CN116768983A - 一种用于慢性乙型肝炎预防和/或治疗的蛋白、编码基因、重组腺相关病毒及其应用 - Google Patents
一种用于慢性乙型肝炎预防和/或治疗的蛋白、编码基因、重组腺相关病毒及其应用 Download PDFInfo
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- C07K2319/00—Fusion polypeptide
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- C—CHEMISTRY; METALLURGY
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- C—CHEMISTRY; METALLURGY
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- C—CHEMISTRY; METALLURGY
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Abstract
本发明提供了一种用于慢性乙型肝炎预防和/或治疗的蛋白、编码基因、重组腺相关病毒及其应用。本发明的用于慢性乙型肝炎预防和/或治疗的蛋白，其氨基酸序列选自SEQ ID NO：1、SEQ ID NO：2、SEQ ID NO：3和SEQ ID NO：4所示的氨基酸序列中的一种。本发明的蛋白及其编码基因克服了机体免疫系统对HBV的免疫耐受，利用含有该编码基因的重组腺相关病毒进行免疫后，乙肝病毒载量明显下降，疫苗效力显著提高，有利于HBV治疗和/或预防性疫苗的开发及应用。
Description
技术领域
本发明涉及生物技术领域，尤其是涉及一种用于慢性乙型肝炎预防和/或治疗的蛋白、编码基因、重组腺相关病毒及其应用。
背景技术
全球约有4.5亿人感染乙型肝炎病毒(hepatitis B virus，HBV)，其中中国约有1亿。慢性乙型肝炎病毒感染是个缓慢的过程，在这个过程中可以产生至少三种抗原：乙肝表面抗原(HBsAg)、乙肝核心抗原(HBcAg)、乙肝E抗原(HBeAg)；其分别对应的抗体为：乙肝表面抗体(HBsAb)、乙肝核心抗体(HBcAb)、乙肝E抗体(HBeAb)；并产生共价互补环状双链DNA(cccDNA)，cccDNA是HBV前基因组RNA复制的原始模板，虽然含量较少，每个肝细胞内只有约5-50个拷贝，但对乙肝病毒的复制以及感染状态的建立具有十分重要的意义。在感染的中后期，有部分有前基因组RNA逆转录产生的双链HBV DNA整合到其宿主肝脏细胞的染色体DNA上，这种整合是HBV感染由量变到质变的重大事件，从此慢性乙型肝炎→肝纤维化→肝硬化→肝癌基本上是一条直线发展。
虽然预防性乙肝疫苗已经上市多年，但仍然存在如下几个问题：(1)70年代及以前出生的人很大比例没有接种疫苗；(2)目前的疫苗有效保护率只有87％，也就是还有13％的免疫人群不能产生保护效果，因此风险很大；(3)预防性疫苗对已经感染HBV的患者是无效的。抗病毒药不能根治HBV感染，且副作用大，依从性差，容易产生抗药突变。干扰素根治率也很低，但流感样等副作用让患者依从性很差。总之，慢性乙肝对人类健康危害极大，研发有效的生物制品势在必行。
鉴于此，特提出本发明。
发明内容
本发明的目的在于提供一种用于慢性乙型肝炎预防和/或治疗的蛋白、编码基因、重组腺相关病毒及其应用，该蛋白及其编码基因克服了机体免疫系统对HBV的免疫耐受，利用含有该编码基因的重组腺相关病毒进行免疫后，乙肝病毒载量明显下降，疫苗效力显著提高。
本发明还提供一种用于慢性乙型肝炎预防和/或治疗的蛋白，其氨基酸序列选自SEQ ID NO：1、SEQ ID NO：2、SEQ ID NO：3和SEQ ID NO：4所示的氨基酸序列中的一种。
具体地，从GenBank查到序列M38454、AF286594、D00630，经过生物信息学分析找出共有序列。HBsAg由226个氨基酸残基组成，其氨基酸序列如SEQ ID NO：1所示；HBcAg由143个氨基酸残基组成，其氨基酸序列如SEQ ID NO：2所示；Pol由771个氨基酸残基组成，其氨基酸序列如SEQ ID NO：3所示；ScPol由1140个氨基酸残基组成，其氨基酸序列如SEQ IDNO：4所示。
即，本发明还提供一系列优化的蛋白的氨基酸序列，其中包括：一种优化的HBsAg氨基酸序列；一种优化的HBcAg氨基酸序列；一种优化的HBV Pol氨基酸序列；一种优化的HbsAg-HBcAg-Pol氨基酸序列(顺序可以自由组合为6种)；一种优化的P1氨基酸序列；一种优化的S1氨基酸序列；一种优化的S2氨基酸序列；一种优化的S1+S2氨基酸序列；一种优化的HBsAg-HBcAg氨基酸序列；一种优化的HBcAg-HBsAg氨基酸序列等。
本发明提供一种用于慢性乙型肝炎预防和/或治疗的编码基因，其编码上述任一所述的蛋白。
具体地，本发明的用于慢性乙型肝炎预防和/或治疗的编码基因，选自核苷酸序列为SEQ ID NO：5的HBsAg编码基因、核苷酸序列为SEQ ID NO：6的HBcAg编码基因和核苷酸序列为SEQ ID NO：7的Pol编码基因中的一种。
在本发明中，HBsAg编码基因是针对人的遗传密码偏爱性全新设计的HBsAg编码基因，其核苷酸序列如SEQ ID NO：5所示；该HBsAg编码基因参考了C亚型的多个病毒株，序列充分考虑了不同病毒株的变异问题，具有广谱性。
在本发明中，HBcAg编码基因是针对人的遗传密码偏爱性全新设计的HBcAg编码基因，其核苷酸序列如SEQ ID NO：6所示；该HBcAg编码基因参考了C亚型的多个病毒株，序列充分考虑了不同病毒株的变异问题，具有广谱性。
在本发明中，Pol编码基因是针对人的遗传密码偏爱性全新设计的Pol编码基因，其核苷酸序列如SEQ ID NO：7所示；该Pol编码基因参考了C亚型的多个病毒株，序列充分考虑了不同病毒株的变异问题，具有广谱性。
进一步地，上述编码基因可以为融合基因；即，本发明还提供一种用于慢性乙型肝炎预防和/或治疗的融合基因，所述融合基因含有核苷酸序列为SEQ ID NO：5的HBsAg编码基因、核苷酸序列为SEQ ID NO：6的HBcAg编码基因和核苷酸序列为SEQ ID NO：7的Pol编码基因中的至少两种。
本发明对上述融合基因的融合方式不作严格限制，融合基因可以为HBsAg编码基因、HBcAg编码基因和Pol编码基因中的任意两者或者三者，其顺序可以自由组合。例如，融合基因可以为HBsAg-HBcAg融合基因、HBcAg-HBsAg融合基因、HBsAg-HBcAg-Pol融合基因等，其中HBsAg-HBcAg-Pol融合基因的顺序可以自由组合为6种。
在一实施方式中，融合基因可以是针对人的遗传密码偏爱性全新设计的SCPol编码基因，其核苷酸序列如SEQ ID NO：8所示；该融合基因具有广谱性信息，与单独的抗原比且包含了更多的细胞毒性T淋巴细胞(CTL)表位，因此清除病毒的能力更强、范围更广。
在另一实施方式中，融合基因还可以是针对人的遗传密码偏爱性全新设计的SCPol编码基因及旁侧序列，其核苷酸序列如SEQ ID NO：9所示。
即，本发明提供上述一系列的优化编码基因序列，其中包括：一种优化的HBsAg基因序列；一种优化的HBcAg基因序列；一种优化的HBV Pol基因序列；一种优化的HBsAg-HBcAg-Pol基因序列(顺序可以自由组合为6种)；一种优化的P1基因序列；一种优化的S1基因序列；一种优化的S2基因序列；一种优化的S1+S2基因序列；一种优化的HBsAg-HBcAg基因序列；一种优化的HBcAg-HBsAg基因序列等。
本发明还提供上述任一所述的蛋白或上述任一所述的编码基因在制备用于慢性乙型肝炎预防和/或治疗的生物制品上的应用。
本发明还提供一种重组腺相关病毒穿梭质粒，其含有上述任一所述的编码基因。
在一实施方式中，重组腺相关病毒穿梭质粒的核苷酸序列如SEQ ID NO：10所示。
本发明还提供一种重组腺相关病毒，由上述的重组腺相关病毒穿梭质粒和辅助质粒共转染工程细胞后包装而成；优选地，所述辅助质粒为pAAV-RC载体和pHelper载体；所述工程细胞为293细胞。
在本发明中，可以采用AAV2包装载体与上述任意的基因进行重组以获得重组体；例如：AAV2包装载体与HbsAg-HBcAg-Pol基因序列(顺序可以自由组合为6种)的重组体；AAV2包装载体与HbsAg-HBcAg基因序列的重组体；AAV2包装载体与HbcAg-HBsAg基因序列的重组体等。此外，还可以采用AAV其它血清型与上述任意的基因进行重组以获得重组体。
本发明还提供重组腺相关病毒在制备用于慢性乙型肝炎预防和/或治疗的疫苗上的应用。具体地，上述重组体的包装病毒体可以作为疫苗成分进行应用。
研究表明：HBsAg、HBcAg可以产生一定的细胞免疫，但目前尚没有成功的产品。腺相关病毒(adeno-associated virus，AAV)属于微小病毒科，是目前发现的一类结构最简单的单链DNA缺陷型病毒，需要辅助病毒(通常为腺病毒)参与复制，病毒直径约20nm。两侧末端有反向重复序列(ITR)，基因组编码cap和rep基因。ITRs对于病毒的复制和包装具有决定性作用。cap基因编码病毒衣壳蛋白，rep基因参与病毒的复制和整合。AAV能感染多种细胞。重组腺相关病毒载体(rAAV)源于非致病的野生型腺相关病毒，其安全性好、宿主细胞范围广(分裂和非分裂细胞)、免疫源性低，在体内表达外源基因时间长等特点，作为转移载体之一被广为重视，在世界范围内的基因治疗和疫苗研究中得到广泛应用。AAV载体疫苗，具有免疫稳定、持久、安全等特点。本发明引入AAV载体，设计研发出安全有效的HBV预防/治疗性疫苗，有望攻克乙肝难题。
本发明的编码基因及其蛋白克服了机体免疫系统对HBV的免疫耐受，利用含有该编码基因的重组腺相关病毒进行免疫后，乙肝病毒载量明显下降，疫苗效力显著提高，有利于HBV治疗和/或预防性疫苗的开发及应用。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案，下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图是本发明的一些实施方式，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为本发明实施例12免疫小鼠试验的试验结果。
具体实施方式
应该指出，以下详细说明都是例示性的，旨在对本申请提供进一步的说明。除非另有指明，本文使用的所有技术和科学术语具有与本申请所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是，这里所使用的术语仅是为了描述具体实施方式，而非意图限制根据本申请的示例性实施方式。如在这里所使用的，除非上下文另外明确指出，否则单数形式也包括复数形式，此外，还应当理解的是，当在本说明中使用术语“包含”和/或“包括”时，其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
下面将结合实施例对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1 HBsAg的氨基酸序列分析
从GenBank查到序列M38454、AF286594、D00630，经过生物信息学分析找出共有序列。
本实施例的HBsAg由226个氨基酸残基组成，其氨基酸序列如SEQ ID NO：1所示。
实施例2 HBcAg的氨基酸序列
本实施例的HBcAg由143个氨基酸残基组成，其氨基酸序列如SEQ ID NO：2所示。
实施例3 Pol的氨基酸序列
本实施例的Pol由771个氨基酸残基组成，其氨基酸序列如SEQ ID NO：3所示。
实施例4 ScPol的氨基酸序列
本实施例的ScPol由1140个氨基酸残基组成，其氨基酸序列如SEQ ID NO：4所示。
实施例5 HBsAg编码基因
本实施例针对人的遗传密码偏爱性全新设计的HBsAg编码基因，其核苷酸序列如SEQ ID NO：5所示。
实施例6 HBcAg编码基因
本实施例针对人的遗传密码偏爱性全新设计的HBcAg编码基因，其核苷酸序列如SEQ ID NO：6所示。
实施例7 Pol编码基因
本实施例针对人的遗传密码偏爱性全新设计的Pol编码基因，其核苷酸序列如SEQID NO：7所示。
实施例8 SCPol编码基因
本实施例针对人的遗传密码偏爱性全新设计的SCPol编码基因，其核苷酸序列如SEQ ID NO：8所示。
实施例9
本实施例针对人的遗传密码偏爱性全新设计的SCPol编码基因及旁侧序列，其核苷酸序列如SEQ ID NO：9所示。
根据以上核苷酸序列SEQ ID NO：9，委托北京瑞芯诺安生物科技有限公司进行合成全序列，按照常规方法克隆于PUC57载体中(pUC57SCPol)，并对其进行测序验证。
实施例10 pAAV-SCPol的构建
对质粒pUC57S1进行BsaI酶切，切胶回收4.7kb片段，溶于50μl去离子水中。对pBlueScriptII-KS+进行XhoI-SacII双酶切并切胶回收，溶于50μl去离子水中。各取5μl于同一个1.5ml的离心管中，加入2μl T4 DNA Ligase缓冲液、0.5μl T4 DNA Ligase，7.5μl去离子水，于16℃连接1h，转化DH5α感受态细胞，涂布含氨苄青霉素的LB平板，15h后挑取单克隆于含氨苄青霉素的LB液体培养基中，于37℃、200RPM培养15h，提取质粒DNA，PCR鉴定。将正确克隆送测序。选取正确的克隆命名为pKS-AAV-SCPol。全序列如下：pAAV-AAV-SCPol的最终全序列，如SEQ ID NO：10所示。
实施例11重组腺相关病毒rAAV-SCPol的制备、纯化、病毒滴度分析
1、重组腺相关病毒穿梭质粒pAAV--SCPol和辅助质粒的制备
使用质粒大量提取试剂盒Omega Plasmid Giga Kits按操作说明提取重组腺相关病毒辅助质粒pHelper、pRC及重组腺相关病毒穿梭质粒pAAV-SCPol。
2、重组腺相关病毒的包装制备
转染传代293细胞于30个T175培养瓶中，根据Quickshuttle试剂盒操作说明进行转染：pHelper、pRC及重组腺相关病毒穿梭质粒pAAV-SCPol各30μg混匀加到500μl无血清培养基中。取160μl转染试剂加到500μl无血清培养基中。二者混匀之后加入到含有30ml细胞培养基的每瓶细胞中，交叉混匀(DNA和转染试剂1：2的比例)，置37℃5％CO2继续培养。转染后72小时，用细胞刮将细胞刮下，1000rpm离心5min，弃上清，用4ml无菌PBS重悬细胞沉淀；-80℃和37℃反复冻融3次，3000rpm取上清，即为重组腺相关病毒粗制品，命名为rAAV2/1-AAV-SCPol，-80℃保存备用。
粗裂解液用10mM Tris-HCl(pH8.0)缓冲液稀释至10毫升的最终体积，然后在39毫升超速离心管中加入按照15％、25％、40％、60％质量体积比梯度加载碘克沙醇。在4℃下用40000×g离心1小时，收集4ml的40％下层组分和1ml的60％上层组分即为纯化液，用50kDa截止超滤管(Millipore)进行超滤置换为病毒保存液。重组病毒保存液为PBS磷酸缓冲液(pH值7.4)。将纯化的rAAV标记为rAAVS1，保存于-80℃冰箱。采用SYBRGreenI qPCR测定病毒滴度。
实施例12 rAAV免疫小鼠
15只4-6周龄的SPF级的HBV转基因雌性小鼠随机分为3组，每组5只，在治疗前分别取静脉血分离血清备检测。在第一周大腿肌肉注射免疫，实验组每只打100μl 1x1011vg，对照组每只打100μl PBS，HBsAg对照组模拟市售苗原液，每只打100μl(浓度100μg/ml)。免疫四周后每二周采集小鼠的静脉血，分离血清，用RT-PCR检测血清HBV DNA拷贝数，共检测3次，结果见图1。
由图1结果可以看出，免疫了rAAV-SCPol的乙肝小鼠，病毒载量明显下降，显示出治疗效果。而PBS对照组和HBsAg市售苗模拟组病毒载量上升，没有治疗效果。
最后应说明的是：以上各实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述各实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
序列表
<110> 王立良
<120> 一种用于慢性乙型肝炎预防和/或治疗的蛋白、编码基因、重组腺相关病毒及其应用
<160> 10
<170> SIPOSequenceListing 1.0
<210> 1
<211> 226
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Met Gly Ala Thr Thr Ser Gly Pro Leu Gly Pro Leu Leu Val Leu Gly
1 5 10 15
Ala Gly Pro Pro Leu Leu Thr Ala Ile Leu Thr Ile Pro Gly Ser Leu
20 25 30
Ala Ser Thr Thr Thr Ser Leu Ala Pro Leu Gly Gly Ala Pro Thr Cys
35 40 45
Pro Gly Gly Ala Ser Gly Ser Pro Thr Ser Ala His Ser Pro Thr Ser
50 55 60
Cys Pro Pro Ile Cys Pro Gly Thr Ala Thr Met Cys Leu Ala Ala Pro
65 70 75 80
Ile Ile Pro Leu Pro Ile Leu Leu Leu Cys Leu Ile Pro Leu Leu Val
85 90 95
Leu Leu Ala Thr Gly Gly Met Leu Pro Val Cys Pro Leu Leu Pro Gly
100 105 110
Thr Ser Thr Thr Ser Thr Gly Pro Cys Leu Thr Cys Thr Ile Pro Ala
115 120 125
Gly Gly Thr Ser Met Pro Pro Ser Cys Cys Cys Thr Leu Pro Ser Ala
130 135 140
Gly Ala Cys Thr Cys Ile Pro Ile Pro Ser Ser Thr Ala Pro Ala Ala
145 150 155 160
Pro Leu Thr Gly Thr Ala Ser Val Ala Pro Ser Thr Leu Ser Leu Leu
165 170 175
Val Pro Pro Val Gly Thr Pro Val Gly Leu Ser Pro Thr Val Thr Leu
180 185 190
Ser Val Ile Thr Met Met Thr Thr Thr Gly Pro Ser Leu Thr Ala Ile
195 200 205
Leu Ser Pro Pro Leu Pro Leu Leu Pro Ile Pro Pro Cys Leu Thr Val
210 215 220
Thr Ile
225
<210> 2
<211> 143
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Met Ala Ile Ala Pro Thr Leu Gly Pro Gly Ala Ser Val Gly Leu Leu
1 5 10 15
Ser Pro Leu Pro Ser Ala Pro Pro Pro Ser Ile Ala Ala Leu Leu Ala
20 25 30
Thr Ala Ser Ala Leu Thr Ala Gly Ala Leu Gly Ser Pro Gly His Cys
35 40 45
Ser Pro His His Thr Ala Leu Ala Gly Ala Ile Leu Cys Thr Gly Gly
50 55 60
Leu Met Ala Leu Ala Thr Thr Val Gly Ser Ala Leu Gly Ala Pro Ala
65 70 75 80
Ser Ala Gly Leu Val Val Ser Thr Val Ala Val Ala Met Gly Leu Leu
85 90 95
Ile Ala Gly Leu Leu Thr Pro His Ile Ser Cys Leu Thr Pro Gly Ala
100 105 110
Gly Thr Val Leu Gly Thr Leu Val Ser Pro Gly Val Thr Ile Ala Thr
115 120 125
Pro Pro Ala Thr Ala Pro Pro Ala Ala Pro Ile Leu Ser Thr Leu
130 135 140
<210> 3
<211> 771
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Met Pro Leu Ser Thr Gly His Pro Ala Leu Leu Leu Leu Leu Ala Ala
1 5 10 15
Gly Ala Gly Pro Leu Gly Gly Gly Leu Pro Ala Leu Ala Ala Gly Gly
20 25 30
Leu Ala Ala Ala Val Ala Gly Ala Leu Ala Leu Gly Ala Leu Ala Val
35 40 45
Ser Ile Pro Thr Thr His Leu Val Gly Ala Pro Thr Gly Leu Thr Ser
50 55 60
Ser Thr Val Pro Val Pro Ala Pro Gly Thr Gly Thr Pro Ser Pro Pro
65 70 75 80
Ala Ile His Leu Gly Gly Ala Ile Ile Ala Ala Cys Gly Gly Thr Val
85 90 95
Gly Pro Leu Thr Val Ala Gly Leu Ala Ala Leu Leu Leu Ile Met Pro
100 105 110
Ala Ala Pro Thr Pro Ala Leu Thr Leu Thr Leu Pro Leu Ala Leu Gly
115 120 125
Ile Leu Pro Thr Thr Pro Gly His Ala Val Ala His Thr Pro Leu Thr
130 135 140
Ala His Thr Leu His Thr Leu Thr Leu Ala Gly Ile Leu Thr Leu Ala
145 150 155 160
Gly Thr Thr Ala Ser Ala Ser Pro Cys Gly Ser Pro Thr Ser Thr Gly
165 170 175
Gly Gly Leu Gly His Gly Ala Leu Val Pro Gly Thr Ser Thr Ala His
180 185 190
Gly Ala Gly Ser Pro Cys Ser Gly Ser Ser Gly Ile Leu Ser Ala Ser
195 200 205
Pro Val Gly Pro Cys Val Ala Ser Gly Leu Leu Gly Ser Ala Leu Gly
210 215 220
Leu Gly Pro Gly Gly Gly Ser Leu Ala Ala Gly Leu Ser Gly Ala Ser
225 230 235 240
Gly Ser Ile Ala Ala Ala Val His Pro Thr Thr Ala Ala Ser Pro Gly
245 250 255
Val Gly Pro Ser Gly Ser Gly His Ile Ala Ala Ser Ala Ser Ser Ala
260 265 270
Ser Ser Cys Leu His Gly Ser Ala Val Ala Leu Thr Ala Thr Ser His
275 280 285
Leu Ser Thr Ser Leu Ala Gly Ser Ser Ser Gly His Ala Val Gly Leu
290 295 300
His Ala Ile Pro Pro Ser Ser Ala Ala Ser Gly Ser Gly Gly Pro Ile
305 310 315 320
Pro Ser Cys Thr Thr Leu Gly Pro Ala Ala Ser Leu Pro Cys Ser Ala
325 330 335
Thr Cys Leu Thr His Ile Val Ala Leu Leu Gly Ala Thr Gly Pro Cys
340 345 350
Thr Gly His Gly Gly His Ala Ile Ala Ile Pro Ala Thr Pro Ala Ala
355 360 365
Val Thr Gly Gly Val Pro Leu Val Ala Leu Ala Pro His Ala Thr Thr
370 375 380
Gly Ser Ala Leu Val Val Ala Pro Ser Gly Pro Ser Ala Gly Ser Thr
385 390 395 400
His Val Ser Thr Pro Leu Pro Ala Val Pro Ala Leu Gly Ser Leu Thr
405 410 415
Ala Leu Leu Ser Ser Ala Leu Ser Thr Leu Ser Leu Ala Val Ser Ala
420 425 430
Ala Pro Thr His Ile Pro Leu His Pro Ala Ala Met Pro His Leu Leu
435 440 445
Val Gly Ser Ser Gly Leu Pro Ala Thr Val Ala Ala Leu Ser Ser Thr
450 455 460
Ser Ala Ala Ile Ala Thr Gly His Gly Thr Met Gly Ala Leu His Ala
465 470 475 480
Ser Cys Ser Ala Ala Leu Thr Val Ser Leu Leu Leu Leu Thr Leu Thr
485 490 495
Pro Gly Ala Leu Leu His Leu Thr Ser His Pro Ile Ile Leu Gly Pro
500 505 510
Ala Leu Ile Pro Met Gly Val Gly Leu Ser Pro Pro Leu Leu Ala Gly
515 520 525
Pro Thr Ser Ala Ile Cys Ser Val Val Ala Ala Ala Pro Pro His Cys
530 535 540
Leu Ala Pro Ser Thr Met Ala Ala Val Val Leu Gly Ala Leu Ser Val
545 550 555 560
Gly His Leu Gly Ser Leu Pro Thr Ser Ile Thr Ala Pro Leu Leu Ser
565 570 575
Leu Gly Ile His Leu Ala Pro Ala Leu Thr Leu Ala Thr Gly Thr Ser
580 585 590
Leu Ala Pro Met Gly Thr Val Ile Gly Ser Thr Gly Thr Leu Pro Gly
595 600 605
Gly His Ile Val Leu Leu Ile Leu Gly Cys Pro Ala Leu Leu Pro Val
610 615 620
Ala Ala Pro Ile Ala Thr Leu Val Cys Gly Ala Ile Val Gly Leu Leu
625 630 635 640
Gly Pro Ala Ala Pro Pro Thr Gly Cys Gly Thr Pro Ala Leu Met Pro
645 650 655
Leu Thr Ala Cys Ile Gly Ser Leu Gly Ala Pro Thr Pro Ser Pro Thr
660 665 670
Thr Leu Ala Pro Leu Cys Leu Gly Thr Leu His Leu Thr Pro Val Ala
675 680 685
Ala Gly Ala Ser Gly Leu Cys Gly Val Pro Ala Ala Ala Thr Pro Thr
690 695 700
Gly Thr Gly Leu Ala Ile Gly His Ala Ala Met Ala Gly Thr Pro Val
705 710 715 720
Ala Pro Leu Pro Ile His Thr Ala Gly Leu Leu Ala Ala Cys Pro Ala
725 730 735
Ala Ser Ala Ser Gly Ala Leu Leu Ile Gly Thr Ala Ala Ser Val Val
740 745 750
Leu Ser Ala Leu Thr Thr Ser Pro Pro Thr Leu Leu Gly Cys Ala Ala
755 760 765
Ala Thr Ile
770
<210> 4
<211> 1140
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Met Gly Ala Thr Thr Ser Gly Pro Leu Gly Pro Leu Leu Val Leu Gly
1 5 10 15
Ala Gly Pro Pro Leu Leu Thr Ala Ile Leu Thr Ile Pro Gly Ser Leu
20 25 30
Ala Ser Thr Thr Thr Ser Leu Ala Pro Leu Gly Gly Ala Pro Thr Cys
35 40 45
Pro Gly Gly Ala Ser Gly Ser Pro Thr Ser Ala His Ser Pro Thr Ser
50 55 60
Cys Pro Pro Ile Cys Pro Gly Thr Ala Thr Met Cys Leu Ala Ala Pro
65 70 75 80
Ile Ile Pro Leu Pro Ile Leu Leu Leu Cys Leu Ile Pro Leu Leu Val
85 90 95
Leu Leu Ala Thr Gly Gly Met Leu Pro Val Cys Pro Leu Leu Pro Gly
100 105 110
Thr Ser Thr Thr Ser Thr Gly Pro Cys Leu Thr Cys Thr Ile Pro Ala
115 120 125
Gly Gly Thr Ser Met Pro Pro Ser Cys Cys Cys Thr Leu Pro Ser Ala
130 135 140
Gly Ala Cys Thr Cys Ile Pro Ile Pro Ser Ser Thr Ala Pro Ala Ala
145 150 155 160
Pro Leu Thr Gly Thr Ala Ser Val Ala Pro Ser Thr Leu Ser Leu Leu
165 170 175
Val Pro Pro Val Gly Thr Pro Val Gly Leu Ser Pro Thr Val Thr Leu
180 185 190
Ser Val Ile Thr Met Met Thr Thr Thr Gly Pro Ser Leu Thr Ala Ile
195 200 205
Leu Ser Pro Pro Leu Pro Leu Leu Pro Ile Pro Pro Cys Leu Thr Val
210 215 220
Thr Ile Met Ala Ile Ala Pro Thr Leu Gly Pro Gly Ala Ser Val Gly
225 230 235 240
Leu Leu Ser Pro Leu Pro Ser Ala Pro Pro Pro Ser Ile Ala Ala Leu
245 250 255
Leu Ala Thr Ala Ser Ala Leu Thr Ala Gly Ala Leu Gly Ser Pro Gly
260 265 270
His Cys Ser Pro His His Thr Ala Leu Ala Gly Ala Ile Leu Cys Thr
275 280 285
Gly Gly Leu Met Ala Leu Ala Thr Thr Val Gly Ser Ala Leu Gly Ala
290 295 300
Pro Ala Ser Ala Gly Leu Val Val Ser Thr Val Ala Val Ala Met Gly
305 310 315 320
Leu Leu Ile Ala Gly Leu Leu Thr Pro His Ile Ser Cys Leu Thr Pro
325 330 335
Gly Ala Gly Thr Val Leu Gly Thr Leu Val Ser Pro Gly Val Thr Ile
340 345 350
Ala Thr Pro Pro Ala Thr Ala Pro Pro Ala Ala Pro Ile Leu Ser Thr
355 360 365
Leu Met Pro Leu Ser Thr Gly His Pro Ala Leu Leu Leu Leu Leu Ala
370 375 380
Ala Gly Ala Gly Pro Leu Gly Gly Gly Leu Pro Ala Leu Ala Ala Gly
385 390 395 400
Gly Leu Ala Ala Ala Val Ala Gly Ala Leu Ala Leu Gly Ala Leu Ala
405 410 415
Val Ser Ile Pro Thr Thr His Leu Val Gly Ala Pro Thr Gly Leu Thr
420 425 430
Ser Ser Thr Val Pro Val Pro Ala Pro Gly Thr Gly Thr Pro Ser Pro
435 440 445
Pro Ala Ile His Leu Gly Gly Ala Ile Ile Ala Ala Cys Gly Gly Thr
450 455 460
Val Gly Pro Leu Thr Val Ala Gly Leu Ala Ala Leu Leu Leu Ile Met
465 470 475 480
Pro Ala Ala Pro Thr Pro Ala Leu Thr Leu Thr Leu Pro Leu Ala Leu
485 490 495
Gly Ile Leu Pro Thr Thr Pro Gly His Ala Val Ala His Thr Pro Leu
500 505 510
Thr Ala His Thr Leu His Thr Leu Thr Leu Ala Gly Ile Leu Thr Leu
515 520 525
Ala Gly Thr Thr Ala Ser Ala Ser Pro Cys Gly Ser Pro Thr Ser Thr
530 535 540
Gly Gly Gly Leu Gly His Gly Ala Leu Val Pro Gly Thr Ser Thr Ala
545 550 555 560
His Gly Ala Gly Ser Pro Cys Ser Gly Ser Ser Gly Ile Leu Ser Ala
565 570 575
Ser Pro Val Gly Pro Cys Val Ala Ser Gly Leu Leu Gly Ser Ala Leu
580 585 590
Gly Leu Gly Pro Gly Gly Gly Ser Leu Ala Ala Gly Leu Ser Gly Ala
595 600 605
Ser Gly Ser Ile Ala Ala Ala Val His Pro Thr Thr Ala Ala Ser Pro
610 615 620
Gly Val Gly Pro Ser Gly Ser Gly His Ile Ala Ala Ser Ala Ser Ser
625 630 635 640
Ala Ser Ser Cys Leu His Gly Ser Ala Val Ala Leu Thr Ala Thr Ser
645 650 655
His Leu Ser Thr Ser Leu Ala Gly Ser Ser Ser Gly His Ala Val Gly
660 665 670
Leu His Ala Ile Pro Pro Ser Ser Ala Ala Ser Gly Ser Gly Gly Pro
675 680 685
Ile Pro Ser Cys Thr Thr Leu Gly Pro Ala Ala Ser Leu Pro Cys Ser
690 695 700
Ala Thr Cys Leu Thr His Ile Val Ala Leu Leu Gly Ala Thr Gly Pro
705 710 715 720
Cys Thr Gly His Gly Gly His Ala Ile Ala Ile Pro Ala Thr Pro Ala
725 730 735
Ala Val Thr Gly Gly Val Pro Leu Val Ala Leu Ala Pro His Ala Thr
740 745 750
Thr Gly Ser Ala Leu Val Val Ala Pro Ser Gly Pro Ser Ala Gly Ser
755 760 765
Thr His Val Ser Thr Pro Leu Pro Ala Val Pro Ala Leu Gly Ser Leu
770 775 780
Thr Ala Leu Leu Ser Ser Ala Leu Ser Thr Leu Ser Leu Ala Val Ser
785 790 795 800
Ala Ala Pro Thr His Ile Pro Leu His Pro Ala Ala Met Pro His Leu
805 810 815
Leu Val Gly Ser Ser Gly Leu Pro Ala Thr Val Ala Ala Leu Ser Ser
820 825 830
Thr Ser Ala Ala Ile Ala Thr Gly His Gly Thr Met Gly Ala Leu His
835 840 845
Ala Ser Cys Ser Ala Ala Leu Thr Val Ser Leu Leu Leu Leu Thr Leu
850 855 860
Thr Pro Gly Ala Leu Leu His Leu Thr Ser His Pro Ile Ile Leu Gly
865 870 875 880
Pro Ala Leu Ile Pro Met Gly Val Gly Leu Ser Pro Pro Leu Leu Ala
885 890 895
Gly Pro Thr Ser Ala Ile Cys Ser Val Val Ala Ala Ala Pro Pro His
900 905 910
Cys Leu Ala Pro Ser Thr Met Ala Ala Val Val Leu Gly Ala Leu Ser
915 920 925
Val Gly His Leu Gly Ser Leu Pro Thr Ser Ile Thr Ala Pro Leu Leu
930 935 940
Ser Leu Gly Ile His Leu Ala Pro Ala Leu Thr Leu Ala Thr Gly Thr
945 950 955 960
Ser Leu Ala Pro Met Gly Thr Val Ile Gly Ser Thr Gly Thr Leu Pro
965 970 975
Gly Gly His Ile Val Leu Leu Ile Leu Gly Cys Pro Ala Leu Leu Pro
980 985 990
Val Ala Ala Pro Ile Ala Thr Leu Val Cys Gly Ala Ile Val Gly Leu
995 1000 1005
Leu Gly Pro Ala Ala Pro Pro Thr Gly Cys Gly Thr Pro Ala Leu Met
1010 1015 1020
Pro Leu Thr Ala Cys Ile Gly Ser Leu Gly Ala Pro Thr Pro Ser Pro
1025 1030 1035 1040
Thr Thr Leu Ala Pro Leu Cys Leu Gly Thr Leu His Leu Thr Pro Val
1045 1050 1055
Ala Ala Gly Ala Ser Gly Leu Cys Gly Val Pro Ala Ala Ala Thr Pro
1060 1065 1070
Thr Gly Thr Gly Leu Ala Ile Gly His Ala Ala Met Ala Gly Thr Pro
1075 1080 1085
Val Ala Pro Leu Pro Ile His Thr Ala Gly Leu Leu Ala Ala Cys Pro
1090 1095 1100
Ala Ala Ser Ala Ser Gly Ala Leu Leu Ile Gly Thr Ala Ala Ser Val
1105 1110 1115 1120
Val Leu Ser Ala Leu Thr Thr Ser Pro Pro Thr Leu Leu Gly Cys Ala
1125 1130 1135
Ala Ala Thr Ile
1140
<210> 5
<211> 681
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 5
atggagaaca ccacctctgg attcctggga ccactgctgg tgctgcaggc tggattcttc 60
ctgctgacca gaatcctgac catcccacag tctctggact cttggtggac ctctctgaac 120
ttcctgggag gagctccaac ctgcccagga cagaactctc agtctccaac ctctaaccac 180
tctccaacct cttgcccacc aatctgccca ggatacagat ggatgtgcct gagaagattc 240
atcatcttcc tgttcatcct gctgctgtgc ctgatcttcc tgctggtgct gctggactac 300
cagggaatgc tgccagtgtg cccactgctg ccaggaacct ctaccacctc taccggacca 360
tgcaagacct gcaccatccc agctcaggga acctctatgt tcccatcttg ctgctgcacc 420
aagccatctg acggaaactg cacctgcatc ccaatcccat cttcttgggc tttcgctaga 480
ttcctgtggg agtgggcttc tgtgagattc tcttggctgt ctctgctggt gccattcgtg 540
cagtggttcg tgggactgtc tccaaccgtg tggctgtctg tgatctggat gatgtggtac 600
tggggaccat ctctgtacaa catcctgtct ccattcctgc cactgctgcc aatcttcttc 660
tgcctgtggg tgtacatctg a 681
<210> 6
<211> 432
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 6
atggacatcg acccatacaa ggagttcgga gcttctgtgg agctgctgtc tttcctgcca 60
tctgacttct tcccatctat cagggacctg ctggacaccg cttctgctct gtacagagag 120
gctctggagt ctccagagca ctgctctcca caccacaccg ctctgagaca ggctatcctg 180
tgctggggag agctgatgaa cctggctacc tgggtgggat ctaacctgga ggacccagct 240
tctagagagc tggtggtgtc ttacgtgaac gtgaacatgg gactgaagat cagacagctg 300
ctgtggttcc acatctcttg cctgaccttc ggaagagaaa ccgtgctgga gtacctggtg 360
tctttcggag tgtggatcag aaccccacca gcttacagac caccaaacgc tccaatcctg 420
tctaccctgt ga 432
<210> 7
<211> 2316
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 7
atgccactgt cttaccagca cttcagaaag ctgctgctgc tggacgacga ggctggacca 60
ctggaggagg agctgccaag actggctgac gagggactga acagaagagt ggctgaggac 120
ctgaacctgg gaaacctgaa cgtgtctatc ccatggaccc acaaggtggg aaacttcacc 180
ggactgtact cttctaccgt gccagtgttc aacccagagt ggcagacccc atctttccca 240
aacatccacc tgcaggagga catcatcaac agatgccagc agtacgtggg accactgacc 300
gtgaacgaga agagaagact gaagctgatc atgccagcta gattctaccc aaacctgacc 360
aagtacctgc cactggacaa gggaatcaag ccatactacc cagagcacgc tgtgaaccac 420
tacttcaaga ccagacacta cctgcacacc ctgtggaagg ctggaatcct gtacaagaga 480
gaaaccacca gatctgcttc tttctgcgga tctccatact cttgggagca ggagctgcag 540
cacggaagac tggtgttcca gacctctacc agacacggag acgagtcttt ctgctctcag 600
tcttctggaa tcctgtctag atctccagtg ggaccatgcg tgagatctca gctgaagcag 660
tctagactgg gactgcagcc acagcaggga tctctggcta gaggaaagtc tggaagatct 720
ggatctatca gagctagagt gcacccaacc accagaagat ctttcggagt ggagccatct 780
ggatctggac acatcgacaa ctctgcttct tctgcttctt cttgcctgca ccagtctgct 840
gtgagaaaga ccgcttactc tcacctgtct acctctaaga gacagtcttc ttctggacac 900
gctgtggagc tgcacaacat cccaccatct tctgctagat ctcagtctga gggaccaatc 960
ttctcttgct ggtggctgca gttcagaaac tctaagccat gctctgacta ctgcctgacc 1020
cacatcgtga acctgctgga ggactgggga ccatgcaccg agcacggaga gcacaacatc 1080
agaatcccaa gaaccccagc tagagtgacc ggaggagtgt tcctggtgga caagaaccca 1140
cacaacacca ccgagtctag actggtggtg gacttctctc agttctctag aggatctacc 1200
cacgtgtctt ggccaaagtt cgctgtgcca aacctgcagt ctctgaccaa cctgctgtct 1260
tctaacctgt cttggctgtc tctggacgtg tctgctgctt tctaccacat cccactgcac 1320
ccagctgcta tgccacacct gctggtggga tcttctggac tgccaagata cgtggctaga 1380
ctgtcttcta cctctagaaa catcaactac cagcacggaa ccatgcagga cctgcacgac 1440
tcttgctcta gaaacctgta cgtgtctctg ctgctgctgt acaagacctt cggaagaaag 1500
ctgcacctgt actctcaccc aatcatcctg ggattcagaa agatcccaat gggagtggga 1560
ctgtctccat tcctgctggc tcagttcacc tctgctatct gctctgtggt gagaagagct 1620
ttcccacact gcctggcttt ctcttacatg gacgacgtgg tgctgggagc taagtctgtg 1680
cagcacctgg agtctctgtt cacctctatc accaacttcc tgctgtctct gggaatccac 1740
ctgaacccaa acaagaccaa gagatgggga tactctctga acttcatggg atacgtgatc 1800
ggatcttggg gaaccctgcc acaggagcac atcgtgctga agatcaagca gtgcttcaga 1860
aagctgccag tgaacagacc aatcgactgg aaggtgtgcc agagaatcgt gggactgctg 1920
ggattcgctg ctccattcac ccagtgcgga tacccagctc tgatgccact gtacgcttgc 1980
atccagtcta agcaggcttt caccttctct ccaacctaca aggctttcct gtgcaagcag 2040
tacctgcacc tgtacccagt ggctagacag agatctggac tgtgccaggt gttcgctgac 2100
gctaccccaa ccggatgggg actggctatc ggacacagaa gaatgagagg aaccttcgtg 2160
gctccactgc caatccacac cgctgagctg ctggctgctt gcttcgctag atctagatct 2220
ggagctaagc tgatcggaac cgacaactct gtggtgctgt ctagaaagta cacctctttc 2280
ccatggctgc tgggatgcgc tgctaactgg atttga 2316
<210> 8
<211> 3467
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 8
gggggtctcg aattcgccac catatcggcc atggagaaca ccacctctgg attcctggga 60
ccactgctgg tgctgcaggc tggattcttc ctgctgacca gaatcctgac catcccacag 120
tctctggact cttggtggac ctctctgaac ttcctgggag gagctccaac ctgcccagga 180
cagaactctc agtctccaac ctctaaccac tctccaacct cttgcccacc aatctgccca 240
ggatacagat ggatgtgcct gagaagattc atcatcttcc tgttcatcct gctgctgtgc 300
ctgatcttcc tgctggtgct gctggactac cagggaatgc tgccagtgtg cccactgctg 360
ccaggaacct ctaccacctc taccggacca tgcaagacct gcaccatccc agctcaggga 420
acctctatgt tcccatcttg ctgctgcacc aagccatctg acggaaactg cacctgcatc 480
ccaatcccat cttcttgggc tttcgctaga ttcctgtggg agtgggcttc tgtgagattc 540
tcttggctgt ctctgctggt gccattcgtg cagtggttcg tgggactgtc tccaaccgtg 600
tggctgtctg tgatctggat gatgtggtac tggggaccat ctctgtacaa catcctgtct 660
ccattcctgc cactgctgcc aatcttcttc tgcctgtggg tgtacatcat ggacatcgac 720
ccatacaagg agttcggagc ttctgtggag ctgctgtctt tcctgccatc tgacttcttc 780
ccatctatca gggacctgct ggacaccgct tctgctctgt acagagaggc tctggagtct 840
ccagagcact gctctccaca ccacaccgct ctgagacagg ctatcctgtg ctggggagag 900
ctgatgaacc tggctacctg ggtgggatct aacctggagg acccagcttc tagagagctg 960
gtggtgtctt acgtgaacgt gaacatggga ctgaagatca gacagctgct gtggttccac 1020
atctcttgcc tgaccttcgg aagagaaacc gtgctggagt acctggtgtc tttcggagtg 1080
tggatcagaa ccccaccagc ttacagacca ccaaacgctc caatcctgtc taccctgatg 1140
ccactgtctt accagcactt cagaaagctg ctgctgctgg acgacgaggc tggaccactg 1200
gaggaggagc tgccaagact ggctgacgag ggactgaaca gaagagtggc tgaggacctg 1260
aacctgggaa acctgaacgt gtctatccca tggacccaca aggtgggaaa cttcaccgga 1320
ctgtactctt ctaccgtgcc agtgttcaac ccagagtggc agaccccatc tttcccaaac 1380
atccacctgc aggaggacat catcaacaga tgccagcagt acgtgggacc actgaccgtg 1440
aacgagaaga gaagactgaa gctgatcatg ccagctagat tctacccaaa cctgaccaag 1500
tacctgccac tggacaaggg aatcaagcca tactacccag agcacgctgt gaaccactac 1560
ttcaagacca gacactacct gcacaccctg tggaaggctg gaatcctgta caagagagaa 1620
accaccagat ctgcttcttt ctgcggatct ccatactctt gggagcagga gctgcagcac 1680
ggaagactgg tgttccagac ctctaccaga cacggagacg agtctttctg ctctcagtct 1740
tctggaatcc tgtctagatc tccagtggga ccatgcgtga gatctcagct gaagcagtct 1800
agactgggac tgcagccaca gcagggatct ctggctagag gaaagtctgg aagatctgga 1860
tctatcagag ctagagtgca cccaaccacc agaagatctt tcggagtgga gccatctgga 1920
tctggacaca tcgacaactc tgcttcttct gcttcttctt gcctgcacca gtctgctgtg 1980
agaaagaccg cttactctca cctgtctacc tctaagagac agtcttcttc tggacacgct 2040
gtggagctgc acaacatccc accatcttct gctagatctc agtctgaggg accaatcttc 2100
tcttgctggt ggctgcagtt cagaaactct aagccatgct ctgactactg cctgacccac 2160
atcgtgaacc tgctggagga ctggggacca tgcaccgagc acggagagca caacatcaga 2220
atcccaagaa ccccagctag agtgaccgga ggagtgttcc tggtggacaa gaacccacac 2280
aacaccaccg agtctagact ggtggtggac ttctctcagt tctctagagg atctacccac 2340
gtgtcttggc caaagttcgc tgtgccaaac ctgcagtctc tgaccaacct gctgtcttct 2400
aacctgtctt ggctgtctct ggacgtgtct gctgctttct accacatccc actgcaccca 2460
gctgctatgc cacacctgct ggtgggatct tctggactgc caagatacgt ggctagactg 2520
tcttctacct ctagaaacat caactaccag cacggaacca tgcaggacct gcacgactct 2580
tgctctagaa acctgtacgt gtctctgctg ctgctgtaca agaccttcgg aagaaagctg 2640
cacctgtact ctcacccaat catcctggga ttcagaaaga tcccaatggg agtgggactg 2700
tctccattcc tgctggctca gttcacctct gctatctgct ctgtggtgag aagagctttc 2760
ccacactgcc tggctttctc ttacatggac gacgtggtgc tgggagctaa gtctgtgcag 2820
cacctggagt ctctgttcac ctctatcacc aacttcctgc tgtctctggg aatccacctg 2880
aacccaaaca agaccaagag atggggatac tctctgaact tcatgggata cgtgatcgga 2940
tcttggggaa ccctgccaca ggagcacatc gtgctgaaga tcaagcagtg cttcagaaag 3000
ctgccagtga acagaccaat cgactggaag gtgtgccaga gaatcgtggg actgctggga 3060
ttcgctgctc cattcaccca gtgcggatac ccagctctga tgccactgta cgcttgcatc 3120
cagtctaagc aggctttcac cttctctcca acctacaagg ctttcctgtg caagcagtac 3180
ctgcacctgt acccagtggc tagacagaga tctggactgt gccaggtgtt cgctgacgct 3240
accccaaccg gatggggact ggctatcgga cacagaagaa tgagaggaac cttcgtggct 3300
ccactgccaa tccacaccgc tgagctgctg gctgcttgct tcgctagatc tagatctgga 3360
gctaagctga tcggaaccga caactctgtg gtgctgtcta gaaagtacac ctctttccca 3420
tggctgctgg gatgcgctgc taactggatt tgagatctga gaccccc 3467
<210> 9
<211> 4601
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 9
ggggtctcct cgagcctgca ggcagctgcg cgctcgctcg ctcactgagg ccgcccgggc 60
aaagcccggg cgtcgggcga cctttggtcg cccggcctca gtgagcgagc gagcgcgcag 120
agagggagtg gccaactcca tcactagggg ttcctgcggc cgcacgcgtg gagctagtta 180
ttaatagtaa tcaattacgg ggtcattagt tcatagccca tatatggagt tccgcgttac 240
ataacttacg gtaaatggcc cgcctggctg accgcccaac gacccccgcc cattgacgtc 300
aataatgacg tatgttccca tagtaacgcc aatagggact ttccattgac gtcaatgggt 360
ggagtattta cggtaaactg cccacttggc agtacatcaa gtgtatcata tgccaagtac 420
gccccctatt gacgtcaatg acggtaaatg gcccgcctgg cattatgccc agtacatgac 480
cttatgggac tttcctactt ggcagtacat ctacgtatta gtcatcgcta ttaccatggt 540
gatgcggttt tggcagtaca tcaatgggcg tggatagcgg tttgactcac ggggatttcc 600
aagtctccac cccattgacg tcaatgggag tttgttttgg caccaaaatc aacgggactt 660
tccaaaatgt cgtaacaact ccgccccatt gacgcaaatg ggcggtaggc gtgtacggtg 720
ggaggtctat ataagcagag ctggtttagt gaaccgtcag atccgctagc gaattcgcca 780
ccatggagaa caccacctct ggattcctgg gaccactgct ggtgctgcag gctggattct 840
tcctgctgac cagaatcctg accatcccac agtctctgga ctcttggtgg acctctctga 900
acttcctggg aggagctcca acctgcccag gacagaactc tcagtctcca acctctaacc 960
actctccaac ctcttgccca ccaatctgcc caggatacag atggatgtgc ctgagaagat 1020
tcatcatctt cctgttcatc ctgctgctgt gcctgatctt cctgctggtg ctgctggact 1080
accagggaat gctgccagtg tgcccactgc tgccaggaac ctctaccacc tctaccggac 1140
catgcaagac ctgcaccatc ccagctcagg gaacctctat gttcccatct tgctgctgca 1200
ccaagccatc tgacggaaac tgcacctgca tcccaatccc atcttcttgg gctttcgcta 1260
gattcctgtg ggagtgggct tctgtgagat tctcttggct gtctctgctg gtgccattcg 1320
tgcagtggtt cgtgggactg tctccaaccg tgtggctgtc tgtgatctgg atgatgtggt 1380
actggggacc atctctgtac aacatcctgt ctccattcct gccactgctg ccaatcttct 1440
tctgcctgtg ggtgtacatc atggacatcg acccatacaa ggagttcgga gcttctgtgg 1500
agctgctgtc tttcctgcca tctgacttct tcccatctat cagggacctg ctggacaccg 1560
cttctgctct gtacagagag gctctggagt ctccagagca ctgctctcca caccacaccg 1620
ctctgagaca ggctatcctg tgctggggag agctgatgaa cctggctacc tgggtgggat 1680
ctaacctgga ggacccagct tctagagagc tggtggtgtc ttacgtgaac gtgaacatgg 1740
gactgaagat cagacagctg ctgtggttcc acatctcttg cctgaccttc ggaagagaaa 1800
ccgtgctgga gtacctggtg tctttcggag tgtggatcag aaccccacca gcttacagac 1860
caccaaacgc tccaatcctg tctaccctga tgccactgtc ttaccagcac ttcagaaagc 1920
tgctgctgct ggacgacgag gctggaccac tggaggagga gctgccaaga ctggctgacg 1980
agggactgaa cagaagagtg gctgaggacc tgaacctggg aaacctgaac gtgtctatcc 2040
catggaccca caaggtggga aacttcaccg gactgtactc ttctaccgtg ccagtgttca 2100
acccagagtg gcagacccca tctttcccaa acatccacct gcaggaggac atcatcaaca 2160
gatgccagca gtacgtggga ccactgaccg tgaacgagaa gagaagactg aagctgatca 2220
tgccagctag attctaccca aacctgacca agtacctgcc actggacaag ggaatcaagc 2280
catactaccc agagcacgct gtgaaccact acttcaagac cagacactac ctgcacaccc 2340
tgtggaaggc tggaatcctg tacaagagag aaaccaccag atctgcttct ttctgcggat 2400
ctccatactc ttgggagcag gagctgcagc acggaagact ggtgttccag acctctacca 2460
gacacggaga cgagtctttc tgctctcagt cttctggaat cctgtctaga tctccagtgg 2520
gaccatgcgt gagatctcag ctgaagcagt ctagactggg actgcagcca cagcagggat 2580
ctctggctag aggaaagtct ggaagatctg gatctatcag agctagagtg cacccaacca 2640
ccagaagatc tttcggagtg gagccatctg gatctggaca catcgacaac tctgcttctt 2700
ctgcttcttc ttgcctgcac cagtctgctg tgagaaagac cgcttactct cacctgtcta 2760
cctctaagag acagtcttct tctggacacg ctgtggagct gcacaacatc ccaccatctt 2820
ctgctagatc tcagtctgag ggaccaatct tctcttgctg gtggctgcag ttcagaaact 2880
ctaagccatg ctctgactac tgcctgaccc acatcgtgaa cctgctggag gactggggac 2940
catgcaccga gcacggagag cacaacatca gaatcccaag aaccccagct agagtgaccg 3000
gaggagtgtt cctggtggac aagaacccac acaacaccac cgagtctaga ctggtggtgg 3060
acttctctca gttctctaga ggatctaccc acgtgtcttg gccaaagttc gctgtgccaa 3120
acctgcagtc tctgaccaac ctgctgtctt ctaacctgtc ttggctgtct ctggacgtgt 3180
ctgctgcttt ctaccacatc ccactgcacc cagctgctat gccacacctg ctggtgggat 3240
cttctggact gccaagatac gtggctagac tgtcttctac ctctagaaac atcaactacc 3300
agcacggaac catgcaggac ctgcacgact cttgctctag aaacctgtac gtgtctctgc 3360
tgctgctgta caagaccttc ggaagaaagc tgcacctgta ctctcaccca atcatcctgg 3420
gattcagaaa gatcccaatg ggagtgggac tgtctccatt cctgctggct cagttcacct 3480
ctgctatctg ctctgtggtg agaagagctt tcccacactg cctggctttc tcttacatgg 3540
acgacgtggt gctgggagct aagtctgtgc agcacctgga gtctctgttc acctctatca 3600
ccaacttcct gctgtctctg ggaatccacc tgaacccaaa caagaccaag agatggggat 3660
actctctgaa cttcatggga tacgtgatcg gatcttgggg aaccctgcca caggagcaca 3720
tcgtgctgaa gatcaagcag tgcttcagaa agctgccagt gaacagacca atcgactgga 3780
aggtgtgcca gagaatcgtg ggactgctgg gattcgctgc tccattcacc cagtgcggat 3840
acccagctct gatgccactg tacgcttgca tccagtctaa gcaggctttc accttctctc 3900
caacctacaa ggctttcctg tgcaagcagt acctgcacct gtacccagtg gctagacaga 3960
gatctggact gtgccaggtg ttcgctgacg ctaccccaac cggatgggga ctggctatcg 4020
gacacagaag aatgagagga accttcgtgg ctccactgcc aatccacacc gctgagctgc 4080
tggctgcttg cttcgctaga tctagatctg gagctaagct gatcggaacc gacaactctg 4140
tggtgctgtc tagaaagtac acctctttcc catggctgct gggatgcgct gctaactgga 4200
tttgagatct gatcataatc agccatacca catttgtaga ggttttactt gctttaaaaa 4260
acctcccaca cctccccctg aacctgaaac ataaaatgaa tgcaattgtt gttgttaact 4320
tgtttattgc agcttataat ggttacaaat aaagcaatag catcacaaat ttcacaaata 4380
aagcattttt ttcactgcat tctagttgtg gtttgtccaa actcatcaat gtatcttagc 4440
ggccgcagga acccctagtg atggagttgg ccactccctc tctgcgcgct cgctcgctca 4500
ctgaggccgg gcgaccaaag gtcgcccgac gcccgggctt tgcccgggcg gcctcagtga 4560
gcgagcgagc gcgcagctgc ctgcaggccg cgggagaccc c 4601
<210> 10
<211> 7746
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
gtggcacttt tcggggaaat gtgcgcggaa cccctatttg tttatttttc taaatacatt 60
caaatatgta tccgctcatg agacaataac cctgataaat gcttcaataa tattgaaaaa 120
ggaagagtat gagtattcaa catttccgtg tcgcccttat tccctttttt gcggcatttt 180
gccttcctgt ttttgctcac ccagaaacgc tggtgaaagt aaaagatgct gaagatcagt 240
tgggtgcacg agtgggttac atcgaactgg atctcaacag cggtaagatc cttgagagtt 300
ttcgccccga agaacgtttt ccaatgatga gcacttttaa agttctgcta tgtggcgcgg 360
tattatcccg tattgacgcc gggcaagagc aactcggtcg ccgcatacac tattctcaga 420
atgacttggt tgagtactca ccagtcacag aaaagcatct tacggatggc atgacagtaa 480
gagaattatg cagtgctgcc ataaccatga gtgataacac tgcggccaac ttacttctga 540
caacgatcgg aggaccgaag gagctaaccg cttttttgca caacatgggg gatcatgtaa 600
ctcgccttga tcgttgggaa ccggagctga atgaagccat accaaacgac gagcgtgaca 660
ccacgatgcc tgtagcaatg gcaacaacgt tgcgcaaact attaactggc gaactactta 720
ctctagcttc ccggcaacaa ttaatagact ggatggaggc ggataaagtt gcaggaccac 780
ttctgcgctc ggcccttccg gctggctggt ttattgctga taaatctgga gccggtgagc 840
gtgggtctcg cggtatcatt gcagcactgg ggccagatgg taagccctcc cgtatcgtag 900
ttatctacac gacggggagt caggcaacta tggatgaacg aaatagacag atcgctgaga 960
taggtgcctc actgattaag cattggtaac tgtcagacca agtttactca tatatacttt 1020
agattgattt aaaacttcat ttttaattta aaaggatcta ggtgaagatc ctttttgata 1080
atctcatgac caaaatccct taacgtgagt tttcgttcca ctgagcgtca gaccccgtag 1140
aaaagatcaa aggatcttct tgagatcctt tttttctgcg cgtaatctgc tgcttgcaaa 1200
caaaaaaacc accgctacca gcggtggttt gtttgccgga tcaagagcta ccaactcttt 1260
ttccgaaggt aactggcttc agcagagcgc agataccaaa tactgtcctt ctagtgtagc 1320
cgtagttagg ccaccacttc aagaactctg tagcaccgcc tacatacctc gctctgctaa 1380
tcctgttacc agtggctgct gccagtggcg ataagtcgtg tcttaccggg ttggactcaa 1440
gacgatagtt accggataag gcgcagcggt cgggctgaac ggggggttcg tgcacacagc 1500
ccagcttgga gcgaacgacc tacaccgaac tgagatacct acagcgtgag ctatgagaaa 1560
gcgccacgct tcccgaaggg agaaaggcgg acaggtatcc ggtaagcggc agggtcggaa 1620
caggagagcg cacgagggag cttccagggg gaaacgcctg gtatctttat agtcctgtcg 1680
ggtttcgcca cctctgactt gagcgtcgat ttttgtgatg ctcgtcaggg gggcggagcc 1740
tatggaaaaa cgccagcaac gcggcctttt tacggttcct ggccttttgc tggccttttg 1800
ctcacatgtt ctttcctgcg ttatcccctg attctgtgga taaccgtatt accgcctttg 1860
agtgagctga taccgctcgc cgcagccgaa cgaccgagcg cagcgagtca gtgagcgagg 1920
aagcggaaga gcgcccaata cgcaaaccgc ctctccccgc gcgttggccg attcattaat 1980
gcagctggca cgacaggttt cccgactgga aagcgggcag tgagcgcaac gcaattaatg 2040
tgagttagct cactcattag gcaccccagg ctttacactt tatgcttccg gctcgtatgt 2100
tgtgtggaat tgtgagcgga taacaatttc acacaggaaa cagctatgac catgattacg 2160
ccaagcgcgc aattaaccct cactaaaggg aacaaaagct gggtaccggg ccccccctcg 2220
agcctgcagg cagctgcgcg ctcgctcgct cactgaggcc gcccgggcaa agcccgggcg 2280
tcgggcgacc tttggtcgcc cggcctcagt gagcgagcga gcgcgcagag agggagtggc 2340
caactccatc actaggggtt cctgcggccg cacgcgtgga gctagttatt aatagtaatc 2400
aattacgggg tcattagttc atagcccata tatggagttc cgcgttacat aacttacggt 2460
aaatggcccg cctggctgac cgcccaacga cccccgccca ttgacgtcaa taatgacgta 2520
tgttcccata gtaacgccaa tagggacttt ccattgacgt caatgggtgg agtatttacg 2580
gtaaactgcc cacttggcag tacatcaagt gtatcatatg ccaagtacgc cccctattga 2640
cgtcaatgac ggtaaatggc ccgcctggca ttatgcccag tacatgacct tatgggactt 2700
tcctacttgg cagtacatct acgtattagt catcgctatt accatggtga tgcggttttg 2760
gcagtacatc aatgggcgtg gatagcggtt tgactcacgg ggatttccaa gtctccaccc 2820
cattgacgtc aatgggagtt tgttttggca ccaaaatcaa cgggactttc caaaatgtcg 2880
taacaactcc gccccattga cgcaaatggg cggtaggcgt gtacggtggg aggtctatat 2940
aagcagagct ggtttagtga accgtcagat ccgctagcga attcgccacc atgtacagga 3000
tgcaactcct gtcttgcatt gcactaagtc ttgcacttgt cacgaattcg atatcggcca 3060
tggagaacac cacctctgga ttcctgggac cactgctggt gctgcaggct ggattcttcc 3120
tgctgaccag aatcctgacc atcccacagt ctctggactc ttggtggacc tctctgaact 3180
tcctgggagg agctccaacc tgcccaggac agaactctca gtctccaacc tctaaccact 3240
ctccaacctc ttgcccacca atctgcccag gatacagatg gatgtgcctg agaagattca 3300
tcatcttcct gttcatcctg ctgctgtgcc tgatcttcct gctggtgctg ctggactacc 3360
agggaatgct gccagtgtgc ccactgctgc caggaacctc taccacctct accggaccat 3420
gcaagacctg caccatccca gctcagggaa cctctatgtt cccatcttgc tgctgcacca 3480
agccatctga cggaaactgc acctgcatcc caatcccatc ttcttgggct ttcgctagat 3540
tcctgtggga gtgggcttct gtgagattct cttggctgtc tctgctggtg ccattcgtgc 3600
agtggttcgt gggactgtct ccaaccgtgt ggctgtctgt gatctggatg atgtggtact 3660
ggggaccatc tctgtacaac atcctgtctc cattcctgcc actgctgcca atcttcttct 3720
gcctgtgggt gtacatcatg gacatcgacc catacaagga gttcggagct tctgtggagc 3780
tgctgtcttt cctgccatct gacttcttcc catctatcag ggacctgctg gacaccgctt 3840
ctgctctgta cagagaggct ctggagtctc cagagcactg ctctccacac cacaccgctc 3900
tgagacaggc tatcctgtgc tggggagagc tgatgaacct ggctacctgg gtgggatcta 3960
acctggagga cccagcttct agagagctgg tggtgtctta cgtgaacgtg aacatgggac 4020
tgaagatcag acagctgctg tggttccaca tctcttgcct gaccttcgga agagaaaccg 4080
tgctggagta cctggtgtct ttcggagtgt ggatcagaac cccaccagct tacagaccac 4140
caaacgctcc aatcctgtct accctgatgc cactgtctta ccagcacttc agaaagctgc 4200
tgctgctgga cgacgaggct ggaccactgg aggaggagct gccaagactg gctgacgagg 4260
gactgaacag aagagtggct gaggacctga acctgggaaa cctgaacgtg tctatcccat 4320
ggacccacaa ggtgggaaac ttcaccggac tgtactcttc taccgtgcca gtgttcaacc 4380
cagagtggca gaccccatct ttcccaaaca tccacctgca ggaggacatc atcaacagat 4440
gccagcagta cgtgggacca ctgaccgtga acgagaagag aagactgaag ctgatcatgc 4500
cagctagatt ctacccaaac ctgaccaagt acctgccact ggacaaggga atcaagccat 4560
actacccaga gcacgctgtg aaccactact tcaagaccag acactacctg cacaccctgt 4620
ggaaggctgg aatcctgtac aagagagaaa ccaccagatc tgcttctttc tgcggatctc 4680
catactcttg ggagcaggag ctgcagcacg gaagactggt gttccagacc tctaccagac 4740
acggagacga gtctttctgc tctcagtctt ctggaatcct gtctagatct ccagtgggac 4800
catgcgtgag atctcagctg aagcagtcta gactgggact gcagccacag cagggatctc 4860
tggctagagg aaagtctgga agatctggat ctatcagagc tagagtgcac ccaaccacca 4920
gaagatcttt cggagtggag ccatctggat ctggacacat cgacaactct gcttcttctg 4980
cttcttcttg cctgcaccag tctgctgtga gaaagaccgc ttactctcac ctgtctacct 5040
ctaagagaca gtcttcttct ggacacgctg tggagctgca caacatccca ccatcttctg 5100
ctagatctca gtctgaggga ccaatcttct cttgctggtg gctgcagttc agaaactcta 5160
agccatgctc tgactactgc ctgacccaca tcgtgaacct gctggaggac tggggaccat 5220
gcaccgagca cggagagcac aacatcagaa tcccaagaac cccagctaga gtgaccggag 5280
gagtgttcct ggtggacaag aacccacaca acaccaccga gtctagactg gtggtggact 5340
tctctcagtt ctctagagga tctacccacg tgtcttggcc aaagttcgct gtgccaaacc 5400
tgcagtctct gaccaacctg ctgtcttcta acctgtcttg gctgtctctg gacgtgtctg 5460
ctgctttcta ccacatccca ctgcacccag ctgctatgcc acacctgctg gtgggatctt 5520
ctggactgcc aagatacgtg gctagactgt cttctacctc tagaaacatc aactaccagc 5580
acggaaccat gcaggacctg cacgactctt gctctagaaa cctgtacgtg tctctgctgc 5640
tgctgtacaa gaccttcgga agaaagctgc acctgtactc tcacccaatc atcctgggat 5700
tcagaaagat cccaatggga gtgggactgt ctccattcct gctggctcag ttcacctctg 5760
ctatctgctc tgtggtgaga agagctttcc cacactgcct ggctttctct tacatggacg 5820
acgtggtgct gggagctaag tctgtgcagc acctggagtc tctgttcacc tctatcacca 5880
acttcctgct gtctctggga atccacctga acccaaacaa gaccaagaga tggggatact 5940
ctctgaactt catgggatac gtgatcggat cttggggaac cctgccacag gagcacatcg 6000
tgctgaagat caagcagtgc ttcagaaagc tgccagtgaa cagaccaatc gactggaagg 6060
tgtgccagag aatcgtggga ctgctgggat tcgctgctcc attcacccag tgcggatacc 6120
cagctctgat gccactgtac gcttgcatcc agtctaagca ggctttcacc ttctctccaa 6180
cctacaaggc tttcctgtgc aagcagtacc tgcacctgta cccagtggct agacagagat 6240
ctggactgtg ccaggtgttc gctgacgcta ccccaaccgg atggggactg gctatcggac 6300
acagaagaat gagaggaacc ttcgtggctc cactgccaat ccacaccgct gagctgctgg 6360
ctgcttgctt cgctagatct agatctggag ctaagctgat cggaaccgac aactctgtgg 6420
tgctgtctag aaagtacacc tctttcccat ggctgctggg atgcgctgct aactggattc 6480
tgagaggaac ctctttcgtg tacgtgccat ctgctctgaa cccagctgac gacccatcta 6540
gaggaagact gggactgtac agaccactgc tgcacctgcc attcagacca accaccggaa 6600
gaacctctct gtacgctgtg tctccatctg tgccatctca cctgccagac agagtgcact 6660
tcgcttctcc actgcacgtg gcttggaggc caccatgaga tctgatcata atcagccata 6720
ccacatttgt agaggtttta cttgctttaa aaaacctccc acacctcccc ctgaacctga 6780
aacataaaat gaatgcaatt gttgttgtta acttgtttat tgcagcttat aatggttaca 6840
aataaagcaa tagcatcaca aatttcacaa ataaagcatt tttttcactg cattctagtt 6900
gtggtttgtc caaactcatc aatgtatctt agcggccgca ggaaccccta gtgatggagt 6960
tggccactcc ctctctgcgc gctcgctcgc tcactgaggc cgggcgacca aaggtcgccc 7020
gacgcccggg ctttgcccgg gcggcctcag tgagcgagcg agcgcgcagc tgcctgcagg 7080
ccgcggtgga gctccaattc gccctatagt gagtcgtatt acgcgcgctc actggccgtc 7140
gttttacaac gtcgtgactg ggaaaaccct ggcgttaccc aacttaatcg ccttgcagca 7200
catccccctt tcgccagctg gcgtaatagc gaagaggccc gcaccgatcg cccttcccaa 7260
cagttgcgca gcctgaatgg cgaatgggac gcgccctgta gcggcgcatt aagcgcggcg 7320
ggtgtggtgg ttacgcgcag cgtgaccgct acacttgcca gcgccctagc gcccgctcct 7380
ttcgctttct tcccttcctt tctcgccacg ttcgccggct ttccccgtca agctctaaat 7440
cgggggctcc ctttagggtt ccgatttagt gctttacggc acctcgaccc caaaaaactt 7500
gattagggtg atggttcacg tagtgggcca tcgccctgat agacggtttt tcgccctttg 7560
acgttggagt ccacgttctt taatagtgga ctcttgttcc aaactggaac aacactcaac 7620
cctatctcgg tctattcttt tgatttataa gggattttgc cgatttcggc ctattggtta 7680
aaaaatgagc tgatttaaca aaaatttaac gcgaatttta acaaaatatt aacgcttaca 7740
atttag 7746
Claims (10)
1.一种用于慢性乙型肝炎预防和/或治疗的蛋白，其氨基酸序列选自SEQ ID NO：1、SEQID NO：2、SEQ ID NO：3和SEQ ID NO：4所示的氨基酸序列中的一种。
2.一种用于慢性乙型肝炎预防和/或治疗的编码基因，其特征在于，其编码权利要求1所述的蛋白。
3.根据权利要求2所述的编码基因，其特征在于，其选自核苷酸序列为SEQ ID NO：5的HBsAg编码基因、核苷酸序列为SEQ ID NO：6的HBcAg编码基因和核苷酸序列为SEQ ID NO：7的Pol编码基因中的一种。
4.根据权利要求2所述的编码基因，其特征在于，其为融合基因，所述融合基因含有核苷酸序列为SEQ ID NO：5的HBsAg编码基因、核苷酸序列为SEQ ID NO：6的HBcAg编码基因和核苷酸序列为SEQ ID NO：7的Pol编码基因中的至少两种。
5.根据权利要求4所述的编码基因，其特征在于，所述融合基因的核苷酸序列为SEQ IDNO：8或SEQ ID NO：9所示的核苷酸序列。
6.权利要求1所述的蛋白或权利要求2-5任一所述的编码基因在制备用于慢性乙型肝炎预防和/或治疗的生物制品上的应用。
7.一种重组腺相关病毒穿梭质粒，其特征在于，其含有权利要求2-5任一所述的编码基因。
8.根据权利要求7所述的重组腺相关病毒穿梭质粒，其特征在于，其核苷酸序列如SEQID NO：10所示。
9.一种重组腺相关病毒，其特征在于，由权利要求7或8所述的重组腺相关病毒穿梭质粒和辅助质粒共转染工程细胞后包装而成；
优选地，所述辅助质粒为pAAV-RC载体和pHelper载体；所述工程细胞为293细胞。
10.权利要求9所述的重组腺相关病毒在制备用于慢性乙型肝炎预防和/或治疗的疫苗上的应用。
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