进一步地,当取代发生在所有这些位置时,赖氨酸继续存在于和第二个赖氨酸(其在这些毒性种株中尚未被取代)相距6至10个氨基酸的位置上。
如表1中所见,即使当在29个氨基酸段中的赖氨酸位置上有取代时,如1957年所见的,当在位置11的K移位至位置10时,那个新位置被保持到2005年。此外,YP(在位置6-7)、SY(在位置12-13)、N(在位置15)和LVLWG(SEQ ID NO.75)(在位置22-26)保持Replikin支架的同源结构且很少有例外。
流感、WSSV和TSV中的同源Replikin支架序列
本发明人还已经确立在毒性流感病毒和TSV和白斑综合征病毒(虾中另一种病毒病原体)之间在所述病毒的Replikin支架部分的关系,如下面表2中可见。尽管存在大量取代,白斑综合征病毒的若干短Replikin还是证明了与流感病毒Replikin序列的显著同源性,特别是就长度和关键的赖氨酸(k)和组氨酸(h)残基而言。相似的但较小的同源性在桃拉综合征病毒中被见到。这些同源性暗示,所述序列是从共享的库衍生来的,和/或Replikin生产的相似机制在两种病毒组中都被使用而且对共享所述同系物的每种病毒的毒力是重要的。因为Replikin结构在库或共享的机制中看似保守,毫不奇怪的是,Replikin结构与快速复制、毒力、死亡率和发病率之间的关系在大范围的病原体和宿主中看似保守,其中所述病原体和宿主包括水产养殖的无脊椎动物如虾、扇贝、蛤、蟹、贻贝等的病原体。
表2-虾的白斑和桃拉综合征支架(SEQ ID NO.76-87,分别地,按出现的顺序)
本发明的另一个方面提供了一种制备预防性或治疗性的化合物的方法,其包括鉴定包括约16至约34个氨基酸的Replikin支架,以及分离或合成所述Replikin支架以用作应对无脊椎动物水产养殖中病原体的预防性或治疗性的处理,其中所述Replikin支架包括:(1)一个末端赖氨酸和与所述末端赖氨酸紧邻的一个赖氨酸;(2)一个末端组氨酸和与所述末端组氨酸紧邻的一个组氨酸;(3)距离另一个赖氨酸约6至约10个氨基酸残基以内的一个赖氨酸;和(4)至少6%的赖氨酸。所述Replikin支架可由27至约33个氨基酸组成,并还可由约30至约33个氨基酸组成。在一个进一步的非限制性的实施方案中,所述Replikin支架由32或33个氨基酸组成。
在本发明的另一个方面,提供了一种预防性或治疗性的化合物,其包括至少一种来自养殖在水中的食用无脊椎动物的病原体的分离的或被合成的Replikin序列,其中所述病原体包括虾中的桃拉综合征病毒和白斑综合征病毒,以及贻贝、蛤、扇贝等中的衣原体样和立克次氏体样细菌病原体。在本发明一个非限制性的实施方案中,提供了一种预防性或治疗性的化合物,其包括从病原体例如TSV中分离的或被合成的至少一种Replikin序列或至少一种Replikin支架序列。在本发明一个非限制性的实施方案中,所述至少一种分离的或被合成的Replikin序列或至少一种Replikin支架序列存在于病原体例如TSV的新出现的种株中。在本发明一个进一步的非限制性的实施方案中,所述预防性或治疗性的化合物包括两种或更多种Replikin序列。在一个进一步的非限制性的实施方案中,所述预防性或治疗性的化合物包括两种或更多种Replikin支架序列。在一个进一步的非限制性的实施方案中,所述预防性或治疗性的化合物包括至少一种Replikin序列和至少一种Replikin支架序列。在另一个非限制性的实施方案中,所述预防性或治疗性的化合物包括至少一种Replikin序列或至少一种Replikin支架序列和药学上可接受的载体。
实施例1-由独立实验室进行的桃拉综合征病毒四个种株的Replikin浓度对比
从夏威夷、伯利兹、泰国和委内瑞拉各自分离的四种桃拉综合征病毒(TSV)蛋白序列的Replikin浓度在不知道四种分离物确切的毒力顺序的情况下被检测,而且所述毒力按照Replikin浓度的顺序被定量地排序。所述四种TSV分离物的毒力在不知道Replikin浓度确切的顺序的情况下在独立实验室中被比较。所述毒力通过凡纳滨对虾幼体(Kona储备,海洋研究中心,夏威夷)的口服实验室感染而被比较。结果显示,伯利兹分离物是最有毒的,泰国分离物是第二有毒的,接着是夏威夷分离物和毒性最弱的委内瑞拉分离物。这是基于在生物测定结束时的累计存活率的分析,并且基于50%死亡率的时间。作为死因的TSV感染被RT-PCR检测中的阳性反应和组织学分析中观察到的特征性损伤的出现所证实。Replikin浓度与死亡率所指示的毒力之间的相关性是可定量的并且基本上是线性的。
攻击方法:
对不含特定病原体的凡纳滨对虾的小幼体(每个储罐20只虾,平均重量:1.8g)以它们的体重5%的量喂食切碎的TSV感染的组织(被源自伯利兹、泰国、委内瑞拉和夏威夷的4种分离物的每一种分别感染)3天。用片状的定量口粮(Rangen 35%)在接下来的12天中维持这些虾。将对特定的分离物的每种进攻生物测定被进行三次。在生物测定期间,每天检查所有储罐中死的或濒死的虾。将所有的死尸移出储罐并冷冻。来自每种分离物的一至三个濒死的虾被保存在Davidson氏AFA固定剂中并处理以进行常规组织学解剖从而确认病毒感染。对于每种分离物,在急性阶段感染中收集六只濒死的虾,并使用高纯RNA组织试剂盒(Roche)从它们的鳃组织提取总RNA。使用实时RT-PCR分析被提取的RNA中TSV的存在。
所有储罐外面都装备有适宜的生物滤器和换气,并用塑料覆盖以含有气溶胶。水的平均盐度是23ppt,而且水温是28℃。攻击研究在15天后被终止,活的动物被算作存活者。
结果
毒力对比:虾的死亡率
在所有4种分离物中,在暴露于TSV后的第2天见到第一例死亡。对于伯利兹分离物,多数(83%)虾截止到第4天时死亡并且在第11天具有0%的存活率。对于泰国分离物,63%的死亡截止到第4天时发生并且在15天的生物测定结束时具有20%的存活率。对于夏威夷分离物,死亡率从第2天开始增长并在第5天达到峰值;最终的累计存活率是22%。对于委内瑞拉分离物,死亡在第2和3天缓慢发生并在第4天达到22%的死亡率,接下来死亡率下降,到研究结束时42%的虾存活下来。参见图5和表6。达到由TSV感染所致的50%死亡率所需要的时间段对于伯利兹、泰国、夏威夷和委内瑞拉分离物来说分别为2.8、3.5、4.5和7天(表3)。
表3.在SPF凡纳滨对虾(Kona储备)中的口服的TSV攻击结果
*在委内瑞拉的三个储罐中观察到大的变化,因此通过使用Statistix 8程序进行卡普兰-迈耶存活率分析而确定50%死亡率之日。
病理学
凡纳滨对虾幼体样品组织学分析被概括在表4中。
表4.组织学发现的概括
严重度:G1:感染迹象;G2:中度的感染迹象;G3:中度至高度的感染迹象;G4:严重感染。
1.TSV损伤=鳃、口、胃、外皮的角化上皮和附属物中TSV特殊病征性的损伤的存在。
2.LOS=淋巴器官中淋巴器官球体的存在。
伯利兹TSV。在一只代表性的虾样品中发现了严重度为G4的诊断性TSV感染的急性损伤。在总体表的角化上皮、附属物、鳃、胃和食管中观察到核固缩和核破裂。还发现淋巴器官球体处于严重度G4。
泰国TSV。在3只虾中的2只中检测到严重的(G4)TSV感染,另一只虾显示了中度至高度的(G3)感染。发现淋巴器官球体处于严重度G2和G3。
夏威夷TSV。在第4天收集的2只虾中检测到中度水平的(G2)TSV感染。发现淋巴器官球体处于严重度G3和G4。
委内瑞拉TSV。在第4天取样的一只代表性的虾中检测到严重的(G4)TSV感染。发现淋巴器官球体处于严重度G2。
实时TSV RT-PCR
所有24个样品(从每种分离物中取6个)对于TSV感染都是阳性的。这确认了在生物测定中观察到的死亡率是来自TSV感染。
表5.在被TSV攻击的虾的鳃中TSV的RNA的平均值和范围
表6.死亡率和盲测的Replikin浓度
4种TSV的毒力(死亡率百分数)与盲测的Replikin计数的对比结果是:
毒力顺序:伯利兹>泰国>(或=)夏威夷>委内瑞拉,与Replikin浓度一致。Replikin浓度的差别看上去小,但它们是统计学上显著的,在p<0.001的水平上。参见图3和4。
实施例2-合成的Replikin的施用增加了宿主对桃拉综合征病毒的抵抗力
概述
在七天内通过在桃拉综合征病毒(夏威夷分离物)的基因组中鉴定十一种Replikin序列并且化学合成对下述虾中疫苗试验足够的量的所述十一种Replikin序列而开发了包括等重量份的KVGSRRYKSH(SEQ IDNO.1)、HFAT0KCFGEVPKK(SEQ ID NO.2)、KAENEFWDGVKQSH(SEQ ID NO.3)、KGHRKVPCEQK(SEQ ID NO.4)、HRKVPCEQK(SEQ ID NO.5)、KVPCEQKIWLH(SEQ ID NO.6)、KIWLHQNPGK(SEQ ID NO.7)、HQNPGKTQQDMK(SEQ ID NO.8)、KGNTRVHVK(SEQ ID NO.9)、KEHVEKIVDK(SEQ ID NO.10)和HVEKIVDKAK(SEQ ID NO.11)的疫苗(T1疫苗)。
在实验室生物测定中通过口服施用于虾(南美白对虾)而测试T1疫苗。接种一个月后,使用TSV经口服攻击虾以确定疫苗是否诱导保护作用。结果显示,用所述疫苗喂养的虾显示了对TSV的抵抗(P=0.0038<0.05)。被接种的虾具有59%的存活率,而且未被接种的虾具有25%的存活率。相对存活率百分数是45%。通过实时RT-PCR检测中的阳性反应或组织学分析中观察到的特征性损伤出现,确认了TSV感染导致虾死亡。
材料和方法
动物和攻击设计:将南美白对虾(120只虾,Kona储备,来自海洋研究中心,平均重量:2.0g)储存在6只储罐(20只虾/储罐)中并在4个星期中每天喂占总体重的5%的疫苗T1。在4个星期结束时,通过在2天早上喂占总体重的5%将虾暴露于TSV;在下午,还给虾喂混合了疫苗的饲料。从第3天开始,用混合了疫苗的饲料将所有虾维持额外的2个星期。
对于未被接种的组,用对照食谱饲料喂60只虾(每个储罐20只虾)4个星期以作为病毒感染的组织的阳性对照。
混合了疫苗的饲料的制备:将冻干的疫苗T1(Replikin,LLC,波士顿,马萨诸塞州)与虾产物35麦芽浆(Rangen)、1%的海藻酸钠、1%的六偏磷酸钠(作为结合剂被添加)和50%的水混合(在冰上)。将所述被混合的饲料挤压,冷冻干燥然后打包成大约42个包以用于每个储罐(对于每个储罐:28个包用于4个星期的接种而14个包用于TSV攻击;每包2g),并且储存在-20℃直到使用。如上所述制备作为阳性对照的虾饲料,但不加入T1疫苗(被命名为对照食谱)。
表7.储罐的设置。所有储罐都装备有适宜的生物滤器和换气,并用塑料覆盖以含有气溶胶。
统计分析。被接种的和未被接种的(阳性对照)组之间的存活率按照相对存活率百分数(RPS:1-被接种的组死亡率/阳性对照组死亡率)×100(Amend DF,1981.Potency testing of fish vaccines.(鱼疫苗效价测试)。于:Anderson DP,Hennessen W(编)Fish Biologies:Serodiagnosticsand vaccines.(鱼生物学:血清诊断和疫苗)S.Karger,Basel.447-454页)而被计算。
结果
通过使用单因素方差分析(one-way ANOVA)对比在第15天的存活率,被接种的组(6个储罐:合并A1-3和B1-3)存活率百分数是51%,这比未被接种的组(3个储罐:C1-3)的25%高。但是此差别不是统计学上显著的(P=0.1010>0.05)。然而,在被接种的组中的储罐B-3是异常值(10%存活率)。在这个储罐中,严重的死亡早早地发生了,而且此储罐的终值是如此远离其他的,因此将它从分析中除去。
在5个被接种的组(A1-3和B1,2)中,第一例死亡在暴露于TSV之后第2天被发现(图1A)。在未被接种的组中,第一例死亡发生在第3天,而且50%的虾到第8.5天时死亡(图1B)。被接种的组对夏威夷TSV感染有显著的(5%水平)抵抗力。通过单因素方差测试分析所得的概率为0.0038。被接种的组有59%的累计存活率,比未被接种的组的25%高,这表明用T1接种提供了免受TSV感染的保护作用。接种后针对TSV的相对存活率(RPS)是45%。
表8.在被接种的南美白对虾中TSV攻击所致的存活率百分数。
因为关于虾(虾似乎不产生抗体)和其他无脊椎动物的免疫系统的细节知道的很少,所以对感染的“抵抗力”现象似乎是基于“原始的免疫系统”,其或许与“Toll受体”和相关系统类似。因此,术语“增加的抵抗力”被用于被观察到的现象,而且有时将Replikin饲料而非“疫苗”用于被施用的增加抵抗力的物质。然而,疫苗包括施用于在本文提供的实施例中公开的试验中的虾的化合物。
实施例3-与合成的Replikin的施用相结合的病毒周期攻击增加了宿主对桃拉综合征病毒的抵抗力
概述
从TSV感染中存活下来的太平洋白虾(南美白对虾)被发现对于第二次TSV感染更具耐受性。三组TSV慢性感染的虾被喂(1)T1疫苗,其含有等重量份的KVGSRRYKSH(SEQ ID NO.1)、HFATKCFGEVPKK(SEQ ID NO.2)、KAENEFWDGVKQ SH(SEQ ID NO.3)、KGHRKVPCEQK(SEQ ID NO.4)、HRKVPCEQK(SEQ ID NO.5)、KVPCEQKIWLH(SEQ ID NO.6)、KIWLHQNPGK(SEQ ID NO.7)、HQNPGKTQQDMK(SEQ ID NO.8)、KGNTRVHVK(SEQ ID NO.9)、KEHVEKIVDK(SEQ ID NO.10)和HVEKIVDKAK(SEQ ID NO.11)(来自桃拉综合征病毒-夏威夷分离物的Replikin序列),(2)抑制的疫苗T2,其含有等重量份的KVGSRRYKSHKKKKKHK(SEQ ID NO.88)、HFATKCFGEVPKKKKKKKHK(SEQ ID NO.89)、KAENEFWDGVKQSHKKKKKHK(SEQ ID NO.90)、KGHRKVPCEQKKKKKKHK(SEQ ID NO.91)、HRKVPCEQKKKKKKHK(SEQ ID NO.92)、KVPCEQKIWLHKKKKKHK(SEQ ID NO.93)、KIWLHQNPGKKKKKKHK(SEQ ID NO.94)、HQNPGKTQQDMKKKKKKHK(SEQ ID NO.95)、KGNTRVHVKKKKKKHK(SEQ ID NO.96)、KEHVEKIVDKKKKKKHK(SEQ ID NO.97)和HVEKIVDKAKKKKKKHK(SEQ ID NO.98)(除了将七个残基的氨基酸尾KKKKKHK(SEQ ID NO.204)添加到所述十一个Replikin序列中每一个的C端以研究确切的Replikin结构对抵抗力作用可能有的影响之外,与T1相同的Replikin序列),或者(3)对照食谱(35%的Rangen)使用2个星期,接着是喂食TSV(夏威夷分离物)感染的组织2天。未被暴露于TSV感染的第4组虾也被喂了对照食谱。截止于暴露在TSV后第15天,91%的被接种的(T1)虾存活了下来。实时TSV RT-PCR也显示,T1接种的虾在试验中的四组虾中具有最低的病毒载量。对于用抑制的疫苗(T2)喂养的虾,60%存活了下来,而且所述虾具有略高的病毒载量。对于用对照食谱喂养的虾,具有75%的存活率,而且所述虾含有10倍高的病毒载量。之前未被暴露于TSV的虾(SPF南美白对虾)在暴露于TSV之后只有25%的存活率。所述试验的设置被描述在下面的表9中。
表9.储罐的设置
1慢性TSV感染,虾被喂T1且被TSV攻击。
2慢性TSV感染,虾被喂T2且被TSV攻击。
3慢性TSV感染,虾被喂对照食谱且被TSV攻击。
材料和方法
混合了疫苗的饲料的制备:将每种冻干的疫苗(T1和T2,由Replikins,LLC,波士顿,马萨诸塞州提供)与虾生产35麦芽浆(Rangen)、1%的海藻酸钠、1%的六偏磷酸钠(作为结合剂被添加)和50%的水混合(在冰上)。将所述被混合的饲料挤压,冷冻干燥,然后打包成大约30个包(每包4g,总共120g混合了疫苗的饲料),并且储存在-20℃直到使用。如上所述制备对照组的虾饲料,但不加入疫苗(被命名为对照食谱)。
被接种的组:对于每组(疫苗T1和抑制的疫苗T2),将11和10只TSV慢性感染的南美白对虾按照表9所述储存在每个1000-L的储罐中,并在2个星期中每天喂占它们总体重的5%的混合了疫苗的饲料。每克总虾体重每天被施用的T1 Replikin序列的总质量是约0.50mg。接着用切碎的TSV感染的组织(夏威夷分离物)以占它们体重5%的量在每天早上喂所述虾2天。在下午,还给虾喂混合了疫苗的饲料。从第3天开始,用混合了疫苗的饲料将所有虾维持额外的2个星期。
未被接种的组:给12只虾(未被接种的,之前从TSV感染存活了下来)喂对照食谱2个星期。接着用切碎的TSV感染的组织以占它们体重5%的量每天喂所述虾2天。从第3天开始,用对照食谱维持所有虾。
组织学。在暴露于夏威夷TSV之后,一天两次检查所有储罐中死的或濒死的虾。将所有的死尸移出储罐并在-70℃冷冻。来自储罐C的一只濒死的虾被保存在Davidson氏AFA固定剂中并处理以进行常规组织学解剖从而评估TSV感染的严重性。
实时TSV RT-PCR。对于每组,在第15天将存活下来的虾取样。使用高纯RNA组织试剂盒(Roche)从腹肢和鳃提取总RNA。使用Tang等人(J.Virol Method 115:109-114,2004)描述的实时RT-PCR分析被提取的RNA中TSV的存在。
结果
图2阐述了对于用T1接种的虾、用抑制的T2疫苗喂养的虾、用对照食谱喂养的慢性感染TSV的虾以及之前未被暴露于TSV的并被喂对照食谱的虾使用TSV再次攻击后,南美白对虾的累计存活率。对于T1接种的虾,直到第13天未出现死亡。这组在暴露于TSV后第15天具有91%的存活率(表10)。对于用抑制的疫苗T2喂养的虾,在第2天观察到第一例死亡。该组具有60%的存活率。对于未被接种的组,第一例死亡发生在第10天,而且该组具有75%的存活率。在喂了夏威夷TSV之后,SPF虾的存活率百分数是25%。
表10.TSV攻击中的存活率百分数
病理学
被TSV攻击后的南美白对虾样品的组织学分析被概述在表11中。
表11.TSV感染的组织学发现
LOS:淋巴器官球体
在第10天收集的未被接种的组中发现中度至高度(G3)水平的淋巴器官球体,表明慢性TSV感染。
实时TSV RT-PCR
使用实时TSV RT-PCR测定对存活的虾的病毒载量进行定量(表12)。结果显示,在用T1接种的虾中病毒载量最低,为2.46×103个拷贝/μl RNA。T2抑制的疫苗喂养的虾含有较高的病毒载量,为8.88×103个拷贝/μl RNA。对于未被接种的组,虾具有最高的病毒载量,为5.20×104个拷贝/μl RNA。
表12.TSV存活虾的平均TSV拷贝数/1RNA
这些结果显示,TSV慢性感染的虾当被TSV再次攻击时具有较高的存活率(60-91%)。特别地,T1接种的南美白对虾具有最高的存活率和最低的病毒载量。被夏威夷TSV攻击的SPF南美白对虾的存活率是25%。
实施例4-从2000年至2005年TSV分离物的公开可得的登录号中Replikin浓度的确定
为带有公开可得于www.pubmed.com的登录号的桃拉综合征病毒所有氨基酸序列确定平均Replikin浓度。扫描所述氨基酸序列的含7至50个氨基酸的Replikin序列,其包括(1)位于所述序列的第一个末端的至少一个赖氨酸残基和位于所述序列的第二个末端的至少一个赖氨酸残基或至少一个组氨酸残基;(2)位于距离第二个赖氨酸残基六至十个残基处的第一个赖氨酸残基;(3)至少一个组氨酸残基;和(4)至少6%的赖氨酸残基。对每个可得的登录号确定Replikin序列的总数。然后将每个登录号中Replikin序列的总数除以该登录号中公开的氨基酸残基总数。所得结果是Replikin浓度。然后确定在特定年份中分离和报道的所有病毒的平均Replikin浓度。表13提供结果。
表13-按年的TSV Replikin浓度
实施例5-登录号为AAM73766和AAY89096的公开可得的2001年和2005年TSV分离物中Replikin浓度的确定
桃拉综合征病毒(TSV)通常是比白斑综合征病毒(WSSV)毒性较低的病毒,而且TSV Replikin支架结构与流感病毒的关系不如WSSVReplikin支架结构近。参见下面的Replikin支架序列。在2000年,TSV具有2.7的Replikin浓度。在2001和2004年之间,TSV具有低至0.6的较低平均Replikin浓度,而且它的Replikin支架消失了。在2005年,Replikin支架再现,并伴随着赖氨酸和组氨酸的增加以及Replikin浓度的相应增加(1.8),接着是2006-2007年中TSV爆发的增加。参见图6和下面的Replikin支架。
下面是从2000年TSV分离物的登录号AAK72220中鉴定的Replikin支架与从2005年TSV分离物的登录号AAY89096中鉴定的Replikin支架的比较。所述TSV Replikin支架还与1918年大流行的H1N1流感病毒和2000年的虾WSSV中的两个Replikin支架序列进行了对比。Replikin支架序列(SEQ ID NO.99-104,分别地,按出现顺序)
下面对登录号AAM73766和AAY89096的分析证明了具有公开可得于www.pubmed.com的登录号的桃拉综合征病毒分离物的氨基酸序列的Replikin浓度分析。
PubMed代码:AAM73766
被分离的:2001年
来源:桃拉综合征病毒
肽的氨基末端部分的Replikin序列
肽的中段分子部分的Replikin序列
零Replikin。
肽的羧基末端部分的Replikin序列
Replikin计数=每100个氨基酸中Replikin的个数=7/1011=0.7
PubMed代码:AAY89096
被分离的:2005年
来源:桃拉综合征病毒
肽的氨基末端部分的Replikin序列
肽的中段分子部分的Replikin序列
肽的羧基末端部分的Replikin序列
实施例6-西尼罗河病毒Replikin的周期性产生和每年的人类发病率以及预测方法
在本发明进一步的一个方面中,鉴定了病毒生物化学周期和病毒发病率周期之间的相关性并将其用来预测病毒在宿主群体中发病率的增加。本发明所述方面的一个非限制性的实施方案提供一种预测病毒性疾病中发病率增加的方法,其包括:(1)在多个连续时间点确定多种病毒分离物基因组中的平均Replikin计数;(2)在至少四个连续时间点比较平均Replikin计数,并在至少四个时间点鉴定至少两个周期的增加的平均Replikin计数;以及(4)在至少一个所述周期中平均Replikin计数的增加之后及时预测发病率的增加。在进一步的一个非限制性的实施方案中,在连续的时间点之间鉴定到逐步的周期。在进一步的一个实施方案中,特定的保守Replikin序列在逐步的周期中被鉴定,例如,KIIQKAHK(SEQ ID NO.199)、HLKCRVKMEK(SEQ ID NO.200)、KLTSGHLK(SEQ ID NO.201)和HNDKRADPAFVCK(SEQ ID NO.202)。
下面的西尼罗河病毒中的数据提供了在病毒中的平均Replikin计数中的周期的例子,其中所述周期预测发病率。所述数据另外还支持水产养殖的无脊椎动物中的疫苗,因为它们支持这种Replikin疫苗和其他疗法所基于的原则,其特别地包括Replikin序列在病毒性疾病的毒力和发病率中所扮演的角色、疾病中的Replikin计数通常与病原性之间的相关性以及Replikin结构在控制快速复制和疾病中的靶向。
周期是可被检测的,由于重复的保守病毒结构和Replikin现象随时间的连续性。被鉴定的周期提供了一种新的方法,该方法(1)确定一种新出现的疾病的生长、蔓延和轨迹,(2)通过手动地或使用计算机程序例如ReplikinsForecastTM(Replikins LLC)跟踪Replikin计数的变化来预测和跟踪病毒和其他生物体爆发的发生和强度(参见例如2005年4月28日提交的序列号为11/116,203的美国申请,其整体通过引用并入本文),(3)设计和化学合成含有较老的和较新的保守Replikin二者的疫苗以提供最准确和最大的抗生物体免疫刺激特性,(4)设计和化学合成含有针对较老的和较新的保守Replikin二者的反应性位点的抗体,以提供最准确和最大的抗生物体免疫保护特性,以及(5)设计和化学合成含有针对较老的和较新的保守Replikin二者的反应性位点的化合物,以提供最准确和最大的抗生物体保护特性。
图7提供了西尼罗河病毒中Replikin计数周期与西尼罗河病毒发病率的周期之间相关性的数据。WNV包膜蛋白每年的Replikin计数(黑色)的平均值和标准偏差,与CDC报告中的美国每年人类病例数(灰色)进行了比较。
2000至2003年:包膜蛋白Replikin计数的平均值的标准偏差从2000年至2001年显著增加(p<0.001)。此变化在所有常见流感病毒种株(与WNV不是相同的病毒属)中被观察到以在病毒爆发前传达快速复制和Replikin计数范围的扩大、由此Replikin计数所定义的病毒群体数量的扩大的信号。2000年至2003年的平均Replikin计数的增加看上去似乎伴随着或先于由疾病控制中心(CDC)独立记录并公布的人WNV病例数量的增加。同样的Replikin计数和发病率之间关系已经在下述中显示:流感种株例如H5N1对人的致死率,和H3N8马脑炎对马的发病率,和锥虫属恶性疟原虫(疟疾)对人的发病率,和虾病毒与虾死亡率。因为所述关系已经在若干物种包括甲壳纲动物、马和人中被证明,所以它看上去是广泛分布的一般原则。2004至2008年:在2004年和2005年出现了Replikin计数和WNV人类病例数量二者自2003年以来的降低。在2006年,出现了Replikin计数的增加,之后在2007年人类病例数量增加。
在图7中,可以观察到两个周期的Replikin浓度(计数)和两个周期的WNV人发病率。据此图显示,由病毒Replikin计数反映的两个“病毒Replikin周期”2000-2003年和2004-2008年,与由每年人类WNV病例数量反映的相同时期的两个“人类感染性周期”相互关联。之前的应用中的有关H1N1和H3N2的之前流感病毒数据暗示这种方式的Replikin计数数据周期,但没有清楚显示,因为未像此处西尼罗河病毒一样记录归因于H1N1或H3N2特定种株的实际病例数量(而不是仅仅“爆发”、“流行”或“大流行”)。
在第二个周期2004-2008年中Replikin计数和病例数量二者上升的数字当与第一个周期比较时,暗示了增加的或“提高的”感染效率,并伴随在第二个周期中的与第一个周期相比增加的Replikin计数。病毒效力的下降可能是由于宿主中抵抗力的产生;随后在第二个周期中感染性的提高与WNV中新的Replikin的出现有关系。再一次证明了Replikin与感染性的紧密关系;二者确实一起升高和下降。
因此,此数据以比在此之前可得的更准确的水平上为Replikin与感染性的关系提供直接的定量证据。例如,就H5N1流感来说,周期开始于1996年的香港爆发。通过完全杀掉香港的鸡,它在1998年暂时结束。H5N1临床“亚周期”在2000年重新开始,持续到现在,并且每年被Replikin计数前瞻性地预测。在这种情况下,由于大多发生在东亚国家,H5N1没有受到像这里所给出的美国的西尼罗河病毒那样的WHO关于发病率和死亡率的确切的流行病学报告,其中CDC保留了有关发病率和死亡率的更准确的监测记录。
虽然不希望被理论所限制,Replikin计数与发病率和死亡率的紧密关系,以及其他证据,已经导致这样的假设:除了紧密地参与快速复制的生物化学,Replikin实际上是感染性单元,而病毒和锥虫(trypanosome)仅仅是Replikin感染性单元的载体,但需要其他病毒或锥虫结构以在宿主中产生感染性。
图7举例说明Replikin计数变化的早期检测可以在疫苗对新出现的Replikin结构的快速响应中被直接翻译,其中所述疫苗可在新出现的Replikin序列被鉴定后七天或更短的时间内使用例如ReplikinForecastTM软件(Replikins LLC)合成。
下面的数据提供从www.pubmed.com可得的登录号的西尼罗河包膜蛋白的登录号、分离物的数量、平均Replikin计数,标准偏差和显著性。所述数据被反映在图7中。
保守的WNV Replikin的例子
按年的序列史:注意在WNV于大约2000年出现在美国之前那些年的记录是来自非美国的标本,如来自中东和非洲。
KIIQKAHK(SEQ ID NO.199)
所述序列按年的所有出现:
1988
P14335位置835,BAA00176位置835.
1999
AAF20205位置835,AAF20092位置835,AAG02040位置835,AAF18443 位置835.
2000
AAK06624位置835,AAG02039位置835,AAG02038位置835.
2001
AAM81753位置835,AAM81752位置835,AAM81751位置835,AAM81750位置835,AAM81749位置835.
2002
AAN85090位置835,AAL87234位置835,CAD60131位置835.
2003
AAP20887位置835,AAX99361位置835,AAQ55854位置835,AAR84614位置835,AAQ00999位置835,AAP22087位置835,AAP22086 位置835,AAP22089位置835.
2004
AAU00153位置835,AAV54504位置835,ABG67747位置835,ABG67746位置835,BAD34491位置835,BAD34490位置835,BAD34489位置835,BAD34488位置835,ABV82765位置835,AAW56064位置835,AAW56066位置835,AAW56065位置835,AAW28871位置835,AAT92099位置835,AAT92098位置835,AAV52690位置835,AAV52689位置835,AAV52688位置835,AAV52687位置835,AAV68177位置835,AAX09982位置835.
2005
YP_001527877位置835,ABB01533位置835,ABA62343位置835,AAY55949位置835,AAZ32750位置835,AAZ32749位置835,AAZ32748 位置835,AAZ32747位置835,AAZ32746位置835,AAZ32745位置835,AAZ32744位置835,AAZ32743位置835,AAZ32742位置835,AAZ32741 位置835,AAZ32740位置835,AAZ32739位置835,AAZ32738位置835,AAZ32737位置835,AAZ32736位置835,AAZ32735位置835,AAZ32734 位置835,AAZ32733位置835,AAZ32732位置835,AAZ32731位置835,AAZ32730位置835,AAZ32729位置835,ABA54595位置835,ABA54594 位置835,ABA54593位置835,ABA54592位置835,ABA54591位置835,ABA54590位置835,ABA54589位置835,ABA54588位置835,ABA54587位置835,ABA54586位置835,ABA54585位置835,ABA54584位置835,ABA54583位置835,ABA54582位置835,ABA54581位置835,ABA54580位置835,ABA54579位置835,ABA54578位置835,ABA54577位置835,ABA54576位置835,ABA54575位置835,AAY54162位置835.
2006
CAL49454位置835,ABI97486位置835,ABG81344位置835,ABG81343 位置835,ABG81342位置835,ABG81341位置835,ABG81340位置835,ABG76816位置835,ABG76815位置835,ABG76814位置835,ABG76813位置835,ABG76812位置835,ABG76811位置835,ABG76810位置835,ABG76809位置835,ABG76808位置835,ABG76807位置835,ABG76806位置835,ABG76805位置835,ABG76804位置835,ABG76803位置835,ABG76802位置835,ABG76801位置835,ABG76800位置835,ABG76799位置835,ABG76798位置835,ABG76797位置835,ABG76796位置835,ABG76795位置835,ABD19642位置835,ABD19641位置835,ABD19640位置835,ABD19513位置835,ABD19512位置835,ABD19511位置835,ABD19510位置835,ABD85083位置835,ABD85082位置835,ABD85081位置835,ABD85080位置835,ABD85078位置835,ABD85077位置835,ABD85076位置835,ABD85075位置835,ABD85074位置835,ABD85073位置835,ABD85072位置835,ABD85070位置835,ABD85069位置835,ABD85068位置835,ABD85067位置835,ABD85066位置835,ABD85065位置835,ABD85064位置835,ABD67762位置835,ABD67761位置835,ABD67760位置835,ABD67759位置835,ABD67758位置835,ABD67757位置835,ABD67756位置835.
2007
ABV22897位置835,ABU54838位置835,ABU52997位置835,ABQ52692位置835,CAM91200位置835,ABR10608位置377.
按年的序列史
HLKCRVKMEK(SEQ ID NO.200)
所述序列按年的所有出现:
1982
ABC49717位置575.
1985
P06935位置571,AAA48498位置571.
1988
P14335位置575,BAA00176位置575.
1989
ABR19636位置575.
1993
NP_776014位置281,NP_041724位置571.
1998
AAD28624位置550.
1999
AAD31720位置285,AAF20205位置575,AAF26360位置575,AAD28623 位置550,AAF20092位置575,AAG02040位置575,AAF18443位置575.
2000
ABR19638位置575,AAK06624位置575,AAG02039位置575,AAG02038位置575.
2001
AAM70028位置285,AAL14222位置285,AAL14221位置285,AAL14220位置285,AAL14219位置285,AAL14218位置285,AAL14217 位置285,AAL14216位置285,AAL14215位置285,AAK58104位置285,AAK58103位置285,AAK58102位置285,AAK58101位置285,AAK58100位置285,AAK58099位置285,AAK58098位置285,AAK58097位置285,AAK58096位置285,AAK52303位置285,AAK52302位置285,AAK52301位置285,AAK52300位置285,AAK62766位置285,AAK62765位置285,AAK62764位置285,AAK62763位置285,AAK62762位置285,AAK62761位置285,AAK62760位置285,AAK62759位置285,AAK62758位置285,AAK62757位置285,AAK62756位置285,AAK91592位置176,ABR19637位置575,AAM81753位置575,AAM81752位置575,AAM81751位置575,AAM81750位置575,AAM81749位置575,AAM21944位置198,AAM21941位置264.
2002
AAO26579位置285,AAO26578位置285,AAN85090位置575,AAO73303位置452,AAO73302位置452,AAO73301位置452,AAO73300位置452,AAO73299位置452,AAO73298位置452,AAO73297位置452,AAO73296位置452,AAO73295位置452,AAL87234位置575,CAD60131位置575.
2003
AAP20887位置575,AAR10793位置128,AAR10784位置128,AAR17575位置285,AAR17574位置285,AAR17573位置285,AAR17572位置285,AAR17571位置285,AAR17570位置285,AAR17569位置285,AAR17568位置285,AAR17567位置285,AAR17566位置285,AAR17565位置285,AAR17564位置285,AAR17563位置285,AAR17562位置285,AAR17561位置285,AAR17560位置285,AAR17559位置285,AAR17558位置285,AAR17557位置285,AAR17556位置285,AAR17555位置285,AAR17554位置285,AAR17553位置285,AAR17552位置285,AAR17551位置285,AAR17550位置285,AAR17549位置285,AAR17548位置285,AAR17547位置285,AAR17546位置285,AAR17545位置285,AAR17544位置285,AAR17543位置285,AAR17542位置285,AAQ87608位置194,AAQ87607位置194,AAQ87606位置58,AAR10804位置128,AAR10803位置128,AAR10802 位置128,AAR10801位置128,AAR10800位置128,AAR10799位置128,AAR10798位置128,AAR10797位置128,AAR10796位置128,AAR10795位置128,AAR10794位置128,AAR10792位置128,AAR10791位置128,AAR10790位置128,AAR10789位置128,AAR10788位置128,AAR10787位置128,AAR10786位置128,AAR10785位置128,AAR10783位置128,AAR10782位置128,AAR10781位置128,AAR10780位置128,AAX99361位置575,AAR84198位置452,AAQ55854位置575,AAR14153位置452,AAR84614位置575,AAR06948位置452,AAR06947位置452,AAR06946位置452,AAR06945位置452,AAR06944位置452,AAR06943位置452,AAR06942位置452,AAR06941位置452,AAR06940位置452,AAR06939位置452,AAR06938位置452,AAR06937位置452,AAR06936位置452,AAR06935位置452,AAR06934位置452,AAR06933位置452,AAR06932位置452,AAR06931位置452,AAQ00999位置575,AAQ00998位置575,AAP22087位置575,AAP22086位置575,AAP22089位置575,AAP22088 位置572.
2004
AAT11553位置285,AAT11552位置285,AAT11551位置285,AAT11550 位置285,AAT11549位置285,AAT11548位置285,AAT11547位置285,AAT11546位置285,AAT11545位置285,AAT11544位置285,AAT11543 位置285,AAT11542位置285,AAT11541位置285,AAT11540位置285,AAT11539位置285,AAT11538位置285,AAT11537位置285,AAT11536 位置285,AAT11535位置285,AAT11534位置285,AAS75296位置128,AAS75295位置128,AAS75294位置128,AAS75293位置128,AAS75292 位置128,AAS75291位置128,AAT95390位置575,AAU00153位置575,AAV54504位置575,AAT02759位置571,ABG67747位置575,ABG67746位置575,BAD34491位置575,BAD34490位置575,BAD34489位置575,BAD34488位置575,ABV82765位置575,AAZ91684位置575,AAW56064位置575,AAW56066位置575,AAW56065位置575,AAW28871位置575,AAT92099位置575,AAT92098位置575,AAV52690位置575,AAV52689位置575,AAV52688位置575,AAV52687位置575,AAV68177位置575,AAX09982位置575.
2005
YP_001527880位置285,ABC40712位置575,YP_001527877位置575,ABB01533位置575,ABA62343位置575,AAY32590位置452,AAY32589位置452,AAY55949位置575,AAZ32750位置575,AAZ32749位置575,AAZ32740位置575,AAZ32739位置575,AAZ32738 位置575,AAZ32737位置575,AAZ32736位置575,AAZ32735位置575,AAZ32734位置575,AAZ32733位置575,AAZ32732位置575,AAZ32731 位置575,AAZ32730位置575,AAZ32729位置575,ABC49716位置571,ABA43046位置452,ABA43045位置452,ABA43044位置452,ABA43043位置452,ABA43042位置452,ABA43041位置452,ABA43040位置452,ABA43039位置452,ABA43038位置452,ABA43037位置452,ABA43036位置452,ABA43035位置452,ABA43034位置452,ABA43033位置452,ABA43032位置452,ABA43031位置452,ABA43030位置452,ABA43029位置452,ABA43028位置452,ABA43027位置452,ABA43026位置452,ABA43025位置452,ABA43024位置452,ABA43023位置452,ABA43022位置452,ABA43021位置452,ABA43020位置452,ABA43019位置452,ABA43018位置452,ABA43017位置452,ABA43016位置452,ABA43015位置452,ABA43014位置452,ABA43013位置452,ABA43012位置452,ABA43011位置452,ABA43010位置452,ABA43009位置452,ABA43008位置452,ABA43007位置452,ABA43006位置452,ABA43005位置452,ABA43004位置452,ABA43003位置452,ABA54595位置575,ABA54594位置575,ABA54593位置575,ABA54592位置575,ABA54591位置575,ABA54590位置575,ABA54589位置575,ABA54588位置575,ABA54587位置575,ABA54586位置575,ABA54585位置575,ABA54584位置575,ABA54583位置575,ABA54582位置575,ABA54581位置575,ABA54580位置575,ABA54579位置575,ABA54578位置575,ABA54577位置575,ABA54576位置575,ABA54575位置575,AAY54162位置575.
2006
ABI81406位置275,ABI81405位置275,ABI81404位置275,ABI81403位 置275,ABI81402位置275,ABI81401位置275,ABI81400位置275,ABI81399位置275,ABI81398位置275,ABI81397位置275,ABI81396位 置275,ABI81395位置275,ABI81394位置275,ABI81393位置275,ABI81392位置275,ABI81391位置275,ABI81390位置275,ABI81389位 置275,ABI81388位置275,ABI81387位置275,ABI81386位置275,ABI81385位置275,ABI81384位置275,ABI81383位置275,ABI81382位 置275,ABI81381位置275,ABI81380位置275,ABI81379位置275,ABI81378位置275,ABI81377位置275,ABI81376位置275,ABI81375位 置275,ABI81374位置275,ABI81373位置275,ABI81372位置275,ABI81371位置275,ABI81370位置275,ABI81369位置275,ABI81368位 置275,ABI81367位置275,ABI81366位置275,ABI81365位置275,ABI81364位置275,ABI81363位置275,ABI81362位置275,ABI81361位 置275,ABI81360位置275,ABI81359位置275,ABI81358位置275,ABI81357位置275,ABI81356位置275,ABI81355位置275,ABI81354位 置275,ABI81353位置275,ABI81351位置275,ABI81350位置275,ABI81349位置275,ABI81348位置275,ABI81347位置275,ABI81346位 置275,ABI81345位置275,ABI81344位置275,ABI81343位置275,ABI81342位置275,ABI81341位置275,ABI81340位置275,ABI81339位 置275,ABI81338位置275,ABI81337位置275,ABI81336位置275,ABI81335位置275,ABI81334位置275,ABI81333位置275,ABI81332位 置275,ABI81331位置275,ABI81330位置275,ABI81329位置275,ABI81328位置275,ABI81327位置275,ABI81326位置275,ABI81325位 置275,ABI81324位置275,ABI81323位置275,ABI81322位置275,ABI81321位置275,ABI81320位置275,ABI81319位置275,ABI81318位 置275,ABI81317位置275,ABI81316位置275,ABI81315位置275,ABI81314位置275,ABI81313位置275,ABI81312位置275,ABI81311位 置275,ABI81310位置275,ABI81309位置275,ABI81308位置275,ABI81307位置275,ABI81306位置275,ABI81305位置275,ABI81304位 置275,ABI81303位置275,ABI81302位置275,ABI81301位置275,ABI81300位置275,ABI81299位置275,ABI81298位置275,ABI81297位 置275,ABI81296位置275,ABI81295位置275,ABI81294位置275,ABI81293位置275,ABI81292位置275,ABI81291位置275,ABI81290位 置275,ABI81289位置275,ABI81288位置275,ABI81287位置275,ABI81286位置275,ABI81285位置275,ABI81284位置275,ABI81283位 置275,ABI81282位置275,ABI81281位置275,ABI81280位置275,ABI81279位置275,ABI81278位置275,ABI81277位置275,ABI81276位 置275,ABI81275位置275,ABI81274位置275,ABI81273位置275,ABI81272位置275,ABI81271位置275,ABI81270位置275,ABI81269位 置275,ABI81268位置275,ABI81267位置275,ABI81266位置275,ABI81265位置275,ABI81264位置275,ABI81263位置275,ABI81262位 置275,ABI81261位置275,ABI81260位置275,ABI81259位置275,ABI81258位置275,ABI81257位置275,ABI81256位置275,ABI81255位 置275,ABI81254位置275,ABI81253位置275,ABI81252位置275,ABI81251位置275,ABI81250位置275,ABI81249位置275,ABI81248位 置275,ABI81247位置275,ABI81246位置275,ABI81245位置275,ABI81244位置275,ABI81243位置275,ABI81242位置275,ABI81241位 置275,ABI81240位置275,ABI81239位置275,ABI81238位置275,ABI81237位置275,ABI81236位置275,ABI81235位置275,ABI81234位 置275,ABI81233位置275,ABI81232位置275,ABI81231位置275,ABI81230位置275,ABI81229位置275,ABI81228位置275,ABJ90133位 置309,ABJ90132位置309,ABJ90131位置309,ABJ90130位置309,ABJ90129位置309,ABJ90128位置309,ABJ90127位置309,ABJ90126位 置309,ABJ90125位置309,ABJ90124位置309,ABJ90123位置309,ABJ90122位置309,ABJ90121位置309,ABJ90120位置309,ABJ90119位 置309,ABJ90118位置309,ABJ90117位置309,ABJ90116位置309,ABJ90115位置309,ABJ90114位置309,ABJ90113位置309,ABJ90112位 置309,ABJ90111位置309,ABJ90110位置309,ABJ90109位置309,ABJ90108位置309,ABJ90107位置309,ABJ90106位置309,ABJ90105位 置309,ABJ90104位置309,ABJ90103位置309,ABJ90102位置309,ABJ90101位置309,ABJ90100位置309,ABJ90099位置309,ABJ90098位 置309,ABJ90097位置309,ABJ90096位置309,ABJ90095位置309,ABJ90094位置309,ABJ90093位置309,ABJ90092位置309,ABJ90091位 置309,ABJ90090位置309,ABJ90088位置309,ABJ90087位置309,ABJ90086位置309,ABJ90085位置309,ABJ90084位置309,ABJ90083位 置309,ABJ90082位置309,ABJ90081位置309,ABJ90080位置309,ABJ90079位置309,ABJ90078位置309,ABJ90077位置309,ABJ90076位 置309,ABJ90075位置309,ABJ90074位置309,ABJ90073位置309,ABJ90072位置309,ABJ90071位置309,ABJ90070位置309,ABJ90069位 置309,ABJ90068位置309,ABJ90067位置309,ABJ90066位置309,CAL49454位置575,ABI97486位置575,ABG36517位置452,ABG81344 位置575,ABG81343位置575,ABG81342位置575,ABG81341位置575,ABG81340位置575,ABG76816位置575,ABG76815位置575,ABG76814位置575,ABG76813位置575,ABG76812位置575,ABG76811位置575,ABG76810位置575,ABG76809位置575,ABG76808位置575,ABG76807位置575,ABG76806位置575,ABG76805位置575,ABG76804位置575,ABG76803位置575,ABG76802位置575,ABG76801位置575,ABG76800位置575,ABG76799位置575,ABG76798位置575,ABG76797位置575,ABG76796位置575,ABG76795位置575,ABI26622位置575,ABI26621 位置575,ABD19642位置575,ABD19641位置575,ABD19640位置575,ABD19513位置575,ABD19512位置575,ABD19511位置575,ABD19510位置575,ABD85083位置575,ABD85082位置575,ABD85081位置575,ABD85080位置575,ABD85078位置575,ABD85077位置575,ABD85076位置575,ABD85075位置575,ABD85074位置575,ABD85073位置575,ABD85072位置575,ABD85070位置575,ABD85069位置575,ABD85068位置575,ABD85067位置575,ABD85066位置575,ABD85065位置575,ABD85064位置575,ABD67762位置575,ABD67761位置575,ABD67760位置575,ABD67759位置575,ABD67758位置575,ABD67757位置575,ABD67756位置575,CAM90885位置285,CAM90884位置285.
2007
ABR19639位置575,ABV22897位置575,ABU54838位置575,ABU52997位置575,ABQ52692位置575,ABO69610位置452,ABO69609位置452,ABO69608位置452,ABO69607位置452,ABO69606位置452,ABO69605位置452,ABO69604位置452,ABO69603位置452,ABO69602位置452,ABO69601位置452,ABO69600位置452,ABO69599位置452,ABO69598位置452,ABO69597位置452,ABO69596位置452,ABO69595位置452,ABO69594位置452,ABO69593位置452,ABO69592位置452,ABU41789位置575,CAM91200位置575.
2008
ABZ10682位置285,ABZ10681位置285,ABZ10680位置285,ABZ10679位置285,ABZ10678位置285.
按年的序列史
KLTSGHLK(SEQ ID NO.201)
所述序列按年的所有出现:
1982
ABC49717位置570.
1985
P06935位置566,AAA48498位置566.
1988
P14335位置570,BAA00176位置570.
1989
ABR19636位置570.
1993
NP_776014位置276,NP_041724位置566.
1998
AAD28624位置545,AAW81711位置570.
1999
AAD31720位置280,AAF20205位置570,AAF26360位置570,AAD28623 位置545,AAF20092位置570,AAG02040位置570,AAF18443位置570.
2000
ABR19638位置570,AAK06624位置570,AAG02039位置570,AAG02038位置570.
2001
AAM70028位置280,AAL14222位置280,AAL14221位置280,AAL14220位置280,AAL14219位置280,AAL14218位置280,AAL14217 位置280,AAL14216位置280,AAL14215位置280,AAK58104位置280,AAK58103位置280,AAK58102位置280,AAK58101位置280,AAK58100位置280,AAK58099位置280,AAK58098位置280,AAK58097位置280,AAK58096位置280,AAK52303位置280,AAK52302位置280,AAK52301位置280,AAK52300位置280,AAK62766位置280,AAK62765位置280,AAK62764位置280,AAK62763位置280,AAK62762位置280,AAK62761位置280,AAK62760位置280,AAK62759位置280,AAK62758位置280,AAK62757位置280,AAK62756位置280,AAK91592位置171,ABR19637位置570,AAM81753位置570,AAM81752位置570,AAM81751位置570,AAM81750位置570,AAM81749位置570,AAM21944位置193,AAM21941位置259.
2002AAO26579位置280,AAO26578位置280,AAN77484位置129,AAN85090位置570,AAO73303位置447,AAO73302位置447,AAO73301位置447,AAO73300位置447,AAO73299位置447,AAO73298位置447,AAO73297位置447,AAO73296位置447,AAO73295位置447,AAL87234位置570,CAD60131位置570.
2003
AAP20887位置570,AAR10793位置123,AAR10784位置123,AAR17575位置280,AAR17574位置280,AAR17573位置280,AAR17572位置280,AAR17571位置280,AAR17570位置280,AAR17569位置280,AAR17568位置280,AAR17567位置280,AAR17566位置280,AAR17565位置280,AAR17564位置280,AAR17563位置280,AAR17562位置280,AAR17561位置280,AAR17560位置280,AAR17559位置280,AAR17558位置280,AAR17557位置280,AAR17556位置280,AAR17555位置280,AAR17554位置280,AAR17553位置280,AAR17552位置280,AAR17551位置280,AAR17550位置280,AAR17549位置280,AAR17548位置280,AAR17547位置280,AAR17546位置280,AAR17545位置280,AAR17544位置280,AAR17543位置280,AAR17542位置280,AAQ87608位置189,AAQ87607位置189,AAQ87606位置53,AAR10804位置123,AAR10803位置123,AAR10802 位置123,AAR10801位置123,AAR10800位置123,AAR10799位置123,AAR10798位置123,AAR10797位置123,AAR10796位置123,AAR10795位置123,AAR10794位置123,AAR10792位置123,AAR10791位置123,AAR10790位置123,AAR10789位置123,AAR10788位置123,AAR10787位置123,AAR10786位置123,AAR10785位置123,AAR10783位置123,AAR10782位置123,AAR10781位置123,AAR10780位置123,AAX99361位置570,AAR84198位置447,AAQ55854位置570,AAR14153位置447,AAR84614位置570,AAR06948位置447,AAR06947位置447,AAR06946位置447,AAR06945位置447,AAR06944位置447,AAR06943位置447,AAR06942位置447,AAR06941位置447,AAR06940位置447,AAR06939位置447,AAR06938位置447,AAR06937位置447,AAR06936位置447,AAR06935位置447,AAR06934位置447,AAR06933位置447,AAR06932位置447,AAR06931位置447,AAQ00999位置570,AAQ00998位置570,AAP22087位置570,AAP22086位置570,AAP22089位置570.
2004
AAT11553位置280,AAT11552位置280,AAT11551位置280,AAT11550 位置280,AAT11549位置280,AAT11548位置280,AAT11547位置280,AAT11546位置280,AAT11545位置280,AAT11544位置280,AAT11543 位置280,AAT11542位置280,AAT11541位置280,AAT11540位置280,AAT11539位置280,AAT11538位置280,AAT11537位置280,AAT11536 位置280,AAT11535位置280,AAT11534位置280,AAS75296位置123,AAS75295位置123,AAS75294位置123,AAS75293位置123,AAS75292 位置123,AAS75291位置123,AAT95390位置570,AAU00153位置570,AAV54504位置570,AAT02759位置566,ABG67747位置570,ABG67746位置570,BAD34491位置570,BAD34490位置570,BAD34489位置570,BAD34488位置570,ABV82765位置570,AAZ91684位置570,AAW56064位置570,AAW56066位置570,AAW56065位置570,AAW28871位置570,AAT92099位置570,AAT92098位置570,AAV52690位置570,AAV52689位置570,AAV52688位置570,AAV52687位置570,AAV68177位置570,AAX09982位置570.
2005
YP_001527880位置280,ABC40712位置570,YP_001527877位置570,ABB01533位置570,ABA62343位置570,AAY32590位置447,AAY32589位置447,AAY55949位置570,AAZ32750位置570,AAZ32749位置570,AAZ32748位置570,AAZ32747位置570,AAZ32746 位置570,AAZ32745位置570,AAZ32744位置570,AAZ32743位置570,AAZ32742位置570,AAZ32741位置570,AAZ32740位置570,AAZ32739 位置570,AAZ32738位置570,AAZ32737位置570,AAZ32736位置570,AAZ32735位置570,AAZ32734位置570,AAZ32733位置570,AAZ32732 位置570,AAZ32731位置570,AAZ32730位置570,AAZ32729位置570,ABC49716位置566,ABA43046位置447,ABA43045位置447,ABA43044位置447,ABA43043位置447,ABA43042位置447,ABA43041位置447,ABA43040位置447,ABA43039位置447,ABA43038位置447,ABA43037位置447,ABA43036位置447,ABA43035位置447,ABA43034位置447,ABA43033位置447,ABA43032位置447,ABA43031位置447,ABA43030位置447,ABA43029位置447,ABA43028位置447,ABA43027位置447,ABA43026位置447,ABA43025位置447,ABA43024位置447,ABA43023位置447,ABA43022位置447,ABA43021位置447,ABA43020位置447,ABA43019位置447,ABA43018位置447,ABA43017位置447,ABA43016位置447,ABA43015位置447,ABA43014位置447,ABA43013位置447,ABA43012位置447,ABA43011位置447,ABA43010位置447,ABA43009位置447,ABA43008位置447,ABA43007位置447,ABA43006位置447,ABA43005位置447,ABA43004位置447,ABA43003位置447,ABA54595位置570,ABA54594位置570,ABA54593位置570,ABA54592位置570,ABA54591位置570,ABA54590位置570,ABA54589位置570,ABA54588位置570,ABA54587位置570,ABA54586位置570,ABA54585位置570,ABA54584位置570,ABA54583位置570,ABA54582位置570,ABA54581位置570,ABA54580位置570,ABA54579位置570,ABA54578位置570,ABA54577位置570,ABA54576位置570,ABA54575位置570,AAY54162位置570.
2006
ABI81406位置270,ABI81405位置270,ABI81404位置270,ABI81403位 置270,ABI81402位置270,ABI81401位置270,ABI81400位置270,ABI81399位置270,ABI81398位置270,ABI81397位置270,ABI81396位 置270,ABI81395位置270,ABI81394位置270,ABI81393位置270,ABI81392位置270,ABI81391位置270,ABI81390位置270,ABI81389位 置270,ABI81388位置270,ABI81387位置270,ABI81386位置270,ABI81385位置270,ABI81384位置270,ABI81383位置270,ABI81382位 置270,ABI81381位置270,ABI81380位置270,ABI81379位置270,ABI81378位置270,ABI81377位置270,ABI81376位置270,ABI81375位 置270,ABI81374位置270,ABI81373位置270,ABI81372位置270,ABI81371位置270,ABI81370位置270,ABI81369位置270,ABI81368位 置270,ABI81367位置270,ABI81366位置270,ABI81365位置270,ABI81364位置270,ABI81363位置270,ABI81362位置270,ABI81361位 置270,ABI81360位置270,ABI81359位置270,ABI81358位置270,ABI81357位置270,ABI81356位置270,ABI81355位置270,ABI81354位 置270,ABI81353位置270,ABI81351位置270,ABI81350位置270,ABI81349位置270,ABI81348位置270,ABI81347位置270,ABI81346位 置270,ABI81345位置270,ABI81344位置270,ABI81343位置270,ABI81342位置270,ABI81341位置270,ABI81340位置270,ABI81339位 置270,ABI81338位置270,ABI81337位置270,ABI81336位置270,ABI81335位置270,ABI81334位置270,ABI81333位置270,ABI81332位 置270,ABI81331位置270,ABI81330位置270,ABI81329位置270,ABI81328位置270,ABI81327位置270,ABI81326位置270,ABI81325位 置270,ABI81324位置270,ABI81323位置270,ABI81322位置270,ABI81321位置270,ABI81320位置270,ABI81319位置270,ABI81318位 置270,ABI81317位置270,ABI81316位置270,ABI81315位置270,ABI81314位置270,ABI81313位置270,ABI81312位置270,ABI81311位 置270,ABI81310位置270,ABI81309位置270,ABI81308位置270,ABI81307位置270,ABI81306位置270,ABI81305位置270,ABI81304位 置270,ABI81303位置270,ABI81302位置270,ABI81301位置270,ABI81300位置270,ABI81299位置270,ABI81298位置270,ABI81297位 置270,ABI81296位置270,ABI81295位置270,ABI81294位置270,ABI81293位置270,ABI81292位置270,ABI81291位置270,ABI81290位 置270,ABI81289位置270,ABI81288位置270,ABI81287位置270,ABI81286位置270,ABI81285位置270,ABI81284位置270,ABI81283位 置270,ABI81282位置270,ABI81281位置270,ABI81280位置270,ABI81279位置270,ABI81278位置270,ABI81277位置270,ABI81276位 置270,ABI81275位置270,ABI81274位置270,ABI81273位置270,ABI81272位置270,ABI81271位置270,ABI81270位置270,ABI81269位 置270,ABI81268位置270,ABI81267位置270,ABI81266位置270,ABI81265位置270,ABI81264位置270,ABI81263位置270,ABI81262位 置270,ABI81261位置270,ABI81260位置270,ABI81259位置270,ABI81258位置270,ABI81257位置270,ABI81256位置270,ABI81255位 置270,ABI81254位置270,ABI81253位置270,ABI81252位置270,ABI81251位置270,ABI81250位置270,ABI81249位置270,ABI81248位 置270,ABI81247位置270,ABI81246位置270,ABI81245位置270,ABI81244位置270,ABI81243位置270,ABI81242位置270,ABI81241位 置270,ABI81240位置270,ABI81239位置270,ABI81238位置270,ABI81237位置270,ABI81236位置270,ABI81235位置270,ABI81234位 置270,ABI81233位置270,ABI81232位置270,ABI81231位置270,ABI81230位置270,ABI81229位置270,ABI81228位置270,ABJ90133位 置304,ABJ90132位置304,ABJ90131位置304,ABJ90130位置304,ABJ90129位置304,ABJ90128位置304,ABJ90127位置304,ABJ90126位 置304,ABJ90125位置304,ABJ90124位置304,ABJ90123位置304,ABJ90122位置304,ABJ90121位置304,ABJ90120位置304,ABJ90119位 置304,ABJ90118位置304,ABJ90117位置304,ABJ90116位置304,ABJ90115位置304,ABJ90114位置304,ABJ90113位置304,ABJ90112位 置304,ABJ90111位置304,ABJ90110位置304,ABJ90109位置304,ABJ90108位置304,ABJ90107位置304,ABJ90106位置304,ABJ90105位 置304,ABJ90104位置304,ABJ90103位置304,ABJ90102位置304,ABJ90101位置304,ABJ90100位置304,ABJ90099位置304,ABJ90098位 置304,ABJ90097位置304,ABJ90096位置304,ABJ90095位置304,ABJ90094位置304,ABJ90093位置304,ABJ90092位置304,ABJ90091位 置304,ABJ90090位置304,ABJ90089位置304,ABJ90088位置304,ABJ90087位置304,ABJ90086位置304,ABJ90085位置304,ABJ90084位 置304,ABJ90083位置304,ABJ90082位置304,ABJ90081位置304,ABJ90080位置304,ABJ90079位置304,ABJ90078位置304,ABJ90077位 置304,ABJ90076位置304,ABJ90075位置304,ABJ90074位置304,ABJ90073位置304,ABJ90072位置304,ABJ90071位置304,ABJ90070位 置304,ABJ90069位置304,ABJ90068位置304,ABJ90067位置304,ABJ90066位置304,CAL49454位置570,ABI97486位置570,ABG36517 位置447,ABG81344位置570,ABG81343位置570,ABG81342位置570,ABG81341位置570,ABG81340位置570,ABG76816位置570,ABG76815位置570,ABG76814位置570,ABG76813位置570,ABG76812位置570,ABG76811位置570,ABG76810位置570,ABG76809位置570,ABG76808位置570,ABG76807位置570,ABG76806位置570,ABG76805位置570,ABG76804位置570,ABG76803位置570,ABG76802位置570,ABG76801位置570,ABG76800位置570,ABG76799位置570,ABG76798位置570,ABG76797位置570,ABG76796位置570,ABG76795位置570,ABI26622 位置570,ABI26621位置570,ABD19642位置570,ABD19641位置570,ABD19640位置570,ABD19513位置570,ABD19512位置570,ABD19511位置570,ABD19510位置570,ABD85083位置570,ABD85082位置570,ABD85081位置570,ABD85080位置570,ABD85078位置570,ABD85077位置570,ABD85076位置570,ABD85075位置570,ABD85074位置570,ABD85073位置570,ABD85072位置570,ABD85070位置570,ABD85069位置570,ABD85068位置570,ABD85067位置570,ABD85066位置570,ABD85065位置570,ABD85064位置570,ABD67762位置570,ABD67761位置570,ABD67760位置570,ABD67759位置570,ABD67758位置570,ABD67757位置570,ABD67756位置570,CAM90885位置280,CAM90884位置280.
2007
ABR19639位置570,ABV22897位置570,ABU54838位置570,ABU52997位置570,ABQ52692位置570,ABO69610位置447,ABO69609位置447,ABO69608位置447,ABO69607位置447,ABO69606位置447,ABO69605位置447,ABO69604位置447,ABO69603位置447,ABO69602位置447,ABO69601位置447,ABO69600位置447,ABO69599位置447,ABO69598位置447,ABO69597位置447,ABO69596位置447,ABO69595位置447,ABO69594位置447,ABO69593位置447,ABO69592位置447,ABU41789位置570,CAM91200位置570.
2008
ABZ10682位置280,ABZ10681位置280,ABZ10680位置280,ABZ10679位置280,ABZ10678位置280.
“最近的到达者”-在1998年出现的WNV Replikin
按年的序列史
HNDKRADPAFVCK(SEQ ID NO.202)
所述序列按年的所有出现:
1998
AAD28624位置346.
2000
AAG02039位置371.
2001
AAL87748位置346,AAL87746位置346.
2003
AAR84614位置371.
被存为文件名475764-seqlisting.txt的、创建于2008年4月23日的而且总共87000个字节的文件的序列表借此以其整体通过引用而被并入。
序列表
<110>BOGOCH,SAMUEL
BOGOCH,ELENORE S.
BOGOCH,SAMUEL WINSTON
BORSANYI,ANNE ELENORE
<120>对抗水产养殖中无脊椎动物的病原体感染的合成Replikin肽
<130>13795/475764
<140>
<141>
<150>12/010,027
<151>2008-01-18
<150>60/991,676
<151>2007-11-03
<150>11/923,559
<151>2007-10-24
<150>60/982,336
<151>2007-10-24
<150>60/982,333
<151>2007-10-24
<150>60/982,338
<151>2007-10-24
<150>60/935,816
<151>2007-08-31
<150>60/935,499
<151>2007-08-16
<150>60/954,743
<151>2007-08-08
<150>11/755,597
<151>2007-05-30
<160>203
<170>PatentIn version 3.3
<210>1
<211>10
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>1
Lys Val Gly Ser Arg Arg Tyr Lys Ser His
1 5 10
<210>2
<211>13
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>2
His Phe Ala Thr Lys Cys Phe Gly Glu Val Pro Lys Lys
1 5 10
<210>3
<211>14
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>3
Lys Ala Glu Asn Glu Phe Trp Asp Gly Val Lys Gln Ser His
1 5 10
<210>4
<211>11
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>4
Lys Gly His Arg Lys Val Pro Cys Glu Gln Lys
1 5 10
<210>5
<211>9
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>5
His Arg Lys Val Pro Cys Glu Gln Lys
1 5
<210>6
<211>11
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>6
Lys Val Pro Cys Glu Gln Lys Ile Trp Leu His
1 5 10
<210>7
<211>10
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>7
Lys Ile Trp Leu His Gln Asn Pro Gly Lys
1 5 10
<210>8
<211>12
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>8
His Gln Asn Pro Gly Lys Thr Gln Gln Asp Met Lys
1 5 10
<210>9
<211>9
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>9
Lys Gly Asn Thr Arg Val His Val Lys
1 5
<210>10
<211>10
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>10
Lys Glu His Val Glu Lys Ile Val Asp Lys
1 5 10
<210>11
<211>10
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>11
His Val Glu Lys Ile Val Asp Lys Ala Lys
1 5 10
<210>12
<211>29
<212>PRT
<213>鹅流感病毒
<400>12
Lys Lys Gly Thr Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Thr Asn Asn
1 5 10 15
Lys Gly Lys Glu Val Leu Val Leu Trp Gly Val His His
20 25
<210>13
<211>29
<212>PRT
<213>人流感病毒
<400>13
Lys Lys Gly Ser Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Val Asn Asn
1 5 10 15
Lys Gly Lys Glu Val Leu Val Leu Trp Gly Val His His
20 25
<210>14
<211>29
<212>PRT
<213>人流感病毒
<400>14
Lys Lys Glu Asn Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Val Asn Asn
1 5 10 15
Lys Gly Lys Glu Val Leu Val Leu Trp Gly Val His His
20 25
<210>15
<211>29
<212>PRT
<213>人流感病毒
<400>15
Lys Lys Gly Asp Ser Tyr Pro Lys Leu Thr Asn Ser Tyr Val Asn Asn
1 5 10 15
Lys Gly Lys Glu Val Leu Val Leu Trp Gly Val His His
20 25
<210>16
<211>29
<212>PRT
<213>人流感病毒
<400>16
Lys Lys Gly Thr Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Thr Asn Asn
1 5 10 15
Lys Gly Lys Glu Val Leu Val Leu Trp Gly Val His His
20 25
<210>17
<211>29
<212>PRT
<213>人流感病毒
<400>17
Lys Lys Gly Thr Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Thr Asn Asn
1 5 10 15
Lys Gly Lys Glu Val Leu Val Leu Trp Gly Val His His
20 25
<210>18
<211>29
<212>PRT
<213>人流感病毒
<400>18
Lys Lys Gly Asn Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Thr Asn Asn
1 5 10 15
Lys Gly Lys Glu Val Leu Val Ile Trp Gly Val His His
20 25
<210>19
<211>29
<212>PRT
<213>人流感病毒
<400>19
Lys Lys Gly Asn Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Thr Asn Asn
1 5 10 15
Lys Gly Lys Glu Val Leu Val Ile Trp Gly Val His His
20 25
<210>20
<211>29
<212>PRT
<213>人流感病毒
<400>20
Lys Lys Gly Thr Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Thr Asn Asn
1 5 10 15
Lys Gly Lys Glu Val Leu Val Leu Trp Gly Val His His
20 25
<210>21
<211>29
<212>PRT
<213>人流感病毒
<400>21
Lys Lys Gly Asn Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Thr Asn Asn
1 5 10 15
Lys Gly Lys Glu Val Leu Val Ile Trp Gly Val His His
20 25
<210>22
<211>29
<212>PRT
<213>人流感病毒
<400>22
Lys Lys Gly Thr Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Thr Asn Asn
1 5 10 15
Lys Gly Lys Glu Val Leu Val Leu Trp Gly Val His His
20 25
<210>23
<211>29
<212>PRT
<213>人流感病毒
<400>23
Lys Lys Gly Thr Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Thr Asn Asn
1 5 10 15
Lys Gly Lys Glu Val Leu Val Leu Trp Gly Val His His
20 25
<210>24
<211>29
<212>PRT
<213>人流感病毒
<400>24
Lys Lys Gly Asn Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Thr Asn Asn
1 5 10 15
Lys Gly Lys Glu Val Leu Val Ile Trp Gly Val His His
20 25
<210>25
<211>29
<212>PRT
<213>人流感病毒
<400>25
Lys Lys Gly Asn Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Thr Asn Asn
1 5 10 15
Lys Gly Lys Glu Val Leu Val Ile Trp Gly Val His His
20 25
<210>26
<211>29
<212>PRT
<213>人流感病毒
<400>26
Lys Lys Gly Asn Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Thr Asn Asn
1 5 10 15
Lys Gly Lys Glu Val Leu Val Ile Trp Gly Val His His
20 25
<210>27
<211>29
<212>PRT
<213>人流感病毒
<400>27
Lys Lys Gly Asp Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Thr Asn Asn
1 5 10 15
Lys Gly Lys Glu Val Leu Val Ile Trp Gly Val His His
20 25
<210>28
<211>29
<212>PRT
<213>人流感病毒
<400>28
Lys Lys Gly Ser Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Val Asn Asn
1 5 10 15
Lys Gly Lys Glu Val Leu Val Leu Trp Gly Val His His
20 25
<210>29
<211>29
<212>PRT
<213>人流感病毒
<400>29
Lys Lys Gly Ser Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Val Asn Asn
1 5 10 15
Lys Gly Lys Glu Val Leu Val Leu Trp Gly Val His His
20 25
<210>30
<211>29
<212>PRT
<213>人流感病毒
<400>30
Lys Lys Gly Asn Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Thr Asn Asn
1 5 10 15
Lys Gly Lys Glu Val Leu Val Ile Trp Gly Val His His
20 25
<210>31
<211>29
<212>PRT
<213>人流感病毒
<400>31
Lys Lys Gly Asn Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Thr Asn Asn
1 5 10 15
Lys Gly Lys Glu Val Leu Val Ile Trp Gly Val His His
20 25
<210>32
<211>29
<212>PRT
<213>人流感病毒
<400>32
Lys Lys Gly Asn Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Thr Asn Asn
1 5 10 15
Lys Gly Lys Glu Val Leu Val Ile Trp Gly Val His His
20 25
<210>33
<211>29
<212>PRT
<213>人流感病毒
<400>33
Lys Lys Gly Asn Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Thr Asn Asn
1 5 10 15
Lys Gly Lys Glu Val Leu Val Ile Trp Gly Val His His
20 25
<210>34
<211>29
<212>PRT
<213>人流感病毒
<400>34
Lys Lys Gly Asn Ser Tyr Pro Lys Ile Ser Lys Ser Tyr Ile Asn Asn
1 5 10 15
Lys Glu Lys Glu Val Leu Val Leu Trp Gly Ile His His
20 25
<210>35
<211>29
<212>PRT
<213>人流感病毒
<400>35
Lys Lys Gly Asn Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Ile Asn Asn
1 5 10 15
Lys Lys Lys Glu Val Leu Val Ile Trp Gly Ile His His
20 25
<210>36
<211>29
<212>PRT
<213>人流感病毒
<400>36
Lys Lys Gly Asn Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Ile Asn Asn
1 5 10 15
Lys Gly Lys Lys Val Leu Val Leu Trp Gly Ile His His
20 25
<210>37
<211>29
<212>PRT
<213>人流感病毒
<400>37
Lys Lys Gly Thr Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Thr Asn Asn
1 5 10 15
Lys Lys Lys Glu Val Leu Val Leu Trp Gly Val His His
20 25
<210>38
<211>28
<212>PRT
<213>人流感病毒
<400>38
Lys Asn Gly Leu Tyr Pro Asn Leu Ser Lys Ser Tyr Ala Asn Asn Lys
1 5 10 15
Glu Lys Glu Val Leu Val Leu Trp Gly Val His His
20 25
<210>39
<211>28
<212>PRT
<213>人流感病毒
<400>39
Lys Asn Gly Leu Tyr Pro Asn Leu Ser Lys Ser Tyr Ala Asn Asn Lys
1 5 10 15
Glu Lys Glu Val Leu Ile Leu Trp Gly Val His His
20 25
<210>40
<211>29
<212>PRT
<213>人流感病毒
<400>40
Lys Lys Gly Pro Asn Tyr Pro Val Ala Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Ser Gly Glu Gln Met Leu Ile Ile Trp Gly Val His His
20 25
<210>41
<211>29
<212>PRT
<213>人流感病毒
<400>41
Lys Lys Gly Pro Asn Tyr Pro Val Ala Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Ser Gly Glu Gln Met Leu Ile Ile Trp Gly Ile His His
20 25
<210>42
<211>29
<212>PRT
<213>人流感病毒
<400>42
Lys Lys Glu Asn Ser Tyr Pro Lys Leu Arg Lys Ser Ile Ile Ile Asn
1 5 10 15
Lys Lys Glu Val Lys Leu Val Ile Trp Gly Ile His His
20 25
<210>43
<211>19
<212>PRT
<213>人流感病毒
<400>43
Lys Ser Tyr Lys Asn Thr Arg Lys Asp Pro Ala Leu Ile Ile Trp Gly
1 5 10 15
Ile His His
<210>44
<211>29
<212>PRT
<213>人流感病毒
<400>44
Lys Lys Asn Asn Ala Tyr Pro Thr Ile Lys Arg Thr Tyr Asn Asn Thr
1 5 10 15
Asn Val Glu Asp Leu Leu Ile Leu Trp Gly Ile His His
20 25
<210>45
<211>29
<212>PRT
<213>人流感病毒
<400>45
Lys Lys Asn Asn Ala Tyr Pro Thr Ile Lys Arg Ser Tyr Ser Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile His His
20 25
<210>46
<211>29
<212>PRT
<213>人流感病毒
<400>46
Lys Lys Asn Asn Ala Tyr Pro Thr Ile Lys Arg Thr Tyr Asn Asn Thr
1 5 10 15
Asn Ile Glu Asp Leu Leu Ile Leu Trp Gly Ile His His
20 25
<210>47
<211>29
<212>PRT
<213>人流感病毒
<400>47
Lys Lys Asn Asn Ala Tyr Pro Thr Ile Lys Arg Thr Tyr Asn Asn Thr
1 5 10 15
Asn Met Glu Asp Leu Leu Ile Leu Trp Gly Ile His His
20 25
<210>48
<211>29
<212>PRT
<213>人流感病毒
<400>48
Lys Lys Gly Asn Ala Tyr Pro Thr Ile Lys Arg Thr Tyr Asn Asn Thr
1 5 10 15
Asn Val Glu Asp Leu Leu Ile Leu Trp Gly Ile His His
20 25
<210>49
<211>29
<212>PRT
<213>人流感病毒
<400>49
Lys Lys Asn Asn Thr Tyr Pro Thr Ile Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Ile Leu Trp Gly Ile His His
20 25
<210>50
<211>29
<212>PRT
<213>人流感病毒
<400>50
Lys Lys Asn Ser Ala Tyr Pro Thr Ile Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile His His
20 25
<210>51
<211>29
<212>PRT
<213>人流感病毒
<400>51
Lys Lys Asn Ser Ala Tyr Pro Thr Ile Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile His His
20 25
<210>52
<211>29
<212>PRT
<213>人流感病毒
<400>52
Lys Lys Asn Ser Ala Tyr Pro Thr Ile Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile His His
20 25
<210>53
<211>29
<212>PRT
<213>人流感病毒
<400>53
Lys Lys Asn Ser Ala Tyr Pro Thr Ile Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile His His
20 25
<210>54
<211>29
<212>PRT
<213>人流感病毒
<400>54
Lys Lys Asn Ser Ala Tyr Pro Thr Ile Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile His His
20 25
<210>55
<211>29
<212>PRT
<213>人流感病毒
<400>55
Lys Lys Asn Ser Ala Tyr Pro Thr Ile Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile His His
20 25
<210>56
<211>29
<212>PRT
<213>人流感病毒
<400>56
Lys Lys Asn Asn Ala Tyr Pro Thr Ile Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile His His
20 25
<210>57
<211>29
<212>PRT
<213>人流感病毒
<400>57
Lys Lys Asn Ser Ala Tyr Pro Thr Ile Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile His His
20 25
<210>58
<211>29
<212>PRT
<213>人流感病毒
<400>58
Lys Lys Asn Ser Thr Tyr Pro Thr Ile Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile His His
20 25
<210>59
<211>29
<212>PRT
<213>人流感病毒
<400>59
Lys Lys Asn Ser Thr Tyr Pro Thr Ile Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile His His
20 25
<210>60
<211>29
<212>PRT
<213>人流感病毒
<400>60
Lys Lys Asn Ser Thr Tyr Pro Thr Ile Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile His His
20 25
<210>61
<211>29
<212>PRT
<213>人流感病毒
<400>61
Lys Lys Asn Ser Thr Tyr Pro Thr Ile Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile His His
20 25
<210>62
<211>29
<212>PRT
<213>人流感病毒
<400>62
Lys Lys Asn Ser Thr Tyr Pro Thr Ile Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile His His
20 25
<210>63
<211>29
<212>PRT
<213>人流感病毒
<400>63
Lys Lys Asn Asn Ala Tyr Pro Thr Ile Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile His His
20 25
<210>64
<211>29
<212>PRT
<213>人流感病毒
<400>64
Lys Lys Asn Ser Thr Tyr Pro Thr Ile Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Met Trp Gly Ile His His
20 25
<210>65
<211>29
<212>PRT
<213>人流感病毒
<400>65
Lys Lys Asn Ser Ala Tyr Pro Thr Ile Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile His His
20 25
<210>66
<211>29
<212>PRT
<213>人流感病毒
<400>66
Lys Lys Asn Ser Thr Tyr Pro Thr Ile Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile His His
20 25
<210>67
<211>29
<212>PRT
<213>人流感病毒
<400>67
Lys Lys Asn Ser Thr Tyr Pro Thr Ile LysArg Ser Tyr Asn Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile His His
20 25
<210>68
<211>29
<212>PRT
<213>人流感病毒
<400>68
Lys Lys Asn Ser Thr Tyr Pro Thr Ile Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile Gln His
20 25
<210>69
<211>29
<212>PRT
<213>人流感病毒
<400>69
Lys Lys Asn Ser Ala Tyr Pro Ile Ile LysArg Ser Tyr Asn Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile His His
20 25
<210>70
<211>29
<212>PRT
<213>鹅流感病毒
<220>
<221>MOD_RES
<222>(13)..(13)
<223>任何氨基酸
<400>70
Lys Lys Asn Ser Ala Tyr Pro Thr Ile Lys Arg Ser Xaa Asn Asn Thr
1 5 10 15
Asn His Glu Asp Leu Leu Val Leu Trp Gly Ile His His
20 25
<210>71
<211>29
<212>PRT
<213>人流感病毒
<400>71
Lys Lys Asn Ser Ala Tyr Pro Thr Ile Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile His His
20 25
<210>72
<211>29
<212>PRT
<213>人流感病毒
<400>72
Lys Lys Asn Asn Ala Tyr Pro Thr Ile Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile His His
20 25
<210>73
<211>29
<212>PRT
<213>人流感病毒
<400>73
Lys Lys Asn Asn Thr Tyr Pro Thr Ile Lys Lys Ser Tyr Asn Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile His His
20 25
<210>74
<211>29
<212>PRT
<213>人流感病毒
<400>74
Lys Lys Asn Ser Thr Tyr Pro Thr Ile Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Ile Trp Gly Ile His His
20 25
<210>75
<211>5
<212>PRT
<213>人流感病毒
<400>75
Leu Val Leu Trp Gly
1 5
<210>76
<211>29
<212>PRT
<213>鹅流感病毒
<400>76
Lys Lys Gly Thr Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Thr Asn Asn
1 5 10 15
Lys Gly Lys Glu Val Leu Val Leu Trp Gly Val His His
20 25
<210>77
<211>29
<212>PRT
<213>猪流感病毒
<400>77
Lys Lys Gly Asn Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Thr Asn Asn
1 5 10 15
Lys Gly Lys Glu Val Leu Val Ile Trp Gly Val His His
20 25
<210>78
<211>29
<212>PRT
<213>虾白斑病毒
<400>78
Lys Lys Asn Val Lys Ser Ala Lys Gln Leu Pro His Leu Lys Val Leu
1 5 10 15
Lys Lys Leu Asp Val Arg Gly Ala Lys Gln Leu Pro His
20 25
<210>79
<211>28
<212>PRT
<213>虾白斑病毒
<400>79
Lys Val His Leu Asp Val Lys Gly Val Lys Gln Leu Leu His Leu Lys
1 5 10 15
Val Arg Leu Asp Val Arg Gly Ala Lys Gln Leu His
20 25
<210>80
<211>29
<212>PRT
<213>人流感病毒
<400>80
Lys Lys Glu Asn Ser Tyr Pro Lys Leu Arg Lys Ser Ile Ile Ile Asn
1 5 10 15
Lys Lys Glu Val Lys Leu Val Ile Trp Gly Ile His His
20 25
<210>81
<211>19
<212>PRT
<213>人流感病毒
<400>81
Lys Ser Tyr Lys Asn Thr Arg Lys Asp Pro Ala Leu Ile Ile Trp Gly
1 5 10 15
Ile His His
<210>82
<211>29
<212>PRT
<213>人流感病毒
<400>82
Lys Lys Gly Pro Asn Tyr Pro Val Ala Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Ser Gly Glu Gln Met Leu Ile Ile Trp Gly Val His His
20 25
<210>83
<211>29
<212>PRT
<213>人流感病毒
<400>83
Lys Lys Gly Pro Asn Tyr Pro Val Ala Lys Arg Ser Tyr Asn Asn Thr
1 5 10 15
Ser Gly Glu Gln Met Leu Ile Ile Trp Gly Ile His His
20 25
<210>84
<211>29
<212>PRT
<213>人流感病毒
<400>84
Lys Lys Asn Asn Ala Tyr Pro Thr Ile Lys Arg Thr Tyr Asn Asn Thr
1 5 10 15
Asn Val Glu Asp Leu Leu Ile Leu Trp Gly Ile His His
20 25
<210>85
<211>29
<212>PRT
<213>人流感病毒
<400>85
Lys Lys Asn Asn Ala Tyr Pro Thr Ile Lys Arg Ser Tyr Ser Asn Thr
1 5 10 15
Asn Gln Glu Asp Leu Leu Val Leu Trp Gly Ile His His
20 25
<210>86
<211>32
<212>PRT
<213>桃拉综合征病毒
<400>86
Lys Lys Val Gln Ala Asn Lys Thr Arg Val Phe Ala Ala Ser Asn Gln
1 5 10 15
Gly Leu Ala Leu Ala Leu Arg Arg Tyr Tyr Leu Ser Phe Leu Asp His
20 25 30
<210>87
<211>33
<212>PRT
<213>桃拉综合征病毒
<400>87
Lys Lys Ala Cys Arg Asn Ala Gly Tyr Lys Glu Ala Cys Leu His Glu
1 5 10 15
Leu Asp Cys Lys Ser Phe Leu Leu Ala Gln Gln Gly Arg Ala Gly Ala
20 25 30
His
<210>88
<211>17
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>88
Lys Val Gly Ser Arg Arg Tyr Lys Ser His Lys Lys Lys Lys Lys His
1 5 10 15
Lys
<210>89
<211>20
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>89
His Phe Ala Thr Lys Cys Phe Gly Glu Val Pro Lys Lys Lys Lys Lys
1 5 10 15
Lys Lys His Lys
20
<210>90
<211>21
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>90
Lys Ala Glu Asn Glu Phe Trp Asp Gly Val Lys Gln Ser His Lys Lys
1 5 10 15
Lys Lys Lys His Lys
20
<210>91
<211>18
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>91
Lys Gly His Arg Lys Val Pro Cys Glu Gln Lys Lys Lys Lys Lys Lys
1 5 10 15
His Lys
<210>92
<211>16
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>92
His Arg Lys Val Pro Cys Glu Gln Lys Lys Lys Lys Lys Lys His Lys
1 5 10 15
<210>93
<211>18
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>93
Lys Val Pro Cys Glu Gln Lys Ile Trp Leu His Lys Lys Lys Lys Lys
1 5 10 15
His Lys
<210>94
<211>17
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>94
Lys Ile Trp Leu His Gln Asn Pro Gly Lys Lys Lys Lys Lys Lys His
1 5 10 15
Lys
<210>95
<211>19
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>95
His Gln Asn Pro Gly Lys Thr Gln Gln Asp Met Lys Lys Lys Lys Lys
1 5 10 15
Lys His Lys
<210>96
<211>16
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>96
Lys Gly Asn Thr Arg Val His Val Lys Lys Lys Lys Lys Lys His Lys
1 5 10 15
<210>97
<211>17
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>97
Lys Glu His Val Glu Lys Ile Val Asp Lys Lys Lys Lys Lys Lys His
1 5 10 15
Lys
<210>98
<211>17
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>98
His Val Glu Lys Ile Val Asp Lys Ala Lys Lys Lys Lys Lys Lys His
1 5 10 15
Lys
<210>99
<211>29
<212>PRT
<213>人流感病毒
<400>99
Lys Lys Gly Ser Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Val Asn Asn
1 5 10 15
Lys Gly Lys Glu Val Leu Val Leu Trp Gly Val His His
20 25
<210>100
<211>28
<212>PRT
<213>人流感病毒
<400>100
Lys Gly Ser Ser Tyr Pro Lys Leu Ser Lys Ser Tyr Val Asn Asn Lys
1 5 10 15
Gly Lys Glu Val Leu Val Leu Trp Gly Val His His
20 25
<210>101
<211>28
<212>PRT
<213>虾白斑病毒
<400>101
Lys Val His Leu Asp Val Lys Gly Val Lys Gln Leu Leu His Leu Lys
1 5 10 15
Val Arg Leu Asp Val Arg Gly Ala Lys Gln Leu His
20 25
<210>102
<211>29
<212>PRT
<213>虾白斑病毒
<400>102
Lys Lys Asn Val Lys Ser Ala Lys Gln Leu Pro His Leu Lys Val Leu
1 5 10 15
Lys Lys Leu Asp Val Arg Gly Ala Lys Gln Leu Pro His
20 25
<210>103
<211>32
<212>PRT
<213>桃拉综合征病毒
<400>103
Lys Lys Val Gln Ala Asn Lys Thr Arg Val Phe Ala Ala Ser Asn Gln
1 5 10 15
Gly Leu Ala Leu Ala Leu Arg Arg Tyr Tyr Leu Ser Phe Leu Asp His
20 25 30
<210>104
<211>33
<212>PRT
<213>桃拉综合征病毒
<400>104
Lys Lys Ala Cys Arg Asn Ala Gly Tyr Lys Glu Ala Cys Leu His Glu
1 5 10 15
Leu Asp Cys Lys Ser Phe Leu Leu Ala Gln Gln Gly Arg Ala Gly Ala
20 25 30
His
<210>105
<211>1011
<212>PRT
<213>桃拉综合征病毒
<400>105
Met Pro Ala Asn Pro Val Glu Ile Asp Asn Phe Asp Thr Thr Thr Ser
1 5 10 15
Gly Gly Leu Ile Pro Gly Gly Ser Val Thr Asn Ser Glu Gly Ser Thr
20 25 30
Ile Leu Met Asn Asp Ile Pro Ile Thr Asn Gln Asn Val Val Leu Ser
35 40 45
Lys Asn Val Thr Asp Asn Leu Phe Glu Val Gln Asp Gln Ala Leu Ile
50 55 60
Glu Ser Leu Ser Arg Asp Val Leu Leu His Asn Asp Ser Trp Thr Ser
65 70 75 80
Ser Asp Asp Glu Ile Gly Thr Thr Met Thr Gln Glu Gln Leu Ala Thr
85 90 95
Glu Phe Asn Gln Pro His Leu Tyr Glu Ile Ser Leu Pro Asp Asp Ile
100 105 110
Val Arg Lys Ser Leu Phe Met Ser Asn Lys Leu Ala Asn Ile Ala Tyr
115 120 125
Met Arg Cys Asp Tyr Glu Val Thr Val Arg Val Gln Ala Thr Pro Phe
130 135 140
Leu Gln Gly Ala Leu Trp Leu Trp Asn Lys Met Asn Ala Lys Gln Thr
145 150 155 160
Ser Ile Ile Arg Arg Thr Leu Thr Glu His Leu Arg Ser Ile Thr Ser
165 170 175
Phe Pro Gly Ile Glu Met Asn Leu Gln Ser Glu Ala Arg Ala Ile Thr
180 185 190
Leu Ser Ile Pro Tyr Thr Ser Glu Phe Gln Val Phe Asn Pro Arg Asn
195 200 205
Val Asn Asn Leu Asn Ser Ile Arg Leu Ser Val Leu Ser Gln Leu Gln
210 215 220
Gly Pro Glu Asp Val Glu Ser Ala Ser Tyr Ser Ile Tyr Gly Arg Leu
225 230 235 240
Lys Asn Ile Lys Leu Tyr Gly His Ala Pro Ser Val Thr Ser Ser Val
245 250 255
Tyr Pro Ser Thr Gln Ser Gly Tyr Asp Asp Asp Cys Pro Ile Val His
260 265 270
Ala Gly Thr Asp Glu Asp Ser Ser Lys Gln Gly Ile Val Ser Arg Val
275 280 285
Ala Asp Thr Val Gly Ala Val Ala Asn Val Val Asp Gly Val Gly Val
290 295 300
Pro Ile Leu Ser Thr Ile Ala Lys Pro Val Ser Trp Val Ser Gly Val
305 310 315 320
Val Ser Asn Val Ala Ser Met Phe Gly Phe Ser Lys Asp Arg Asp Met
325 330 335
Thr Lys Val Asn Ala Tyr Glu Asn Leu Pro Gly Lys Gly Phe Thr His
340 345 350
Gly Val Gly Phe Asp Tyr Gly Val Pro Leu Ser Leu Phe Pro Asn Asn
355 360 365
Ala Ile Asp Pro Thr Ile Ala Val Pro Glu Gly Leu Asp Glu Met Ser
370 375 380
Ile Glu Tyr Leu Ala Gln Arg Pro Tyr Met Leu Asn Arg Tyr Thr Ile
385 390 395 400
Arg Gly Gly Asp Thr Pro Asp Val His Gly Thr Ile Val Ala Asp Ile
405 410 415
Pro Val Ser Pro Val Asn Phe Ser Leu Tyr Gly Lys Val Ile Ala Lys
420 425 430
Tyr Arg Thr Leu Phe Ala Ala Pro Val Ser Leu Ala Val Ala Met Ala
435 440 445
Asn Trp Trp Arg Gly Asn Ile Asn Leu Asn Leu Arg Phe Ala Lys Thr
450 455 460
Gln Tyr His Gln Cys Arg Leu Leu Val Gln Tyr Leu Pro Tyr Gly Ser
465 470 475 480
Gly Val Gln Pro Ile Glu Ser Ile Leu Ser Gln Ile Ile Asp Ile Ser
485 490 495
Gln Val Asp Asp Lys Gly Ile Asp Ile Ala Phe Pro Ser Val Tyr Pro
500 505 510
Asn Lys Trp Met Arg Val Tyr Asp Pro Ala Lys Val Gly Tyr Thr Ala
515 520 525
Asp Cys Ala Pro Gly Arg Ile Val Ile Ser Val Leu Asn Pro Leu Ile
530 535 540
Ser Ala Ser Thr Val Ser Pro Asn Ile Val Met Tyr Pro Trp Val His
545 550 555 560
Trp Ser Asn Leu Glu Val Ala Glu Pro Gly Thr Leu Ala Lys Ala Ala
565 570 575
Ile Gly Phe Asn Tyr Pro Ala Asp Val Pro Glu Glu Pro Thr Phe Ser
580 585 590
Val Thr Arg Ala Pro Val Ser Gly Thr Leu Phe Thr Leu Leu Gln Asp
595 600 605
Thr Lys Val Ser Leu Gly Glu Ala Asp Gly Val Phe Ser Leu Tyr Phe
610 615 620
Thr Asn Thr Thr Thr Gly Arg Arg His Arg Leu Thr Tyr Ala Gly Leu
625 630 635 640
Pro Gly Glu Leu Gly Ser Cys Glu Ile Val Lys Leu Pro Gln Gly Gln
645 650 655
Tyr Ser Ile Glu Tyr Ala Ala Thr Ser Ala Pro Thr Leu Val Leu Asp
660 665 670
Arg Pro Ile Phe Ser Glu Pro Ile Gly Pro Lys Tyr Val Val Thr Lys
675 680 685
Val Lys Asn Gly Asp Val Val Ser Ile Ser Glu Glu Thr Leu Val Thr
690 695 700
Cys Gly Ser Met Ala Ala Leu Gly Gly Ala Thr Val Ala Leu Gln Ser
705 710 715 720
Val Asp Glu Thr Ile Glu Ile Leu Lys Leu Glu Ser Asp Phe Glu Ser
725 730 735
Lys Ala Pro Val Lys Phe Thr Pro Gly Asn Tyr Thr Val Val Thr Glu
740 745 750
Ala Ser Asp Val Glu Leu Val Thr Asn Gln Asp Ile Thr Val Asn Glu
755 760 765
His Asn Pro Arg Thr His Ala Gly Ile Asp Glu Glu Pro Pro Val Lys
770 775 780
Arg Ser Val Ile Gly Arg Ile Val Arg Arg Val Ala Arg Tyr Val Pro
785 790 795 800
Asn Lys Leu Ile Arg Arg Ile Leu Arg Asp Leu Ser Gln Ser Pro Cys
805 810 815
Ile Tyr Pro Ser Thr His Ala Gly Leu Asp Tyr Ser Ser Ser Asp Thr
820 825 830
Ser Thr Met Leu Thr Thr Met Gly Glu Gln Phe Val Ser Leu Arg Met
835 840 845
Leu Thr Arg Arg Ser Ser Pro Val Asp Ile Leu Arg Gly Asp Leu Val
850 855 860
Thr Leu Pro Gly Ile Ser Phe Gly Thr Asp Asn Ser Leu Arg Gln Ser
865 870 875 880
Leu Val Asn Ile Ile Ser Tyr Met Tyr Arg Phe Thr His Gly Ser Ile
885 890 895
Ser Tyr Lys Ile Ile Pro Lys Asn Lys Gly Asp Leu Tyr Ile Thr Thr
900 905 910
Thr Ser Pro Asp Ser Ile Glu Thr Ser Thr Ser Ala Tyr Gln Phe Asp
915 920 925
Thr Asn Arg Ala Met His Tyr Ile Asn Thr Ser Leu Asn Pro Met Ala
930 935 940
Gln Ile Ser Leu Pro Tyr Tyr Ser Pro Ala Glu Asn Leu Val Ile Asp
945 950 955 960
Ser Lys Ser Phe Pro Gln Leu Ser Asp Leu Ser Ile Ser Asn Leu Glu
965 970 975
Arg Thr Glu Asn Glu Tyr Phe Val Leu Ala Ser Ala Gly Asp Asp His
980 985 990
Thr Phe Ser Gln Leu Ala Gly Cys Pro Ala Phe Thr Phe Gly Pro Ala
995 1000 1005
Glu Leu Ala
1010
<210>106
<211>21
<212>PRT
<213>桃拉综合征病毒
<400>106
His Leu Tyr Glu Ile Ser Leu Pro Asp Asp Ile Val Arg Lys Ser Leu
1 5 10 15
Phe Met Ser Asn Lys
20
<210>107
<211>21
<212>PRT
<213>桃拉综合征病毒
<400>107
Lys Asp Arg Asp Met Thr Lys Val Asn Ala Tyr Glu Asn Leu Pro Gly
1 5 10 15
Lys Gly Phe Thr His
20
<210>108
<211>15
<212>PRT
<213>桃拉综合征病毒
<400>108
Lys Val Asn Ala Tyr Glu Asn Leu Pro Gly Lys Gly Phe Thr His
1 5 10 15
<210>109
<211>46
<212>PRT
<213>桃拉综合征病毒
<400>109
Lys Leu Glu Ser Asp Phe Glu Ser Lys Ala Pro Val Lys Phe Thr Pro
1 5 10 15
Gly Asn Tyr Thr Val Val Thr Glu Ala Ser Asp Val Glu Leu Val Thr
20 25 30
Asn Gln Asp Ile Thr Val Asn Glu His Asn Pro Arg Thr His
35 40 45
<210>110
<211>41
<212>PRT
<213>桃拉综合征病毒
<400>110
Lys Leu Glu Ser Asp Phe Glu Ser Lys Ala Pro Val Lys Phe Thr Pro
1 5 10 15
Gly Asn Tyr Thr Val Val Thr Glu Ala Ser Asp Val Glu Leu Val Thr
20 25 30
Asn Gln Asp Ile Thr Val Asn Glu His
35 40
<210>111
<211>13
<212>PRT
<213>桃拉综合征病毒
<400>111
His Gly Ser Ile Ser Tyr Lys Ile Ile Pro Lys Asn Lys
1 5 10
<210>112
<211>36
<212>PRT
<213>桃拉综合征病毒
<400>112
Lys Ile Ile Pro Lys Asn Lys Gly Asp Leu Tyr Ile Thr Thr Thr Ser
1 5 10 15
Pro Asp Ser Ile Glu Thr Ser Thr Ser Ala Tyr Gln Phe Asp Thr Asn
20 25 30
Arg Ala Met His
35
<210>113
<211>2107
<212>PRT
<213>桃拉综合征病毒
<400>113
Met Ala Ser Tyr Tyr Leu Asn Ile Lys Thr His Asn Leu Arg Arg Thr
1 5 10 15
Pro Gly Ala His Arg Ala Phe Tyr Val Met Asn Asp Asp Gly Glu Asn
20 25 30
Arg Ile Tyr Ser Leu Ile Gly Thr Leu Arg Arg Ala Pro Ala Phe Lys
35 40 45
Val Gly Ser Arg Arg Tyr Lys Ser His Ile Pro Tyr Arg Arg Lys Ala
50 55 60
Thr Val Ala Glu Leu Cys Asn Gln Leu His Asp Arg Val Leu Pro Phe
65 70 75 80
Ala Asn Pro Gln Val Trp Lys Glu Val Ile Ser Glu Asn Lys Val Gln
85 90 95
Pro Asp Ser Met Leu Lys Ala Ala Phe Gly Asn Trp Glu Glu Trp Pro
100 105 110
Lys Asp Lys Val Cys Glu Glu Leu Tyr Ser Glu Cys Glu Cys Gly Tyr
115 120 125
Val Gly Thr Cys Tyr Val Ser Val Asp Trp Leu Arg Pro Gln Ala Thr
130 135 140
Lys Cys Asn Asp Cys Ile Leu Lys Met Asn Arg Asn Val Glu Tyr Pro
145 150 155 160
Tyr His Thr Ile Gly Val Ser Gly Asn Val Val Thr Asn Thr Asp Ile
165 170 175
Val Tyr Thr Gly Tyr Ala Asp Val Phe Lys Cys Glu Lys Cys Asp Leu
180 185 190
Leu Met Gly Ala Trp Ala Pro Asn Asp Ile Pro Ala Leu Thr His Asn
195 200 205
Ile Arg Ser Ser Gln Cys Val Gln Phe Lys Leu Pro Thr Glu Asn Leu
210 215 220
Ala Ala Arg Asn Tyr Val Leu Leu Cys Glu Glu Ile Glu Arg Glu Asn
225 230 235 240
Ile Pro Val Ile Phe Gln Asp Tyr Ser Glu Gly Asn Val Phe Thr Cys
245 250 255
Arg Ile Val Ser Gly Asp Leu Thr Ala Val Gly Thr Ala Ser Asn Met
260 265 270
Tyr Thr Ala Arg Asp Val Ala Ser Lys Ser Leu Leu Asp Gln Leu His
275 280 285
Asn Thr Pro Asn Val His Met His Ser Leu His Ser Leu Pro Tyr Glu
290 295 300
Asn Phe Pro Cys Glu Ala Leu Glu Phe Ala Val Glu Gln Gly Ile Ile
305 310 315 320
Pro Pro Val Thr Phe Asp Glu Val Phe Ala Asn Asp Glu Tyr Val Ile
325 330 335
Thr Ile Ser Cys Ser Leu Leu Val Val Ser Asp Val Gly Pro Thr Gln
340 345 350
Ala Val Ala Arg Glu Arg Ala Ala Lys Arg Phe Leu Lys Met Tyr Asp
355 360 365
Tyr Ser Ala Ser Tyr Pro Ser Thr His Met Phe Thr Leu Ser Thr Leu
370 375 380
Pro Gln Arg Ser Gly Glu Thr Leu Glu Leu Ala Asn Ala Thr Leu Asn
385 390 395 400
His Val Asn Asn Val Ile Asp Arg His Asp Glu Ala Ile Ser Asn Val
405 410 415
Arg Gln Asn Val Glu Val Lys Leu Thr Asp Val Ser Arg Gln Val Gly
420 425 430
Ala Met Leu Pro Lys Val Glu Thr Val Ile Asp Asp Val Ser Ser Thr
435 440 445
Leu Ser Ser Phe Arg Gly Val Leu Asp Lys Ile Ser Ala Trp Met Pro
450 455 460
Ser Ser Asn Pro Lys Ile Ile Asp Leu Ile Lys Glu Thr Phe Val Ser
465 470 475 480
Leu Phe Phe Ala Ile Leu Thr Lys Ser Leu Tyr ProIle Ile Gln Gly
485 490 495
Ile Ser Ser Tyr Ala Leu Arg Asn Asn Leu Met Ala Asn His Leu Thr
500 505 510
Ala Leu Ser Glu Trp Leu Met Thr Leu Glu Tyr Asp Ser Pro Asp Glu
515 520 525
Glu Glu Met Pro Ser Thr His Gly Phe Met Asp Asp Leu Thr Ser Arg
530 535 540
Leu Pro Gly Leu Asn Gly Ala Lys Val Gln Ala Ala Thr Ile Tyr Glu
5455 505 555 60
Ser Ile Gly Thr Gly Leu Cys Val Ala Leu Ser Gly Ile Leu Ser Phe
565 570 575
Ile Ala Val Met Cys Leu Gly Ile Thr Asp Leu Ser Ala Val Thr Phe
580 585 590
Asn Lys Leu Leu Thr Gln Ser Ser Leu Val Gly Arg Ala Leu Val Gly
595 600 605
Val Arg Ser Phe Lys Asp Val Phe Phe Gly Ile Trp Asp Tyr Val Asp
610 615 620
Asn Gln Val Cys Glu Ile Leu Tyr Gly Lys Ser Arg Lys Asn Leu Asp
625 630 635 640
Leu Leu Lys Glu Tyr Pro Ser Leu Asp Ser Leu Leu Ser Ile Phe Asn
645 650 655
Tyr Phe His Asp Thr Val Asp Ala Asn Val Leu Ile Ser Cys Asn Arg
660 665 670
Ala Ala Cys Glu Leu Leu Val Lys Ala Asp Asn Leu Tyr Gln Gly Tyr
675 680 685
Leu Asp Lys Ser Ile Thr Leu Met His Arg Glu Ile Ser Ser Arg Leu
690 695 700
Lys Glu Ala Arg Asn Ser Val Lys Asp Leu Ile Ala Lys Ala Gln Val
705 710 715 720
Tyr Leu Thr Cys Gly Asp Gly Ser Arg Val Pro Pro Val Val Val Tyr
725 730 735
Met Tyr Gly Asp Ala Gly Cys Gly Lys Thr Glu Leu Ser Met Ala Leu
740 745 750
Gln Asp His Phe Ala Thr Lys Tyr Phe Gly Glu Val Pro Lys Lys Asp
755 760 765
Val Ile Tyr Ser Arg Lys Ala Glu Asn Glu Phe Trp Asp Gly Val Lys
770 775 780
Gln Ser His Lys Ile Ile Ala Tyr Asp Asp Val Leu Gln Ile Val Asp
785 790 795 800
Ser Ala Gln Lys Pro Asn Pro Glu Leu Phe Glu Phe Ile Arg Leu Asn
805 810 815
Asn Ser Asp Pro Tyr Gln Val His Met Ser Ser Val Ser Asp Lys Ala
820 825 830
Asn Thr Phe Ile Ala Pro Ser Phe Val Phe Ala Thr Ser Asn Val Asn
835 840 845
Pro Gly Thr Tyr Val Pro Lys Ser Ile His Ser Ala Asp Ala Phe Arg
850 855 860
Arg Arg Leu Asp Leu Cys Val Tyr Val Asp Val Lys Asp Glu Phe Ala
865 870 875 880
Arg Ile Val Ala Gly Ser Lys Gly His Arg Lys Val Pro Cys Glu Gln
885 890 895
Lys Ile Trp Leu His Gln Asn Pro Gly Lys Thr Gln His Asp Met Lys
900 905 910
His Glu Ile Val Ala Gly Thr Tyr Lys Ile Thr Pro Glu Thr Ala Val
915 920 925
Tyr Glu Leu His Val Asp Thr Thr Leu Ala Gly Asp Ala Gln Ser Lys
930 935 940
Val Cys Ala Tyr Asp Gly Leu Val Ser Leu Ile Glu Gln Val Arg Arg
945 950 955 960
Leu Arg Val Ala Ala His Ser Asp Lys Val Glu Thr Asp Val Pro Val
965 970 975
Leu Pro Thr Arg Leu His Glu Leu Ser Gln Glu Thr Phe Pro Asn Thr
980 985 990
His Ala Gly Val Gly Phe Gln Phe Ala Thr Asp Trp Leu Gly Asp Phe
995 1000 1005
Asp Arg Pro Val Glu Ala Leu Ser Tyr Leu Asn Lys Thr Leu Glu
1010 1015 1020
Ala His Phe Val Ser Arg Ser Ala Asn Asp Gly Ser Met Phe Ile
1025 1030 1035
Pro Ala Ser Glu Val Ala Asp Leu Leu Cys Gln Arg His Asn Asn
1040 1045 1050
Thr Asn Leu Asn Glu Glu Leu Val Tyr Leu Thr Trp Met Thr Gln
1055 1060 1065
Ile Thr Asp Lys Glu Leu Ala Ser Ser Leu Val Tyr Phe Thr Asn
1070 1075 1080
Asn Gly Met Asp Lys Ser Ile Trp Lys Lys Ser Ala Glu Arg Ser
1085 1090 1095
Ala Gln Ala Ile Ser Gln Cys Lys Asn Ala Trp Thr Arg Ile Asn
1100 1105 1110
Asp Phe Leu Lys Asn His Trp Ile Ser Ile Ser Ala Val Ile Gly
1115 1120 1125
Ser Ala Leu Leu Ile Gly Gly Val Ser Ser Ala Val Lys Cys Ala
1130 1135 1140
Thr Lys Cys Arg Val Arg Lys Ile Leu Gln Asp Gly Gly Ser Ile
1145 1150 1155
Met Gln Leu Val Gly Val Arg Ser Cys Met Tyr Ala Cys Gln Leu
1160 1165 1170
Cys Lys Arg Ile Lys Asn Cys Asp Leu Arg Leu Arg Val Arg Asn
1175 1180 1185
Arg Ser Glu Gly Val Thr Thr Phe Val Pro Gly Asp Val Arg Arg
1190 1195 1200
Val Ala Arg His Val Ile Ser Ala Ala Asp Val Cys Glu Val Pro
1205 1210 1215
Val His His Ser Phe Ile Gln Ser Leu Cys Asp Glu Ala Phe Thr
1220 1225 1230
Val His Ser Asp Lys Glu Glu Thr Phe Ser Ile Leu Asp Phe Thr
1235 1240 1245
Pro Glu Ala Lys Gly Arg Asn Pro Pro Glu Ser Ala Val Val Glu
1250 1255 1260
Ser His Gln Asp Tyr Arg Val Lys Ala Ala Val Val Glu Ser His
1265 1270 1275
Gln Asp Phe Lys Pro Lys Asp Ala Ile Val Glu Ser Thr Ile Asp
1280 1285 1290
Thr Val Phe Thr Glu Ser His Gln Asp Val Arg Val Lys Leu His
1295 1300 1305
Pro Gln Ile Glu Ser His Gln Asp Phe Arg Ala Lys Asn Pro Ile
1310 1315 1320
Val Glu Ser Arg Lys Pro Asp Tyr Gln Val Glu Trp Thr Asp Leu
1325 1330 1335
Arg Thr Glu Ser Ser Asn Asp Arg Asn Ala Gln Asp Ile Ser Asn
1340 1345 1350
Arg Ile Leu Ser Arg Asn Phe Val Arg Leu Tyr Val Pro Gly Ser
1355 1360 1365
Ser Leu Tyr Thr His Gly Leu Phe Ala Tyr Gly Arg Met Leu Leu
1370 1375 1380
Met Pro Lys His Met Phe Asp Met Leu Asn Gly Ser Val Glu Ile
1385 1390 1395
Val Ser Ile Ala Asp Lys Gly Asn Thr Arg Val His Val Lys Ile
1400 1405 1410
Gln Ser His Lys Thr Val Thr Arg Gly Gly Tyr Glu Val Asp Ile
1415 1420 1425
Val Ile Cys Glu Met Gly Asn Ser Ile Ser Ala Arg Lys Asp Ile
1430 1435 1440
Thr Ser Tyr Phe Pro Thr Val Lys Glu Leu Pro Gly Leu Thr Gly
1445 1450 1455
Met Met Ser Ser Gly Arg Met Arg Val Phe Ser Thr Ala Lys Phe
1460 1465 1470
Lys Ala Ser Asp Ser Cys Ser Tyr Leu Met Pro Gln Asp Phe Val
1475 1480 1485
Ala Lys Tyr Ile Ala Ala Val Asp His Ile Thr Ser Lys Ser Pro
1490 1495 1500
Glu Lys Lys Ser Tyr Phe Ile Arg Gln Gly Phe Glu Ala Glu Ser
1505 1510 1515
Asp Ser Met Gln Gly Asp Cys Cys Ser Pro Tyr Val Leu Phe Asn
1520 1525 1530
Ser Ala Ser Arg Ala Lys Ile Val Gly Leu His Cys Ala Gly Phe
1535 1540 1545
Asp Gly Thr Ala Arg Val Phe Ala Gln Ile Ile Thr Gln Glu Asp
1550 1555 1560
Ile Met Ala Ala Thr Pro Thr Thr His Ala Gly Arg Val Thr Thr
1565 1570 1575
Glu Phe Pro His Thr Ser Leu Arg Asp Ser Pro Leu Pro Asn Ser
1580 1585 1590
Met Ala Ile Gly Ser Val Lys Thr Ala Pro Asn Pro Thr Lys Ser
1595 1600 1605
Glu Ile Thr Arg Ser Pro Ile His Gly Cys Phe Pro Val Arg Thr
1610 1615 1620
Ala Pro Ala Thr Leu Tyr Ser Pro Thr Glu Asn Leu Leu Ile Lys
1625 1630 1635
Asn Ala Met Lys Val Thr Lys Asn Val Glu Leu Leu Glu Glu Asp
1640 1645 1650
Leu Ile Asp Ala Cys Val His Asp Val Lys Arg Ile Leu Asn Ala
1655 1660 1665
Pro Gly Val Ser Asp Val Glu Lys Arg Val Leu Thr His Glu Glu
1670 1675 1680
Ser Ile Thr Gly Ile Glu Asn Arg Gln Tyr Met Asn Ala Leu Asn
1685 1690 1695
Arg Ser Thr Ser Ala Gly Phe Pro Tyr Ser Ser Arg Lys Ala Lys
1700 1705 1710
Gly Lys Ser Gly Lys Gln Thr Trp Leu Gly Ser Glu Glu Phe Ile
1715 1720 1725
Val Asp Asn Pro Asp Leu Lys Glu His Val Glu Lys Ile Val Asp
1730 1735 1740
Lys Ala Lys Asp Gly Ile Val Asp Val Ser Leu Gly Ile Phe Ala
1745 1750 1755
Ala Thr Leu Lys Asp Glu Arg Arg Pro Leu Glu Lys Val Gln Ala
1760 1765 1770
Asn Lys Thr Arg Val Phe Ala Ala Ser Asn Gln Gly Leu Ala Leu
1775 1780 1785
Ala Leu Arg Arg Tyr Tyr Leu Ser Phe Leu Asp His Val Met Thr
1790 1795 1800
Asn Arg Ile Asp Asn Glu Ile Gly Leu Gly Val Asn Val Tyr Ser
1805 1810 1815
Tyr Asp Trp Thr Arg Ile Val Asn Lys Leu Lys Arg Val Gly Asp
1820 1825 1830
Lys Val Ile Ala Gly Asp Phe Ser Asn Phe Asp Gly Ser Leu Asn
1835 1840 1845
Ser Gln Ile Leu Ser Arg Val Ser Glu Ile Val Thr Asp Trp Tyr
1850 1855 1860
Gly Asp Asp Ala Glu Asn Gly Leu Ile Arg His Thr Leu Leu Glu
1865 1870 1875
Tyr Leu Phe Asn Ala Thr Trp Leu Met Asn Gly Lys Val Phe Gln
1880 1885 1890
Leu Asn His Ser Gln Pro Ser Gly Asn Pro Leu Thr Thr Leu Ile
1895 1900 1905
Asn Cys Val Tyr Asn Met Ile Ile Phe Arg Tyr Val Tyr Leu Leu
1910 1915 1920
Ala Gln Arg Glu Asn Gly Phe Pro Met Thr Leu Ser Gly Phe Thr
1925 1930 1935
Thr Asn Val Ala Cys Ile Phe Tyr Gly Asp Asp Ser Leu Cys Ser
1940 1945 1950
Val Ser Asp Lys Val Ser Glu Trp Phe Asn Gln His Val Ile Thr
1955 1960 1965
Arg Leu Met Ala Ala Thr Gly His Glu Tyr Thr Asp Glu Thr Lys
1970 1975 1980
Ser Gly Ser Pro Pro Pro Tyr Arg Ser Leu Asn Glu Val Thr Phe
1985 1990 1995
Leu Lys Arg Glu Phe Val Leu Arg Asp His Phe Trp Ile Ala Pro
2000 2005 2010
Leu Ser Arg Asn Thr Ile Glu Asp Met Cys Met Trp Ser Arg Lys
2015 2020 2025
Asn Ile Asp Ala Gln Asp Ala Leu Leu Gln Thr Thr Arg Ile Ala
2030 2035 2040
Ser Phe Glu Ala Ser Leu His Glu Lys Asn Tyr Phe Leu Met Phe
2045 2050 2055
Cys Asp Val Ile Lys Lys Ala Cys Arg Asn Ala Gly Tyr Lys Glu
2060 2065 2070
Ala Cys Leu His Glu Leu Asp Cys Lys Ser Phe Leu Leu Ala Gln
2075 2080 2085
Gln Gly Arg Ala Gly Ala His Asp Ser Glu Phe Leu Ser Gln Leu
2090 2095 2100
Leu Asp Leu Asn
2105
<210>114
<211>44
<212>PRT
<213>桃拉综合征病毒
<400>114
His Arg Ala Phe Tyr Val Met Asn Asp Asp Gly Glu Asn Arg Ile Tyr
1 5 10 15
Ser Leu Ile Gly Thr Leu Arg Arg Ala Pro Ala Phe Lys Val Gly Ser
20 25 30
Arg Arg Tyr Lys Ser His Ile Pro Tyr Arg Arg Lys
35 40
<210>115
<211>10
<212>PRT
<213>桃拉综合征病毒
<400>115
Lys Val Gly Ser Arg Arg Tyr Lys Ser His
1 5 10
<210>116
<211>27
<212>PRT
<213>桃拉综合征病毒
<400>116
Lys Val Gly Ser Arg Arg Tyr Lys Ser His Ile Pro Tyr Arg Arg Lys
1 5 10 15
Ala Thr Val Ala Glu Leu Cys Asn Gln Leu His
20 25
<210>117
<211>9
<212>PRT
<213>桃拉综合征病毒
<400>117
Lys Ser His Ile Pro Tyr Arg Arg Lys
1 5
<210>118
<211>20
<212>PRT
<213>桃拉综合征病毒
<400>118
Lys Ser His Ile Pro Tyr Arg Arg Lys Ala Thr Val Ala Glu Leu Cys
1 5 10 15
Asn Gln Leu His
20
<210>119
<211>38
<212>PRT
<213>桃拉综合征病毒
<400>119
His Ile Pro Tyr Arg Arg Lys Ala Thr Val Ala Glu Leu Cys Asn Gln
1 5 10 15
Leu His Asp Arg Val Leu Pro Phe Ala Asn Pro Gln Val Trp Lys Glu
20 25 30
Val Ile Ser Glu Asn Lys
35
<210>120
<211>46
<212>PRT
<213>桃拉综合征病毒
<400>120
His Ile Pro Tyr Arg Arg Lys Ala Thr Val Ala Glu Leu Cys Asn Gln
1 5 10 15
Leu His Asp Arg Val Leu Pro Phe Ala Asn Pro Gln Val Trp Lys Glu
20 25 30
Val Ile Ser Glu Asn Lys Val Gln Pro Asp Ser Met Leu Lys
35 40 45
<210>121
<211>29
<212>PRT
<213>桃拉综合征病毒
<400>121
His Asp Arg Val Leu Pro Phe Ala Asn Pro Gln Val Trp Lys Glu Val
1 5 10 15
Ile Ser Glu Asn Lys Val Gln Pro Asp Ser Met Leu Lys
20 25
<210>122
<211>21
<212>PRT
<213>桃拉综合征病毒
<400>122
His Asp Arg Val Leu Pro Phe Ala Asn Pro Gln Val Trp Lys Glu Val
1 5 10 15
Ile Ser Glu Asn Lys
20
<210>123
<211>18
<212>PRT
<213>桃拉综合征病毒
<400>123
Lys Cys Asn Asp Cys Ile Leu Lys Met Asn Arg Asn Val Glu Tyr Pro
1 5 10 15
Tyr His
<210>124
<211>42
<212>PRT
<213>桃拉综合征病毒
<400>124
Lys Ile Ile Asp Leu Ile Lys Glu Thr Phe Val Ser Leu Phe Phe Ala
1 5 10 15
Ile Leu Thr Lys Ser Leu Tyr Pro Ile Ile Gln Gly Ile Ser Ser Tyr
20 25 30
Ala Leu Arg Asn Asn Leu Met Ala Asn His
35 40
<210>125
<211>26
<212>PRT
<213>桃拉综合征病毒
<400>125
Lys Ser Arg Lys Asn Leu Asp Leu Leu Lys Glu Tyr Pro Ser Leu Asp
1 5 10 15
Ser Leu Leu Ser Ile Phe Asn Tyr Phe His
20 25
<210>126
<211>23
<212>PRT
<213>桃拉综合征病毒
<400>126
Lys Asn Leu Asp Leu Leu Lys Glu Tyr Pro Ser Leu Asp Ser Leu Leu
1 5 10 15
Ser Ile Phe Asn Tyr Phe His
20
<210>127
<211>16
<212>PRT
<213>桃拉综合征病毒
<400>127
His Arg Glu Ile Ser Ser Arg Leu Lys Glu Ala Arg Asn Ser Val Lys
1 5 10 15
<210>128
<211>51
<212>PRT
<213>桃拉综合征病毒
<400>128
Lys Glu Ala Arg Asn Ser Val Lys Asp Leu Ile Ala Lys Ala Gln Val
1 5 10 15
Tyr Leu Thr Cys Gly Asp Gly Ser Arg Val Pro Pro Val Val Val Tyr
20 25 30
Met Tyr Gly Asp Ala Gly Cys Gly Lys Thr Glu Leu Ser Met Ala Leu
35 40 45
Gln Asp His
50
<210>129
<211>12
<212>PRT
<213>桃拉综合征病毒
<400>129
His Phe Ala Thr Lys Tyr Phe Gly Glu Val Pro Lys
1 5 10
<210>130
<211>13
<212>PRT
<213>桃拉综合征病毒
<400>130
His Phe Ala Thr Lys Tyr Phe Gly Glu Val Pro Lys Lys
1 5 10
<210>131
<211>20
<212>PRT
<213>桃拉综合征病毒
<400>131
His Phe Ala Thr Lys Tyr Phe Gly Glu Val Pro Lys Lys Asp Val Ile
1 5 10 15
Tyr Ser Arg Lys
20
<210>132
<211>30
<212>PRT
<213>桃拉综合征病毒
<400>132
His Phe Ala Thr Lys Tyr Phe Gly Glu Val Pro Lys Lys Asp Val Ile
1 5 10 15
Tyr Ser Arg Lys Ala Glu Asn Glu Phe Trp Asp Gly Val Lys
20 25 30
<210>133
<211>29
<212>PRT
<213>桃拉综合征病毒
<400>133
Lys Tyr Phe Gly Glu Val Pro Lys Lys Asp Val Ile Tyr Ser Arg Lys
1 5 10 15
Ala Glu Asn Glu Phe Trp As p Gly Val Lys Gln Ser His
20 25
<210>134
<211>22
<212>PRT
<213>桃拉综合征病毒
<400>134
Lys Lys Asp Val Ile Tyr Ser Arg Lys Ala Glu Asn Glu Phe Trp Asp
1 5 10 15
Gly Val Lys Gln Ser His
20
<210>135
<211>21
<212>PRT
<213>桃拉综合征病毒
<400>135
Lys Asp Val Ile Tyr Ser Arg Lys Ala Glu Asn Glu Phe Trp Asp Gly
1 5 10 15
Val Lys Gln Ser His
20
<210>136
<211>14
<212>PRT
<213>桃拉综合征病毒
<400>136
Lys Ala Glu Asn Glu Phe Trp Asp Gly Val Lys Gln Ser His
1 5 10
<210>137
<211>51
<212>PRT
<213>桃拉综合征病毒
<400>137
Lys Ala Glu Asn Glu Phe Trp Asp Gly Val Lys Gln Ser His Lys Ile
1 5 10 15
Ile Ala Tyr Asp Asp Val Leu Gln Ile Val Asp Ser Ala Gln Lys Pro
20 25 30
Asn Pro Glu Leu Phe Glu Phe Ile Arg Leu Asn Asn Ser Asp Pro Tyr
35 40 45
Gln Val His
50
<210>138
<211>49
<212>PRT
<213>桃拉综合征病毒
<400>138
His Ser Ala Asp Ala Phe Arg Arg Arg Leu Asp Leu Cys Val Tyr Val
1 5 10 15
Asp Val Lys Asp Glu Phe Ala Arg Ile Val Ala Gly Ser Lys Gly His
20 25 30
Arg Lys Val Pro Cys Glu Gln Lys Ile Trp Leu His Gln Asn Pro Gly
35 40 45
Lys
<210>139
<211>40
<212>PRT
<213>桃拉综合征病毒
<400>139
His Ser Ala Asp Ala Phe Arg Arg Arg Leu Asp Leu Cys Val Tyr Val
1 5 10 15
Asp Val Lys Asp Glu Phe Ala Arg Ile Val Ala Gly Ser Lys Gly His
20 25 30
Arg Lys Val Pro Cys Glu Gln Lys
35 40
<210>140
<211>46
<212>PRT
<213>桃拉综合征病毒
<400>140
Lys Gly His Arg Lys Val Pro Cys Glu Gln Lys Ile Trp Leu His Gln
1 5 10 15
Asn Pro Gly Lys Thr Gln His Asp Met Lys His Glu Ile Val Ala Gly
20 25 30
Thr Tyr Lys Ile Thr Pro Glu Thr Ala Val Tyr Glu Leu His
35 40 45
<210>141
<211>15
<212>PRT
<213>桃拉综合征病毒
<400>141
Lys Gly His Arg Lys Val Pro Cys Glu Gln Lys Ile Trp Leu His
1 5 10 15
<210>142
<211>11
<212>PRT
<213>桃拉综合征病毒
<400>142
Lys Gly His Arg Lys Val Pro Cys Glu Gln Lys
1 5 10
<210>143
<211>23
<212>PRT
<213>桃拉综合征病毒
<400>143
Lys Gly His Arg Lys Val Pro Cys Glu Gln Lys Ile Trp Leu His Gln
1 5 10 15
Asn Pro Gly Lys Thr Gln His
20
<210>144
<211>27
<212>PRT
<213>桃拉综合征病毒
<400>144
Lys Gly His Arg Lys Val Pro Cys Glu Gln Lys Ile Trp Leu His Gln
1 5 10 15
Asn Pro Gly Lys Thr Gln His Asp Met Lys His
20 25
<210>145
<211>33
<212>PRT
<213>桃拉综合征病毒
<400>145
His Arg Lys Val Pro Cys Glu Gln Lys Ile Trp Leu His Gln Asn Pro
1 5 10 15
Gly Lys Thr Gln His Asp Met Lys His Glu Ile Val Ala Gly Thr Tyr
20 25 30
Lys
<210>146
<211>18
<212>PRT
<213>桃拉综合征病毒
<400>146
His Arg Lys Val Pro Cys Glu Gln Lys Ile Trp Leu His Gln Asn Pro
1 5 10 15
Gly Lys
<210>147
<211>9
<212>PRT
<213>桃拉综合征病毒
<400>147
His Arg Lys Val Pro Cys Glu Gln Lys
1 5
<210>148
<211>24
<212>PRT
<213>桃拉综合征病毒
<400>148
His Arg Lys Val Pro Cys Glu Gln Lys Ile Trp Leu His Gln Asn Pro
1 5 10 15
Gly Lys Thr Gln His Asp Met Lys
20
<210>149
<211>11
<212>PRT
<213>桃拉综合征病毒
<400>149
Lys Val Pro Cys Glu Gln Lys Ile Trp Leu His
1 5 10
<210>150
<211>19
<212>PRT
<213>桃拉综合征病毒
<400>150
Lys Val Pro Cys Glu Gln Lys Ile Trp Leu His Gln Asn Pro Gly Lys
1 5 10 15
Thr Gln His
<210>151
<211>23
<212>PRT
<213>桃拉综合征病毒
<400>151
Lys Val Pro Cys Glu Gln Lys Ile Trp Leu His Gln Asn Pro Gly Lys
1 5 10 15
Thr Gln His Asp Met Lys His
20
<210>152
<211>42
<212>PRT
<213>桃拉综合征病毒
<400>152
Lys Val Pro Cys Glu Gln Lys Ile Trp Leu His Gln Asn Pro Gly Lys
1 5 10 15
Thr Gln His Asp Met Lys His Glu Ile Val Ala Gly Thr Tyr Lys Ile
20 25 30
Thr Pro Glu Thr Ala Val Tyr Glu Leu His
35 40
<210>153
<211>10
<212>PRT
<213>桃拉综合征病毒
<400>153
Lys Ile Trp Leu His Gln Asn Pro Gly Lys
1 5 10
<210>154
<211>13
<212>PRT
<213>桃拉综合征病毒
<400>154
Lys Ile Trp Leu His Gln Asn Pro Gly Lys Thr Gln His
1 5 10
<210>155
<211>17
<212>PRT
<213>桃拉综合征病毒
<400>155
Lys Ile Trp Leu His Gln Asn Pro Gly Lys Thr Gln His Asp Met Lys
1 5 10 15
His
<210>156
<211>36
<212>PRT
<213>桃拉综合征病毒
<400>156
Lys Ile Trp Leu His Gln Asn Pro Gly Lys Thr Gln His Asp Met Lys
1 5 10 15
His Glu Ile Val Ala Gly Thr Tyr Lys Ile Thr Pro Glu Thr Ala Val
20 25 30
Tyr Glu Leu His
35
<210>157
<211>12
<212>PRT
<213>桃拉综合征病毒
<400>157
His Gln Asn Pro Gly Lys Thr Gln His Asp Met Lys
1 5 10
<210>158
<211>21
<212>PRT
<213>桃拉综合征病毒
<400>158
His Gln Asn Pro Gly Lys Thr Gln His Asp Met Lys His Glu Ile Val
1 5 10 15
Ala Gly Thr Tyr Lys
20
<210>159
<211>7
<212>PRT
<213>桃拉综合征病毒
<400>159
Lys Thr Gln His Asp Met Lys
1 5
<210>160
<211>8
<212>PRT
<213>桃拉综合征病毒
<400>160
Lys Thr Gln His Asp Met Lys His
1 5
<210>161
<211>27
<212>PRT
<213>桃拉综合征病毒
<400>161
Lys Thr Gln His Asp Met Lys His Glu Ile Val Ala Gly Thr Tyr Lys
1 5 10 15
Ile Thr Pro Glu Thr Ala Val Tyr Glu Leu His
20 25
<210>162
<211>13
<212>PRT
<213>桃拉综合征病毒
<400>162
His Asp Met Lys His Glu Ile Val Ala Gly Thr Tyr Lys
1 5 10
<210>163
<211>10
<212>PRT
<213>桃拉综合征病毒
<400>163
Lys His Glu Ile Val Ala Gly Thr Tyr Lys
1 5 10
<210>164
<211>21
<212>PRT
<213>桃拉综合征病毒
<400>164
Lys His Glu Ile Val Ala Gly Thr Tyr Lys Ile Thr Pro Glu Thr Ala
1 5 10 15
Val Tyr Glu Leu His
20
<210>165
<211>32
<212>PRT
<213>桃拉综合征病毒
<400>165
His Trp Ile Ser Ile Ser Ala Val Ile Gly Ser Ala Leu Leu Ile Gly
1 5 10 15
Gly Val Ser Ser Ala Val Lys Cys Ala Thr Lys Cys Arg Val Arg Lys
20 25 30
<210>166
<211>51
<212>PRT
<213>桃拉综合征病毒
<400>166
His Gln Asp Phe Lys Pro Lys Asp Ala Ile Val Glu Ser Thr Ile Asp
1 5 10 15
Thr Val Phe Thr Glu Ser His Gln Asp Val Arg Val Lys Leu His Pro
20 25 30
Gln Ile Glu Ser His Gln Asp Phe Arg Ala Lys Asn Pro Ile Val Glu
35 40 45
Ser Arg Lys
50
<210>167
<211>29
<212>PRT
<213>桃拉综合征病毒
<400>167
His Gln Asp Val Arg Val Lys Leu His Pro Gln Ile Glu Ser His Gln
1 5 10 15
Asp Phe Arg Ala Lys Asn Pro Ile Val Glu Ser Arg Lys
20 25
<210>168
<211>21
<212>PRT
<213>桃拉综合征病毒
<400>168
His Pro Gln Ile Glu Ser His Gln Asp Phe Arg Ala Lys Asn Pro Ile
1 5 10 15
Val Glu Ser Arg Lys
20
<210>169
<211>15
<212>PRT
<213>桃拉综合征病毒
<400>169
His Gln Asp Phe Arg Ala Lys Asn Pro Ile Val Glu Ser Arg Lys
1 5 10 15
<210>170
<211>40
<212>PRT
<213>桃拉综合征病毒
<400>170
His Gly Leu Phe Ala Tyr Gly Arg Met Leu Leu Met Pro Lys His Met
1 5 10 15
Phe Asp Met Leu Asn Gly Ser Val Glu Ile Val Ser Ile Ala Asp Lys
20 25 30
Gly Asn Thr Arg Val His Val Lys
35 40
<210>171
<211>26
<212>PRT
<213>桃拉综合征病毒
<400>171
His Met Phe Asp Met Leu Asn Gly Ser Val Glu Ile Val Ser Ile Ala
1 5 10 15
Asp Lys Gly Asn Thr Arg Val His Val Lys
20 25
<210>172
<211>9
<212>PRT
<213>桃拉综合征病毒
<400>172
Lys Gly Asn Thr Arg Val His Val Lys
1 5
<210>173
<211>13
<212>PRT
<213>桃拉综合征病毒
<400>173
Lys Gly Asn Thr Arg Val His Val Lys Ile Gln Ser His
1 5 10
<210>174
<211>42
<212>PRT
<213>桃拉综合征病毒
<400>174
His Val Lys Ile Gln Ser His Lys Thr Val Thr Arg Gly Gly Tyr Glu
1 5 10 15
Val Asp Ile Val Ile Cys Glu Met Gly Asn Ser Ile Ser Ala Arg Lys
20 25 30
Asp Ile Thr Ser Tyr Phe Pro Thr Val Lys
35 40
<210>175
<211>36
<212>PRT
<213>桃拉综合征病毒
<400>175
His Lys Thr Val Thr Arg Gly Gly Tyr Glu Val Asp Ile Val Ile Cys
1 5 10 15
Glu Met Gly Asn Ser Ile Ser Ala Arg Lys Asp Ile Thr Ser Tyr Phe
20 25 30
Pro Thr Val Lys
35
<210>176
<211>26
<212>PRT
<213>桃拉综合征病毒
<400>176
His Thr Ser Leu Arg Asp Ser Pro Leu Pro Asn Ser Met Ala Ile Gly
1 5 10 15
Ser Val Lys Thr Ala Pro Asn Pro Thr Lys
20 25
<210>177
<211>17
<212>PRT
<213>桃拉综合征病毒
<400>177
Lys Thr Ala Pro Asn Pro Thr Lys Ser Glu Ile Thr Arg Ser Pro Ile
1 5 10 15
His
<210>178
<211>30
<212>PRT
<213>桃拉综合征病毒
<400>178
His Gly Cys Phe Pro Val Arg Thr Ala Pro Ala Thr Leu Tyr Ser Pro
1 5 10 15
Thr Glu Asn Leu Leu Ile Lys Asn Ala Met Lys Val Thr Lys
20 25 30
<210>179
<211>23
<212>PRT
<213>桃拉综合征病毒
<400>179
Lys Asn Ala Met Lys Val Thr Lys Asn Val Glu Leu Leu Glu Glu Asp
1 5 10 15
Leu Ile Asp Ala Cys Val His
20
<210>180
<211>44
<212>PRT
<213>桃拉综合征病毒
<400>180
Lys Asn Ala Met Lys Val Thr Lys Asn Val Glu Leu Leu Glu Glu Asp
1 5 10 15
Leu Ile Asp Ala Cys Val His Asp Val Lys Arg Ile Leu Asn Ala Pro
20 25 30
Gly Val Ser Asp Val Glu Lys Arg Val Leu Thr His
35 40
<210>181
<211>38
<212>PRT
<213>桃拉综合征病毒
<400>181
His Glu Glu Ser Ile Thr Gly Ile Glu Asn Arg Gln Tyr Met Asn Ala
1 5 10 15
Leu Asn Arg Ser Thr Ser Ala Gly Phe Pro Tyr Ser Ser Arg Lys Ala
20 25 30
Lys Gly Lys Ser Gly Lys
35
<210>182
<211>27
<212>PRT
<213>桃拉综合征病毒
<400>182
Lys Ala Lys Gly Lys Ser Gly Lys Gln Thr Trp Leu Gly Ser Glu Glu
1 5 10 15
Phe Ile Val Asp Asn Pro Asp Leu Lys Glu His
20 25
<210>183
<211>10
<212>PRT
<213>桃拉综合征病毒
<400>183
Lys Glu His Val Glu Lys Ile Val Asp Lys
1 5 10
<210>184
<211>34
<212>PRT
<213>桃拉综合征病毒
<400>184
His Val Glu Lys Ile Val Asp Lys Ala Lys Asp Gly Ile Val Asp Val
1 5 10 15
Ser Leu Gly Ile Phe Ala Ala Thr Leu Lys Asp Glu Arg Arg Pro Leu
20 25 30
Glu Lys
<210>185
<211>10
<212>PRT
<213>桃拉综合征病毒
<400>185
His Val Glu Lys Ile Val Asp Lys Ala Lys
1 5 10
<210>186
<211>39
<212>PRT
<213>桃拉综合征病毒
<400>186
Lys Asp Glu Arg Arg Pro Leu Glu Lys Val Gln Ala Asn Lys Thr Arg
1 5 10 15
Val Phe Ala Ala Ser Asn Gln Gly Leu Ala Leu Ala Leu Arg Arg Tyr
20 25 30
Tyr Leu Ser Phe Leu Asp His
35
<210>187
<211>35
<212>PRT
<213>桃拉综合征病毒
<400>187
His Val Met Thr Asn Arg Ile Asp Asn Glu Ile Gly Leu Gly Val Asn
1 5 10 15
Val Tyr Ser Tyr Asp Trp Thr Arg Ile Val Asn Lys Leu Lys Arg Val
20 25 30
Gly Asp Lys
35
<210>188
<211>48
<212>PRT
<213>桃拉综合征病毒
<400>188
Lys Leu Lys Arg Val Gly Asp Lys Val Ile Ala Gly Asp Phe Ser Asn
1 5 10 15
Phe Asp Gly Ser Leu Asn Ser Gln Ile Leu Ser Arg Val Ser Glu Ile
20 25 30
Val Thr Asp Trp Tyr Gly Asp Asp Ala Glu Asn Gly Leu Ile Arg His
35 40 45
<210>189
<211>23
<212>PRT
<213>桃拉综合征病毒
<400>189
His Glu Lys Asn Tyr Phe Leu Met Phe Cys Asp Val Ile Lys Lys Ala
1 5 10 15
Cys Arg Asn Ala Gly Tyr Lys
20
<210>190
<211>33
<212>PRT
<213>桃拉综合征病毒
<400>190
His Glu Lys Asn Tyr Phe Leu Met Phe Cys Asp Val Ile Lys Lys Ala
1 5 10 15
Cys Arg Asn Ala Gly Tyr Lys Glu Ala Cys Leu His Glu Leu Asp Cys
20 25 30
Lys
<210>191
<211>15
<212>PRT
<213>桃拉综合征病毒
<400>191
Lys Lys Ala Cys Arg Asn Ala Gly Tyr Lys Glu Ala Cys Leu His
1 5 10 15
<210>192
<211>33
<212>PRT
<213>桃拉综合征病毒
<400>192
Lys Lys Ala Cys Arg Asn Ala Gly Tyr Lys Glu Ala Cys Leu His Glu
1 5 10 15
Leu Asp Cys Lys Ser Phe Leu Leu Ala Gln Gln Gly Arg Ala Gly Ala
20 25 30
His
<210>193
<211>32
<212>PRT
<213>桃拉综合征病毒
<400>193
Lys Ala Cys Arg Asn Ala Gly Tyr Lys Glu Ala Cys Leu His Glu Leu
1 5 10 15
Asp Cys Lys Ser Phe Leu Leu Ala Gln Gln Gly Arg Ala Gly Ala His
20 25 30
<210>194
<211>14
<212>PRT
<213>桃拉综合征病毒
<400>194
Lys Ala Cys Arg Asn Ala Gly Tyr Lys Glu Ala Cys Leu His
1 5 10
<210>195
<211>11
<212>PRT
<213>桃拉综合征病毒
<400>195
Lys Glu Ala Cys Leu His Glu Leu Asp Cys Lys
1 5 10
<210>196
<211>24
<212>PRT
<213>桃拉综合征病毒
<400>196
Lys Glu Ala Cys Leu His Glu Leu Asp Cys Lys Ser Phe Leu Leu Ala
1 5 10 15
Gln Gln Gly Arg Ala Gly Ala His
20
<210>197
<211>32
<212>PRT
<213>桃拉综合征病毒
<400>197
Lys Lys Val Gln Ala Asn Lys Thr Arg Val Phe Ala Ala Ser Asn Gln
1 5 10 15
Gly Leu Ala Leu Ala Leu Arg Arg Tyr Tyr Leu Ser Phe Leu Asp His
20 25 30
<210>198
<211>33
<212>PRT
<213>桃拉综合征病毒
<400>198
Lys Lys Ala Cys Arg Asn Ala Gly Tyr Lys Glu Ala Cys Leu His Glu
1 5 10 15
Leu Asp Cys Lys Ser Phe Leu Leu Ala Gln Gln Gly Arg Ala Gly Ala
20 25 30
His
<210>199
<211>8
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>199
Lys Ile Ile Gln Lys Ala His Lys
1 5
<210>200
<211>10
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>200
His Leu Lys Cys Arg Val Lys Met Glu Lys
1 5 10
<210>201
<211>8
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>201
Lys Leu Thr Ser Gly His Leu Lys
1 5
<210>202
<211>13
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>202
His Asn Asp Lys Arg Ala Asp Pro Ala Phe Val Cys Lys
1 5 10
<210>203
<211>7
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>203
Lys Lys Lys Lys Lys His Lys
1 5
Claims (32)
1.一种用于在水产养殖中提高无脊椎动物的抵抗力的物质,其包括以下肽中每种的等重混合物,其中所述肽可以是分离的或合成的:KVGSRRYKSH(SEQ ID NO.1)、HFATKCFGEVPKK(SEQ ID NO.2)、KAENEFWDGVKQSH(SEQ ID NO.3)、KGHRKVPCEQK(SEQ ID NO.4)、HRKVPCEQK(SEQ ID NO.5)、KVPCEQKIWLH(SEQ ID NO.6)、KIWLHQNPGK(SEQ ID NO.7)、HQNPGKTQQDMK(SEQ ID NO.8)、KGNTRVHVK(SEQ ID NO.9)、KEHVEKIVDK(SEQ ID NO.10)和HVEKIVDKAK(SEQ ID NO.11)。
2.如权利要求1所述的物质,其中所述无脊椎动物是甲壳纲动物。
3.如权利要求2所述的物质,其中所述甲壳纲动物是虾。
4.如权利要求1所述的物质,其中所述肽中的每种都是合成的。
5.一种疫苗,其包括权利要求1所述的物质。
6.如权利要求5所述的疫苗,其还包括药学上可接受的载体。
7.如权利要求5所述的疫苗,其中所述疫苗提供针对甲壳纲动物中至少一种病原体的保护。
8.如权利要求5所述的疫苗,其中所述疫苗提供针对虾中至少一种病原体的保护。
9.如权利要求8所述的疫苗,其中所述病原体是病毒。
10.如权利要求9所述的疫苗,其中所述病原体是桃拉综合征病毒。
11.如权利要求8所述的疫苗,其中所述疫苗与虾饲料混合。
12.如权利要求11所述的疫苗,其中所述疫苗与每日定量的虾饲料混合。
13.如权利要求10所述的疫苗,其中将所述物质以每天每只虾的每克体重0.01mg至2mg疫苗的剂量施用于虾。
14.如权利要求13所述的疫苗,其中所述剂量是每天每只虾的每克体重0.2mg至1.0mg疫苗。
15.如权利要求14所述的疫苗,其中所述剂量是每天每只虾的每克体重0.5mg疫苗。
16.如权利要求10所述的疫苗,其中将所述疫苗作为预防性疗法在桃拉综合征病毒的症状发作前施用于虾。
17.如权利要求10所述的疫苗,其中将所述疫苗作为疗法在桃拉综合征病毒的症状发作后施用于虾。
18.如权利要求10所述的疫苗,其中将所述疫苗作为预防性疗法以亚治疗浓度施用于虾。
19.如权利要求18所述的疫苗,其中在至少一只虾的基本上全部的生命周期中施用所述疫苗。
20.权利要求1的物质在制备用于在无脊椎动物中提供对病原体的抵抗力的疫苗中的用途。
21.如权利要求20所述的用途,其中所述疫苗用于口服施用、用于通过将所述无脊椎动物浸没在含有所述疫苗的水介质中而施用或用于通过注射施用。
22.如权利要求21所述的用途,其中所述疫苗用于口服施用。
23.如权利要求20所述的用途,其中所述无脊椎动物是甲壳纲动物。
24.如权利要求23所述的用途,其中所述甲壳纲动物是虾。
25.动物饲料,其包括权利要求1的物质。
26.动物饲料,其包括虾生产Rangen35麦芽浆、1%的海藻酸钠、1%的六偏磷酸钠和权利要求1的物质。
27.如权利要求1所述的物质,其中所述无脊椎动物是蛤、贻贝、扇贝、牡蛎、其他软体动物或龙虾。
28.如权利要求5所述的疫苗,其中所述疫苗提供针对于蛤、贻贝、扇贝、牡蛎、其他软体动物或龙虾的至少一种病原体的保护。
29.如权利要求20所述的用途,其中所述无脊椎动物是蛤、贻贝、扇贝、牡蛎、其他软体动物或龙虾。
30.如权利要求1所述的物质,其中所述无脊椎动物是螯虾。
31.如权利要求5所述的疫苗,其中所述疫苗提供针对于螯虾的至少一种病原体的保护。
32.如权利要求20所述的用途,其中所述无脊椎动物是螯虾。
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US11/755,597 US20080260764A1 (en) | 2006-05-30 | 2007-05-30 | Replikin peptides and uses thereof |
US11/755,597 | 2007-05-30 | ||
US95474307P | 2007-08-08 | 2007-08-08 | |
US60/954,743 | 2007-08-08 | ||
US93549907P | 2007-08-16 | 2007-08-16 | |
US60/935,499 | 2007-08-16 | ||
US93581607P | 2007-08-31 | 2007-08-31 | |
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US98233807P | 2007-10-24 | 2007-10-24 | |
US98233607P | 2007-10-24 | 2007-10-24 | |
US98233307P | 2007-10-24 | 2007-10-24 | |
US60/982,338 | 2007-10-24 | ||
US11/923,559 US8050871B2 (en) | 2006-10-24 | 2007-10-24 | Method of predicting influenza outbreaks by correlating an increase in replikin count in shrimp white spot syndrome virus and/or taura syndrome virus |
US11/923,559 | 2007-10-24 | ||
US60/982,333 | 2007-10-24 | ||
US60/982,336 | 2007-10-24 | ||
US99167607P | 2007-11-30 | 2007-11-30 | |
US60/991,676 | 2007-11-30 | ||
US12/010,027 US20090017052A1 (en) | 2007-01-18 | 2008-01-18 | Methods of determining lethality of pathogens and malignancies involving replikin peak genes |
US12/010,027 | 2008-01-18 | ||
PCT/US2008/061336 WO2008156914A2 (en) | 2007-05-30 | 2008-04-23 | Synthetic replikin peptides against pathogenic infection of invertebrates in aquaculture |
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US (1) | US9408902B2 (zh) |
EP (2) | EP2594578A1 (zh) |
JP (1) | JP5675348B2 (zh) |
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IL (1) | IL202296A0 (zh) |
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JP2010500880A (ja) | 2006-08-14 | 2010-01-14 | マサチューセッツ・インスティテュート・オブ・テクノロジー | ヘマグルチニンポリペプチド、ならびにヘマグルチニンポリペプチドに関連する試薬および方法 |
WO2008140557A2 (en) * | 2006-10-24 | 2008-11-20 | Samuel Bogoch | A method of predicting influenza outbreaks |
WO2008143717A2 (en) * | 2007-01-18 | 2008-11-27 | Samuel Bogoch | Methods of determining lethality of pathogens and malignancies involving replikin peak genes |
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EP2594578A1 (en) | 2007-05-30 | 2013-05-22 | Samuel Bogoch | Replikin peptides directed against pathogenic infections of invertebrates in aquaculture |
-
2008
- 2008-04-23 EP EP13000747.9A patent/EP2594578A1/en not_active Withdrawn
- 2008-04-23 KR KR1020097024437A patent/KR20100006574A/ko not_active Application Discontinuation
- 2008-04-23 JP JP2010510390A patent/JP5675348B2/ja not_active Expired - Fee Related
- 2008-04-23 NZ NZ581332A patent/NZ581332A/en not_active IP Right Cessation
- 2008-04-23 MX MX2009013091A patent/MX2009013091A/es unknown
- 2008-04-23 CA CA002689181A patent/CA2689181A1/en not_active Abandoned
- 2008-04-23 WO PCT/US2008/061336 patent/WO2008156914A2/en active Application Filing
- 2008-04-23 US US12/108,458 patent/US9408902B2/en not_active Expired - Fee Related
- 2008-04-23 CN CN2008800182411A patent/CN101969993B/zh not_active Expired - Fee Related
- 2008-04-23 AU AU2008266702A patent/AU2008266702A1/en not_active Abandoned
- 2008-04-23 EP EP08825968A patent/EP2167122A2/en not_active Withdrawn
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EP2594578A1 (en) | 2013-05-22 |
JP2010528610A (ja) | 2010-08-26 |
IL202296A0 (en) | 2011-08-01 |
JP5675348B2 (ja) | 2015-02-25 |
MX2009013091A (es) | 2010-07-30 |
US9408902B2 (en) | 2016-08-09 |
WO2008156914A3 (en) | 2009-03-19 |
CN101969993A (zh) | 2011-02-09 |
CA2689181A1 (en) | 2008-12-24 |
NZ581332A (en) | 2012-06-29 |
EP2167122A2 (en) | 2010-03-31 |
US20090041795A1 (en) | 2009-02-12 |
KR20100006574A (ko) | 2010-01-19 |
AU2008266702A1 (en) | 2008-12-24 |
WO2008156914A2 (en) | 2008-12-24 |
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