CN101228267A - 生产冠状病毒的细胞系 - Google Patents
生产冠状病毒的细胞系 Download PDFInfo
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Abstract
本发明涉及冠状病毒的生产。本发明特别涉及通过使用表达功能性SARS－CoV受体的细胞生产SARS－CoV的方法。
Description
发明领域
本发明涉及医药学领域。本发明特别涉及冠状病毒如人类SARS-CoV的生产。
发明背景
严重急性呼吸困难综合症(SARS)是由SARS冠状病毒(SARS-CoV)导致的一种新的人类呼吸系统疾病。这种疾病于2003年初在中国及在东南亚的许多国家出现，随后迅速传播至世界范围。尽管该疾病在2003年6月已经消失，但不能排除其再度出现。因此，目前更多的努力是开发关于SARS-CoV的治疗和预防性疗法。
尽管SARS-CoV与先前所有已知的人和动物冠状病毒在种系发生方面截然不同，但是对于SARS-CoV的分子和细胞生物学方面的了解已经取得显著进展。在鉴别了SARS-CoV基因组的完整序列之后(见Marra et al.(2003)；Rota et al.(2003))，最近Li et al.(2003)鉴别了一种锌金属肽酶-血管紧张素转换酶2(ACE2蛋白质)为SARS-CoV的功能受体。有关SARS-CoV的分子和细胞生物学的这一知识和其它知识提供了开发抗病毒和疫苗策略的途径。
抗SARS-CoV的保护性疫苗的研发主要集中于两个方面，即使用失活的完整SARS-CoV(Tang et al.(2004)；Takasuka et al.(2004))和使用SARS-CoV蛋白质(Zhang et al.(2004)；Yang et al.(2004)；Kim et al.(2004))。失活的完整病毒疫苗的制备一般是通过在组织培养物中产生大量的病毒，然后在不破坏其免疫学性质的条件下，使得所述病毒无害。为了在细胞培养物中进行病毒的优化生产，关键的是相应的病毒能感染细胞并在所述细胞中复制。迄今为止，据报道仅有有限数量的细胞对SARS-CoV感染易感并支持SARS-CoV在培养物中的复制(见Mossel et al.(2005))。在这方面最常使用的细胞是源自非洲绿猴的肾细胞如Vero或Vero E6细胞。这些细胞的一个缺点是其需要存在血清和/或粘附于固体支持物以生长，由此导致纯化和安全性问题以及大规模生产所需的复杂系统。另外，所述细胞不是人细胞。
最近揭示了通过使得耐受SARS-CoV感染的细胞表达功能受体即人ACE2受体而可以允许SARS-CoV复制。在WO 2005/032487中，揭示了用ACE2蛋白质转染的人293T细胞支持SARS-CoV复制且适于生产SARS-CoV。然而，用这些细胞获得的产量较低，无经济学利用价值。总之，在本领域仍需要一种在宿主细胞系统中生产SARS-CoV的方法，以改良现有的细胞培养系统，特别是改良获得的产量。
本发明通过提供表达ACE2蛋白质的原代人视网膜母细胞(HER细胞)而解决了这种需要。这些细胞提供出乎意料的高SARS-CoV产量。它们所具备的另一个优势是在大规模生产、悬浮生长及不依赖于生长因子方面已经有大量记载并且与现有技术中的细胞相比具备更好的作用。特别是所述细胞可以以高度可再生方式悬浮的事实使其非常适于大规模生产。另外，本发明的细胞可有利地用于复制人SARS-CoV的各种分离株，并且进一步地其不仅适于生产SARS-CoV，也适于生产利用ACE2蛋白质作为功能受体的其它人冠状病毒。
附图简述
图1示出SARS-CoV S蛋白片段(第318-510位氨基酸)与表达ACE2蛋白质的PER.C6
细胞的结合。与野生型S318-510片段相比，变体F包含突变N9S，变体H包含突变K344RF360S、L472P、D480G、T487S。
发明概述
本发明提供了适于生产冠状病毒的细胞。在一个优选的实施方案中，所述细胞是表达人ACE2蛋白质的HER细胞。本发明进一步提供了使用所述细胞生产冠状病毒、特别是SARS-CoV的方法。
发明详述
第一方面，本发明包含表达人ACE2蛋白质的细胞。由于最近已经发现ACE2基因多态性不影响严重急性呼吸困难综合症的结果(见Chiu et al.(2004))，因此表达ACE2蛋白质的变体的细胞也是本发明的一部分。所述变体当然是仍能发挥作为SARS-CoV受体的功能。本发明的细胞是E1永生化的视网膜细胞。它们通过用腺病毒E1序列例如E1A和E1B序列永生化而衍生自视网膜细胞。所述E1A序列可以受其内源腺病毒E1A启动子的影响，但也可以由异源启动子控制，例如PGK启动子。E1A蛋白质具有转化活性，而E1B蛋白质具有抗细胞凋亡活性。另外，E1A可有助于增加从细胞表达的水平。优选地，本发明的细胞衍生自原代细胞。它们可以是任何来源的细胞，优选来源于人。在一个优选方面，所述细胞衍生自原代人胚胎视网膜细胞，换句话说，本发明的细胞衍生自原代人胚胎视网膜母细胞(HER细胞)，在其基因组中包含编码腺病毒E1A和E1B的序列。原代HER细胞可以分离自胎儿(见Byrd et al.(1982)；Byrd et al.(1988))。用腺病毒E1序列对细胞进行永生化例如见于美国专利5,994,128所描述。因此，通过这种方法可以获得已经用腺病毒E1序列永生化的胚胎视网膜细胞。因此可制备表达腺病毒E1A和E1B的其它细胞。
为本发明方法和应用最优选的HER细胞是于1996年2月29日以保藏号96022940保藏在ECACC的细胞或其衍生物。可用于本发明并具有以保藏号96022940保藏在ECACC的细胞的特征的一种E1永生化细胞系是由Crucell Holland B.V销售的商标为PER.C6
的细胞系。用于本发明的PER.C6
细胞是指来自以ECACC no.96022940保藏的细胞的上游或下游传代或者其上游或下游传代的后代。PER.C6
较例如也已经由腺病毒E1区域永生化的转化的人293细胞在操作性方面的表现更好。另外，PER.C6
细胞已经充分鉴定并且广泛论证，它们在大规模生产、悬浮生长及不依赖于生长因子方面的表现显著更好。特别是PER.C6
细胞可以以高度可再生的方式悬浮的事实使其非常适于大规模生产。另外，它们可以在指定的没有任何人或动物血清蛋白质的无血清培养基中生长，其生长与滚瓶、摇瓶、转瓶和生物反应器培养相容及倍增时间大约35小时的事实使其适于作为生长中的病毒的宿主。
E1A和E1B序列可衍生自任何腺病毒血清型，包括腺病毒血清型2、5、12和35(其它合适的腺病毒血清型见例如EP 1 054 064中表1所示)。
本发明的细胞可包含稳定整合进基因组材料中或者作为自主复制载体一部分的编码人ACE2蛋白质的多核苷酸，即人ACE2蛋白质可以瞬时表达，但是优选人ACE2蛋白质的长期、高产量稳定表达。换句话说，本发明的细胞经工程化以表达人ACE2蛋白质。例如，本发明的细胞可以使用表达载体转化，所述表达载体可含有病毒复制起点和/或内源表达元件及在同一或不同载体上的选择标记基因。在导入载体后，可以使细胞在富集培养基中生长1-2天，之后将其移至选择性培养基中。所述选择标记的目的是赋予选择抗性，其存在可以使成功表达ACE2蛋白质的细胞得以生长和回收。可以使用适于本发明细胞的组织培养技术使稳定转化的细胞的抗性克隆增殖。包含大量本发明细胞的细胞培养物也是本发明的一部分，其可用于如下的方法中。
另一方面，本发明提供了一种生产冠状病毒例如人SARS-CoV的方法，所述方法包括用冠状病毒感染本发明的细胞并从培养基或细胞中收获所述冠状病毒。在一个实施方案中，所述生产方法包括如下步骤：a)将编码人ACE2蛋白质的核酸分子提供给上述人细胞，例如衍生自原代人胚胎视网膜母细胞的人细胞，所述细胞在其基因组中包含编码腺病毒E1A和E1B的序列，b)将所述细胞在适于人ACE2蛋白质表达的条件下培养，c)用冠状病毒感染所述细胞，和d)从所述培养基或细胞中收获所述冠状病毒。培养所述细胞以优化ACE2蛋白质的表达。这可以在所述细胞的常规培养基中实现。如果需要，可以针对例如适当的选择、扩增或转录的诱导而对培养基进行改良。细胞的培养条件如温度、pH、营养成分等为本领域技术人员所熟知。将经工程化的细胞在有助于冠状病毒生产的条件下培养。可以在一旦观察到CPE时即开始收获。产生的冠状病毒可以从无细胞提取液中回收/收获，但也可以从培养基中回收/收获。从无细胞提取物或者培养基中回收病毒的方法为本领域技术人员所熟知，可包括离心或层析步骤。优选地，本发明方法中使用的人细胞是以ECACC no.96022940保藏的PER.C6
或其衍生物。在一个优选的实施方案中，所述人细胞能悬浮生长和/或可以在无血清条件下培养。
在一个优选的实施方案中，冠状病毒选自用ACE2蛋白质作为感染入口的受体的一组冠状病毒。这种冠状病毒包括但不限于人冠状病毒，包括人SARS-CoV分离株和CoV-NL63(见Hofmann et al.(2005))。在一个实施方案中，工程化的细胞可适于生产所有的人SARS-CoV分离株(已知人SARS-CoV分离株见表1所示)。
人ACE2蛋白质可以瞬时表达，但优选稳定表达。通过合适的核酸构建体例如载体可以将编码人ACE2蛋白质的核酸分子提供给所述细胞。载体可以衍生自质粒如F、R1、RP1、Co1、pBR322、TOL、Ti等；粘粒；噬菌体如λ、λ样、M13、Mu、P1、P22、Qβ、T-even、T-odd、T2、T4、T7等；植物病毒；或者动物病毒。载体的选择依赖于进行的重组方法及使用的细胞。将载体导入细胞中可以通过磷酸钙转染、病毒感染、DEAE-葡聚糖介导的转染、脂染或者电穿孔方法实现。载体可以是自主复制的，或者可以与已经整合的染色体一起复制。优选地，所述载体含有一或多个选择标记。标记的选择可依赖于所选择的宿主细胞，正如本领域技术人员所熟知的那样，这对于本发明不是关键的。所述标记包括但不限于卡那霉素、新霉素、嘌呤霉素、潮霉素、zeocin、单纯疱疹病毒的胸苷激酶基因(HSV-TK)、小鼠的二氢叶酸还原酶基因(dhfr)。如果需要，载体可包含编码ACE2蛋白质的核酸分子，其与编码可用于分离目的的蛋白质或肽的一或多个核酸分子可操作连接。这些蛋白质或肽包括但不限于谷胱苷肽-S-转移酶、麦芽糖结合蛋白、金属结合多组氨酸、绿色荧光蛋白、荧光素酶和β-半乳糖苷酶。所述核酸构建体可包含调节表达的核酸序列。在此使用的这个术语是指对于可操作连接的编码序列在特定宿主生物体中的表达而言所必需的和/或影响所述的表达的多核苷酸序列。所述调节表达的核酸序列可以是在选择的宿主生物体中显示出活性的任何核酸序列和可以衍生自编码与宿主生物体同源或异源的蛋白质的基因，所述调节表达的核酸序列如适当的转录起始序列、终止序列、启动子序列、增强子序列；阻抑物或激活物序列；有效的RNA加工信号剪接信号和聚腺苷酸化信号；稳定胞质mRNA的序列；增强翻译效率的序列(例如核糖体结合位点)；增强蛋白质稳定性的序列；及当需要时增强蛋白质分泌的序列。本领域技术人员熟知调节表达的序列的鉴别与应用。通常使用的表达和/或转染载体包括质粒载体和逆转录病毒载体。本发明优选质粒载体，因为逆转录病毒载体具有仅感染和结合分裂细胞的缺点。其它问题包括制备麻烦及相对较低的效价，插入的基因的大小限制，难于控制或保证表达，及由于随机整合进宿主基因组而具有潜在遗传破坏性。在实验室中使用逆转录病毒载体包括潜在的毒性，特别是病毒可感染人细胞所产生的安全性问题是使用逆转录病毒载体的另一缺点。
另一方面，本发明提供了一种方法，其进一步包括失活或减毒收获的冠状病毒的步骤。失活的或减毒的冠状病毒可以在所述失活或减毒步骤之前、期间或之后纯化。纯化可以通过适于病毒的纯化方法进行，例如通过甘油垫离心或者本领域技术人员熟知的其它方法进行。失活可以通过本领域技术人员熟知的方法进行，例如γ射线或UV放射、热处理或者用化合物如甲醛、丙酮、乙醇和烷化剂如乙撑氧、乙撑亚胺、乙酰乙撑亚胺和B-丙内酯处理而失活。在失活步骤后，可以测试病毒在细胞培养物中的感染性的存在与否。测试病毒是否仍存在感染性或者部分或完全失活的方法为本领域技术人员所熟知。一旦确定不存在感染性，则这样获得的失活的病毒制品可进一步应用，例如用于疫苗制备。
减毒降低了病毒的毒力，由此尽管其仍存活，但其不可再导致疾病。最常用的减毒方法包括使生物体适应在非寻常条件下生长，以便使其丧失对其惯常宿主的适应性。最常用的病毒减毒方法是延长组织培养生长。延长的组织培养生长包括用病毒感染组织培养平板，进行多个世代。由于病毒在组织培养物中不再具有毒力，因此对于毒力不再选择，所述病毒丧失其导致疾病的能力。用于产生减毒的疫苗的组织培养物优选来自用所述减毒的疫苗接种的相同物种，以降低组织免疫反应的机会。在这方面，人细胞优选作为组织培养系统。
所述失活的或减毒的冠状病毒可用于疫苗中。可以利用本领域已知的方法配制疫苗。通常包括加入佐剂和/或合适的载体。
在一个实施方案中，收获的冠状病毒的病毒效价在感染后24小时为至少4.00、4.25、4.50、4.75、5.00、5.25、5.50、5.75、6.00、6.25、6.50、6.75、7.00、7.25、7.50，优选至少7.75log10TCID50/ml。
另外，本发明提供了本发明的人细胞在生产冠状病毒、优选人冠状病毒如SARS-CoV或HCoV-NL63中的应用。本发明的人细胞也可用于筛选抗冠状病毒的抗病毒剂。所述抗病毒剂可以是以任何方式影响病毒与受体结合或者影响ACE2蛋白质的受体功能的分子或化合物。它们可例如通过测定候选分子与所述细胞或携带ACE2蛋白质的细胞膜的结合而获得，可包括化学化合物、肽、多肽、抗体或其片段。
另一方面，本发明提供了一种鉴别能抑制冠状病毒感染和/或复制的分子的方法，所述方法包括如下步骤：a)将本发明的细胞与冠状病毒在有和无候选分子的条件下保温，b)确定候选分子的存在是否抑制冠状病毒感染和/或复制。本领域技术人员意识到本发明方法的一些步骤包括洗涤步骤和保温条件需要优化。可以将所述病毒和所述候选分子混合在一起，之后再与细胞接触。本发明还提供了一种选择能降低冠状病毒对细胞的感染的抗病毒分子的方法，其中所述方法包括如下步骤：a)将本发明的细胞与冠状病毒的表面蛋白在有或无候选抗病毒分子的条件下接触，所述表面蛋白参与冠状病毒与由所述细胞表达的人ACE2蛋白质的结合，所述表面蛋白如冠状病毒S蛋白，b)测定所述细胞与所述表面蛋白之间的结合，c)选择这样的候选抗病毒分子，即其中在存在所述候选抗病毒分子的条件下的结合相互作用与不存在所述抗病毒分子的条件下的结合相互作用相比降低或减少。携带ACE2蛋白质的细胞膜也可用于上述选择方法。所述细胞和细胞膜也可以用于筛选特异性结合ACE2蛋白质的化合物库中使用的筛选分析中。由于ACE2蛋白质在某些冠状病毒如SARS-CoV和HcoV-NL63进入细胞中发挥作用，因此这种化合物可用于治疗或预防冠状病毒感染。因此，本发明提供了一种筛选影响人ACE2蛋白质的这种功能的化合物的方法。这些化合物可抑制受体的功能。可用本发明的筛选/鉴别/选择方法鉴别的化合物和分子可衍生自各种来源，包括化学化合物库或(天然)化合物的混合物。所述方法可包括测定候选分子或化合物与本发明的细胞或其携带ACE2蛋白质的细胞膜的结合。可以直接或间接测定结合。例如利用与候选分子相关的标记可直接测定结合。也可以间接测定结合。例如间接测定候选分子的结合可包括用(标记的)竞争物进行竞争结合。候选分子的结合的测定也可例如在基于细胞的分析中确定，其中可以确定候选分子是否能阻断冠状病毒进入细胞。在这种情况中，可以确定在存在候选分子或化合物的条件下，细胞是否仍可被冠状病毒感染。或者，可以将与ACE2蛋白质结合的标记的人SARS-CoV S蛋白质或其片段与本发明的细胞在有或无候选化合物的条件下接触。接下来，可以确定所述候选化合物是否降低与所述细胞结合的S蛋白或其片段的量。候选分子或化合物可以是化学化合物或者也可以是其它分子，例如抗体或抗体片段。所述候选分子或化合物能结合ACE2蛋白质或者能结合参与感染和/或复制的冠状病毒的蛋白质如S蛋白。或者，所述候选分子或化合物可以以任何其它方式降低或抑制/消除病毒进入和/或复制。抑制冠状病毒感染和/或复制的所述候选分子或化合物可用于治疗或预防冠状病毒感染的方法中。
实施例
为了举例描述本发明，提供了如下实施例。所述实施例不以任何方式限制本发明的范围。
实施例1：稳定转染的人ACE2PER.C6
细胞系的产生
为了评价重组表达血管紧张素转换酶2(ACE2，人SARS-CoV和HCoV-NL63的天然受体)的PER.C6
细胞使SARS-CoV及其它冠状病毒生长的能力，将PER.C6
细胞用携带编码ACE2蛋白质的cDNA序列(见Donoghue et al.(2000)和Tipnis et al.(2000)所述；也见GenBank编号AAF78220和AAF99721；及SEQ ID NO：1)的质粒转染。使用本领域技术人员已知的标准技术选择稳定的转染体(见Coligan JE，Dunn BM，Ploegh HL，Speicher DW and Wingfield PT(eds.)(2001)Current protocols in protein science，volume I.John Wiley&Sons，Inc.New York)。将编码ACE2蛋白质的cDNA作为HindIII-XbaI片段克隆在pcDNA2004neo(-)(SEQ ID NO：2)中。使用标准技术在PER.C6
细胞中进行DNA转染。在存在0.5mg/ml G418(Gibco)的条件下选择稳定的克隆。使用流式细胞计量术监测ACE2的表达。将转染的细胞与山羊抗人ACE2胞外域多克隆抗体(R&D系统)在4℃保温1小时。将细胞用含有0.5％BSA的PBS洗涤3次，与藻红蛋白-偶联的F(ab′)2猴抗山羊IgG保温45分钟，在FACSCalibur上使用CELLQuest Pro软件(Becton Dickinson)分析。分析表明大约40％被分析的克隆表达ACE2蛋白质。所有表达ACE2蛋白质的克隆均结合SARS-CoV S318-510片段(见下文实施例3)。
实施例2：人SARS-CoV在表达ACE2蛋白质的PER.C6
细胞上的生产
为了评价ACE2稳定转染的PER.C6
细胞是否是人SARS-CoV容许的以及是否支持人SARS-CoV生长，将三组表达ACE2蛋白质的PER.C6
细胞培养物用人SARS-CoV Frankfurt 1毒株以0.1的感染复数(MOI)平行感染。容许SARS-CoV的Vero细胞作为阳性对照细胞系。在感染后(pi)12、24、48和72小时收获感染的培养物上清并在-80℃速冻。在收集了所有样品之后，将上清解冻并通过离心澄清。制备10倍系列稀释液，在Vero细胞的铺满培养物上滴定以确定效价。表2中示出的计算效价表明表达人ACE2蛋白质的PER.C6
细胞能产生与Vero细胞相似水平的SARS-CoV，高于经工程化表达ACE2蛋白质的其它细胞如293T细胞。
实施例3：刺突(spike)蛋白片段与表达ACE2蛋白质的PER.C6
细胞的结合
使用流式细胞计量术分析S蛋白的重组片段与ACE2转染的PER.C6细胞的结合。将表达ACE2的PER.C6
细胞与饱和浓度的myc-标记的S318-510片段在4℃保温1小时。重组S片段的构建和表达基本如van den Brink et al.(2005)所述进行。简而言之，将SARS-CoV毒株Frankfurt 1的刺突糖蛋白的S1亚基的第318-510位氨基酸在293T细胞中瞬时表达为myc/His-标记的蛋白质，使用Ni-层析法纯化(野生型Frankfurt 1S318-510片段的氨基酸序列见SEQ ID NO：3；包括信号序列、myc标记和his标记的S318-510片段的氨基酸序列见SEQ ID NO：4)。
接下来，将衍生自公开的人SARS-CoV S蛋白质序列的选择的突变导入S318-510片段中。所述突变相应于在毒株BJ302cl.2(变体F，GenBank no.AY429073；突变N479S)和GD03T0013(变体H，GenBank no.AY525636；突变K344R、F360S、L472P、D480G、T487S)中发现的突变。在三次洗涤后，通过流式细胞计量术使用生物素酰化的抗-myc抗体(Santa Cruz Biotechnology Inc.)和链霉抗生物素偶联的藻红蛋白(Caltag)分析检测结合的片段。所有保温和洗涤均在4℃在补加了0.5％牛血清白蛋白(BSA)的PBS中进行。抗-ACE2IgG与重组S片段的结合表明在传代18次后没有观察到ACE2表达丧失(数据未示出)。如图1所示，所有片段均能结合表达ACE2蛋白质的PER.C6
细胞，野生型S318-510片段及片段变体F的结合最强。一些人SARS-CoV分离株的S蛋白片段与表达ACE2的PER.C6
细胞的结合示出所述细胞可用于生产人SARS-CoV分离株。
表1：能在表达ACE2蛋白的PER.C6
细胞上生长的人SARS-CoV毒株列表
| 病毒株 | 基因/基因组 | Genbank | FASTA |
| SARS冠状病毒AS | SARS冠状病毒AS，完整基因组. | AY427439 | 37576845 |
| SARS冠状病毒BJ01 | SARS冠状病毒BJ01，完整基因组. | AY278488 | 30275666 |
| SARS冠状病毒BJ02 | SARS冠状病毒BJ02，完整基因组. | AY278487 | 31416292 |
| SARS冠状病毒BJ03 | SARS冠状病毒BJ03，完整基因组. | AY278490 | 31416305 |
| SARS冠状病毒BJ04 | SARS冠状病毒BJ04，完整基因组. | AY279354 | 31416306 |
| SARS冠状病毒BJ2232 | |||
| SARS冠状病毒BJ302 | |||
| SARS冠状病毒CUHK-AG01 | SARS冠状病毒CUHK-AG01，完整基因组. | AY345986 | 33114190 |
| SARS冠状病毒CUHK-AG02 | SARS冠状病毒CUHK-AG02，完整基因组. | AY345987 | 33114202 |
| SARS冠状病毒CUHK-AG03 | SARS冠状病毒CUHK-AG03，完整基因组. | AY345988 | 33114214 |
| SARS冠状病毒CUHK-L2 | |||
| SARS冠状病毒CUHK-Su10 | SARS冠状病毒CUHK-Su10，完整基因组. | AY282752 | 38304867 |
| SARS冠状病毒CUHK-W1 | SARS冠状病毒CUHK-W1，完整基因组. | AY278554 | 30027610 |
| SARS冠状病毒cw037 | |||
| SARS冠状病毒cw049 | |||
| SARS冠状病毒FRA | SARS冠状病毒FRA，完整基因组. | AY310120 | 33578015 |
| SARS冠状病毒Frankfurt 1 | SARS冠状病毒Frankfurt 1，完整基因组. | AY291315 | 31581502 |
| SARS冠状病毒GD01 | SARS冠状病毒GD01，完整基因组. | AY278489 | 31416290 |
| SARS冠状病毒GD03T0013 | SARS冠状病毒GD03T0013刺突糖蛋白基因，完整cds. | AY525636 | 41764105 |
| SARS冠状病毒GD69 | SARS冠状病毒GD69，完整基因组. | AY313906 | 37960831 |
| SARS冠状病毒GZ-A | SARS冠状病毒GZ-A，部分基因组. | AY394977 | 37624320 |
| SARS冠状病毒GZ-B | SARS冠状病毒GZ-B，完整基因组. | AY394978 | 37624321 |
| SARS冠状病毒GZ-C | SARS冠状病毒GZ-C，完整基因组. | AY394979 | 37624322 |
| SARS冠状病毒GZ-D | SARS冠状病毒GZ-D，部分基因组. | AY394980 | 37624323 |
| SARS冠状病毒GZ02 | SARS冠状病毒GZ02，完整基因组. | AY390556 | 41323719 |
| SARS冠状病毒GZ43 | SARS冠状病毒GZ43，部分基因组. | AY304490 | 34482141 |
| SARS冠状病毒GZ50 | SARS冠状病毒GZ50，完整基因组. | AY304495 | 34482146 |
| SARS冠状病毒GZ60 | SARS冠状病毒GZ60，部分基因组. | AY304491 | 34482142 |
| SARS冠状病毒HB | |||
| SARS冠状病毒HGZ8L1-A | SARS冠状病毒HGZ8L1-A，部分基因组. | AY394981 | 37624324 |
| SARS冠状病毒HGZ8L1-B | SARS冠状病毒HGZ8L1-B，部分基因组. | AY394982 | 37624325 |
| SARS冠状病毒HGZ8L2 | SARS冠状病毒HGZ8L2，完整基因组. | AY394993 | 37624336 |
| SARS冠状病毒HKU-36871 | SARS冠状病毒HKU-36871，部分基因组. | AY304492 | 34482143 |
| SARS冠状病毒HKU-39849 | SARS冠状病毒HKU-39849，完整基因组. | AY278491 | 30023963 |
| SARS冠状病毒HKU-65806 | SARS冠状病毒HKU-65806，部分基因组. | AY304493 | 34482144 |
| SARS冠状病毒HKU-66078 | SARS冠状病毒HKU-66078，部分基因组. | AY304494 | 34482145 |
| SARS冠状病毒HongKong/03/2003 | |||
| SARS冠状病毒HPZ-2003 | |||
| SARS冠状病毒HSR 1 | SARS冠状病毒HSR 1，完整基因组. | AY323977 | 33115118 |
| SARS冠状病毒HSZ-A | SARS冠状病毒HSZ-A，部分基因组. | AY394984 | 37624327 |
| SARS冠状病毒HSZ-Bb | SARS冠状病毒HSZ-Bb，完整基因组. | AY394985 | 37624328 |
| SARS冠状病毒HSZ-Bc | SARS冠状病毒HSZ-Bc，完整基因组. | AY394994 | 37624337 |
| SARS冠状病毒HSZ-Cb | SARS冠状病毒HSZ-Cb，完整基因组. | AY394986 | 37624329 |
| SARS冠状病毒HSZ-Cc | SARS冠状病毒HSZ-Cc，完整基因组. | AY394995 | 37624338 |
| SARS冠状病毒HSZ2-A | SARS冠状病毒HSZ2-A，完整基因组. | AY394983 | 37624326 |
| SARS冠状病毒HZS2-Bb | SARS冠状病毒HZS2-Bb，部分基因组. | AY395004 | 37624347 |
| SARS冠状病毒HZS2-C | SARS冠状病毒HZS2-C，完整基因组. | AY394992 | 37624335 |
| SARS冠状病毒HZS2-D | SARS冠状病毒HZS2-D，完整基因组. | AY394989 | 37624332 |
| SARS冠状病毒HZS2-E | SARS冠状病毒HZS2-E，完整基因组. | AY394990 | 37624333 |
| SARS冠状病毒HZS2-Fb | SARS冠状病毒HZS2-Fb，完整基因组. | AY394987 | 37624330 |
| SARS冠状病毒HZS2-Fc | SARS冠状病毒HZS2-Fc，完整基因组. | AY394991 | 37624334 |
| SARS冠状病毒JMD | SARS冠状病毒JMD，部分基因组. | AY394988 | 37624331 |
| SARS冠状病毒LC1 | SARS冠状病毒LC1，完整基因组. | AY394998 | 37624341 |
| SARS冠状病毒LC2 | SARS冠状病毒LC2，完整基因组. | AY394999 | 37624342 |
| SARS冠状病毒LC3 | SARS冠状病毒LC3，完整基因组. | AY395000 | 37624343 |
| SARS冠状病毒LC4 | SARS冠状病毒LC4，完整基因组. | AY395001 | 37624344 |
| SARS冠状病毒LC5 | SARS冠状病毒LC5，完整基因组. | AY395002 | 37624345 |
| SARS冠状病毒NS-1 | SARS冠状病毒NS-1，完整基因组. | AY508724 | 40795744 |
| SARS冠状病毒PUMC01 | SARS冠状病毒PUMC01，完整基因组. | AY350750 | 38231927 |
| SARS冠状病毒PUMC02 | SARS冠状病毒PUMC02，完整基因组. | AY357075 | 38231932 |
| SARS冠状病毒PUMC03 | SARS冠状病毒PUMC03，完整基因组. | AY357076 | 38231937 |
| SARS冠状病毒sf098 | |||
| SARS冠状病毒sf099 | |||
| SARS冠状病毒ShanghaiQXC1 | SARS冠状病毒ShanghaiQXC1，完整基因组. | AY463059 | 40457433 |
| SARS冠状病毒ShanghaiQXC2 | SARS冠状病毒ShanghaiQXC2，完整基因组. | AY463060 | 40457448 |
| SARS冠状病毒Shanhgai LY | SARS冠状病毒Shanhgai LY刺突糖蛋白基因，完整cds. | AY322205S3 | 32454341 |
| SARS冠状病毒Sin0409 | |||
| SARS冠状病毒Sin2500 | SARS冠状病毒Sin2500，完整基因组. | AY283794 | 30468042 |
| SARS冠状病毒Sin2677 | SARS冠状病毒Sin2677，完整基因组. | AY283795 | 30468043 |
| SARS冠状病毒Sin2679 | SARS冠状病毒Sin2679，完整基因组. | AY283796 | 30468044 |
| SARS冠状病毒Sin2748 | SARS冠状病毒Sin2748，完整基因组. | AY283797 | 30468045 |
| SARS冠状病毒Sin2774 | SARS冠状病毒Sin2774，完整基因组. | AY283798 | 37361915 |
| SARS冠状病毒Sin3408 | SARS冠状病毒Sin3408，完整基因组 | AY559083 | 45644998 |
| SARS冠状病毒Sin3408L | SARS冠状病毒Sin3408L，完整基因组 | AY559097 | 45645024 |
| SARS冠状病毒Sin3725V | SARS冠状病毒Sin3725V，完整基因组 | AY559087 | 45645004 |
| SARS冠状病毒Sin3765V | SARS冠状病毒Sin3765V，完整基因组 | AY559084 | 45645000 |
| SARS冠状病毒Sin842 | SARS冠状病毒Sin842，完整基因组 | AY559081 | 45644994 |
| SARS冠状病毒Sin845 | SARS冠状病毒Sin845，完整基因组 | AY559093 | 45645019 |
| SARS冠状病毒Sin846 | SARS冠状病毒Sin846，完整基因组 | AY559094 | 45645021 |
| SARS冠状病毒Sin847 | SARS冠状病毒Sin847，完整基因组 | AY559095 | 45645022 |
| SARS冠状病毒Sin848 | SARS冠状病毒Sin848，完整基因组 | AY559085 | 45645001 |
| SARS冠状病毒Sin849 | SARS冠状病毒Sin849，完整基因组 | AY559086 | 45645003 |
| SARS冠状病毒Sin850 | SARS冠状病毒Sin850，完整基因组 | AY559096 | 45645023 |
| SARS冠状病毒Sin852 | SARS冠状病毒Sin852，完整基因组 | AY559082 | 45644996 |
| SARS冠状病毒Sin_WNV | |||
| SARS冠状病毒Sino1-11 | SARS冠状病毒Sino1-11，完整基因组. | AY485277 | 38505482 |
| SARS冠状病毒Sino3-11 | SARS冠状病毒Sino3-11，完整基因组. | AY485278 | 38505491 |
| SARS冠状病毒SinP1 | SARS冠状病毒SinP1，完整基因组 | AY559088 | 45645007 |
| SARS冠状病毒SinP2 | SARS冠状病毒SinP2，完整基因组 | AY559089 | 45645010 |
| SARS冠状病毒SinP3 | SARS冠状病毒SinP3，完整基因组 | AY559090 | 45645013 |
| SARS冠状病毒SinP4 | SARS冠状病毒SinP4，完整基因组 | AY559091 | 45645016 |
| SARS冠状病毒SinP5 | SARS冠状病毒SinP5，完整基因组 | AY559092 | 45645017 |
| SARS冠状病毒SoD | SARS冠状病毒SoD，完整基因组. | AY461660 | 38385714 |
| SARS冠状病毒SZ1 | SARS冠状病毒SZ1，部分基因组. | AY304489 | 34482140 |
| SARS冠状病毒SZ13 | SARS冠状病毒SZ13，部分基因组. | AY304487 | 34482138 |
| SARS冠状病毒SZ16 | SARS冠状病毒SZ16，完整基因组. | AY304488 | 34482139 |
| SARS冠状病毒SZ3 | SARS冠状病毒SZ3，完整基因组. | AY304486 | 34482137 |
| SARS冠状病毒Taiwan | |||
| SARS冠状病毒Taiwan JC-2003 | |||
| SARS冠状病毒Taiwan TC1 | SARS冠状病毒Taiwan TC1，完整基因组. | AY338174 | 32493129 |
| SARS冠状病毒Taiwan TC2 | SARS冠状病毒Taiwan TC2，完整基因组. | AY338175 | 32493130 |
| SARS冠状病毒Taiwan TC3 | SARS冠状病毒Taiwan TC3，完整基因组. | AY348314 | 33188324 |
| SARS冠状病毒Tor2 | SARS冠状病毒TOR2，完整基因组. | AY274119 | 30248028 |
| SARS冠状病毒TW | |||
| SARS冠状病毒TW-GD1 | |||
| SARS冠状病毒TW-GD2 | |||
| SARS冠状病毒TW-GD3 | |||
| SARS冠状病毒TW-GD4 | |||
| SARS冠状病毒TW-GD5 | |||
| SARS冠状病毒TW-HP1 | |||
| SARS冠状病毒TW-HP2 | |||
| SARS冠状病毒TW-HP3 | |||
| SARS冠状病毒TW-HP4 | |||
| SARS冠状病毒TW-JC2 | |||
| SARS冠状病毒TW-KC1 | |||
| SARS冠状病毒TW-KC3 | |||
| SARS冠状病毒TW-PH1 |
| SARS冠状病毒TW-PH2 | |||
| SARS冠状病毒TW-YM1 | |||
| SARS冠状病毒TW-YM2 | |||
| SARS冠状病毒TW-YM3 | |||
| SARS冠状病毒TW-YM4 | |||
| SARS冠状病毒TW1 | SARS冠状病毒TW1，完整基因组. | AY291451 | 30698326 |
| SARS冠状病毒TW10 | SARS冠状病毒TW10，完整基因组. | AY502923 | 40548873 |
| SARS冠状病毒TW11 | SARS冠状病毒TW11，完整基因组. | AY502924 | 40548885 |
| SARS冠状病毒TW2 | SARS冠状病毒TW2，完整基因组. | AY502925 | 40548897 |
| SARS冠状病毒TW3 | SARS冠状病毒TW3，完整基因组. | AY502926 | 40548909 |
| SARS冠状病毒TW4 | SARS冠状病毒TW4，完整基因组. | AY502927 | 40548921 |
| SARS冠状病毒TW5 | SARS冠状病毒TW5，完整基因组. | AY502928 | 40548933 |
| SARS冠状病毒TW6 | SARS冠状病毒TW6，完整基因组. | AY502929 | 40548945 |
| SARS冠状病毒TW7 | SARS冠状病毒TW7，完整基因组. | AY502930 | 40548957 |
| SARS冠状病毒TW8 | SARS冠状病毒TW8，完整基因组. | AY502931 | 40548969 |
| SARS冠状病毒TW9 | SARS冠状病毒TW9，完整基因组. | AY502932 | 40548981 |
| SARS冠状病毒TWC | SARS冠状病毒TWC，完整基因组. | AY321118 | 31873092 |
| SARS冠状病毒TWC2 | SARS冠状病毒TWC2，完整基因组. | AY362698 | 33518724 |
| SARS冠状病毒TWC3 | SARS冠状病毒TWC3，完整基因组. | AY362699 | 33518725 |
| SARS冠状病毒TWH | SARS冠状病毒TWH基因组RNA，完整基因组. | AP006557 | 33411399 |
| SARS冠状病毒TWJ | SARS冠状病毒TWJ基因组RNA，完整基因组. | AP006558 | 33411414 |
| SARS冠状病毒TWK | SARS冠状病毒TWK基因组RNA，完整基因组. | AP006559 | 33411429 |
| SARS冠状病毒TWS | SARS冠状病毒TWS基因组RNA，完整基因组. | AP006560 | 33411444 |
| SARS冠状病毒TWY | SARS冠状病毒TWY基因组RNA，完整基因组. | AP006561 | 33411459 |
| SARS冠状病毒Urbani | SARS冠状病毒Urbani，完整基因组. | AY278741 | 30027617 |
| SARS冠状病毒Vietnam | |||
| SARS冠状病毒WHU | SARS冠状病毒WHU，完整基因组. | AY394850 | 40795428 |
| SARS冠状病毒xw002 | |||
| SARS冠状病毒ZJ01 | SARS冠状病毒ZJ01，完整基因组. | AY297028 | 30910859 |
| SARS冠状病毒ZMY1 | SARS冠状病毒ZMY1，完整基因组. | AY351680 | 33304219 |
| SARS冠状病毒ZS-A | SARS冠状病毒ZS-A，完整基因组. | AY394997 | 37624340 |
| SARS冠状病毒ZS-B | SARS冠状病毒ZS-B，完整基因组. | AY394996 | 37624339 |
| SARS冠状病毒ZS-C | SARS冠状病毒ZS-C，完整基因组. | AY395003 | 37624346 |
| SARS冠状病毒，TOR2完整基因组，curated | NC_004718 | 30271926 | |
| SARS冠状病毒ZJ01，部分基因组. | AY286320 | 39980888 | |
| SARS冠状病毒BJ302克隆1刺突糖蛋白基因，完整 | AY429072 | 38016580 | |
| SARS冠状病毒BJ302克隆2刺突糖蛋白基因，完整 | AY429073 | 38016582 | |
| SARS冠状病毒BJ302克隆3刺突糖蛋白基因，完整 | AY429074 | 38016584 | |
| SARS冠状病毒BJ302克隆4刺突糖蛋白基因，完整 | AY429075 | 38016586 | |
| SARS冠状病毒BJ302克隆5刺突糖蛋白基因，完整 | AY429076 | 38016588 | |
| SARS冠状病毒BJ302克隆6刺突糖蛋白基因， | AY429077 | 38016590 |
| 完整 | |||
| SARS冠状病毒BJ302克隆7刺突糖蛋白基因，完整 | AY429078 | 38016592 | |
| SARS冠状病毒BJ302克隆8刺突糖蛋白基因，完整 | AY429079 | 38016594 | |
| 人冠状病毒NL63 | Human冠状病毒NL63，完整基因组 | AY567487 | 49035964 |
| 与肺炎相关的人冠状病毒1群 | 与肺炎相关的人冠状病毒1群，完整基因组 | AY518894 | 46369870 |
表2在PER.C6
和Vero培养物以MOI 0.1感染12，24，48和72小时之后收获的培养物上清中测定的SARS-CoV效价。效价表示为log10±log10标准误。
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<110>克鲁塞尔荷兰公司(Crucell Holland B.V.)
<120>生产冠状病毒的细胞系
<130>0122 WO 00 ORD
<160>4
<170>PatentIn version 3.1
<210>1
<211>805
<212>PRT
<213>Homo sapiens
<400>1
Met Ser Ser Ser Ser Trp Leu Leu Leu Ser Leu Val Ala Val Thr Ala
1 5 10 15
Ala Gln Ser Thr Ile Glu Glu Gln Ala Lys Thr Phe Leu Asp Lys Phe
20 25 30
Asn His Glu Ala Glu Asp Leu Phe Tyr Gln Ser Ser Leu Ala Ser Trp
35 40 45
Asn Tyr Asn Thr Asn Ile Thr Glu Glu Asn Val Gln Asn Met Asn Asn
50 55 60
Ala Gly Asp Lys Trp Ser Ala Phe Leu Lys Glu Gln Ser Thr Leu Ala
65 70 75 80
Gln Met Tyr Pro Leu Gln Glu Ile Gln Asn Leu Thr Val Lys Leu Gln
85 90 95
Leu Gln Ala Leu Gln Gln Asn Gly Ser Ser Val Leu Ser Glu Asp Lys
100 105 110
Ser Lys Arg Leu Asn Thr Ile Leu Asn Thr Met Ser Thr Ile Tyr Ser
115 120 125
Thr Gly Lys Val Cys Asn Pro Asp Asn Pro Gln Glu Cys Leu Leu Leu
130 135 140
Glu Pro Gly Leu Asn Glu Ile Met Ala Asn Ser Leu Asp Tyr Asn Glu
145 150 155 160
Arg Leu Trp Ala Trp Glu Ser Trp Arg Ser Glu Val Gly Lys Gln Leu
165 170 175
Arg Pro Leu Tyr Glu Glu Tyr Val Val Leu Lys Asn Glu Met Ala Arg
180 185 190
Ala Asn His Tyr Glu Asp Tyr Gly Asp Tyr Trp Arg Gly Asp Tyr Glu
195 200 205
Val Asn Gly Val Asp Gly Tyr Asp Tyr Ser Arg Gly Gln Leu Ile Glu
210 215 220
Asp Val Glu His Thr Phe Glu Glu Ile Lys Pro Leu Tyr Glu His Leu
225 230 235 240
His Ala Tyr Val Arg Ala Lys Leu Met Asn Ala Tyr Pro Ser Tyr Ile
245 250 255
Ser Pro Ile Gly Cys Leu Pro Ala His Leu Leu Gly Asp Met Trp Gly
260 265 270
Arg Phe Trp Thr Asn Leu Tyr Ser Leu Thr Val Pro Phe Gly Gln Lys
275 280 285
Pro Asn Ile Asp Val Thr Asp Ala Met Val Asp Gln Ala Trp Asp Ala
290 295 300
Gln Arg Ile Phe Lys Glu Ala Glu Lys Phe Phe Val Ser Val Gly Leu
305 310 315 320
Pro Asn Met Thr Gln Gly Phe Trp Glu Asn Ser Met Leu Thr Asp Pro
325 330 335
Gly Asn Val Gln Lys Ala Val Cys His Pro Thr Ala Trp Asp Leu Gly
340 345 350
Lys Gly Asp Phe Arg Ile Leu Met Cys Thr Lys Val Thr Met Asp Asp
355 360 365
Phe Leu Thr Ala His His Glu Met Gly His Ile Gln Tyr Asp Met Ala
370 375 380
Tyr Ala Ala Gln Pro Phe Leu Leu Arg Asn Gly Ala Asn Glu Gly Phe
385 390 395 400
His Glu Ala Val Gly Glu Ile Met Ser Leu Ser Ala Ala Thr Pro Lys
405 410 415
His Leu Lys Ser Ile Gly Leu Leu Ser Pro Asp Phe Gln Glu Asp Asn
420 425 430
Glu Thr Glu Ile Asn Phe Leu Leu Lys Gln Ala Leu Thr Ile Val Gly
435 440 445
Thr Leu Pro Phe Thr Tyr Met Leu Glu Lys Trp Arg Trp Met Val Phe
450 455 460
Lys Gly Glu Ile Pro Lys Asp Gln Trp Met Lys Lys Trp Trp Glu Met
465 470 475 480
Lys Arg Glu Ile Val Gly Val Val Glu Pro Val Pro His Asp Glu Thr
485 490 495
Tyr Cys Asp Pro Ala Ser Leu Phe His Val Ser Asn Asp Tyr Ser Phe
500 505 510
Ile Arg Tyr Tyr Thr Arg Thr Leu Tyr Gln Phe Gln Phe Gln Glu Ala
515 520 525
Leu Cys Gln Ala Ala Lys His Glu Gly Pro Leu His Lys Cys Asp Ile
530 535 540
Ser Asn Ser Thr Glu Ala Gly Gln Lys Leu Phe Asn Met Leu Arg Leu
545 550 555 560
Gly Lys Ser Glu Pro Trp Thr Leu Ala Leu Glu Asn Val Val Gly Ala
565 570 575
Lys Asn Met Asn Val Arg Pro Leu Leu Asn Tyr Phe Glu Pro Leu Phe
580 585 590
Thr Trp Leu Lys Asp Gln Asn Lys Asn Ser Phe Val Gly Trp Ser Thr
595 600 605
Asp Trp Ser Pro Tyr Ala Asp Gln Ser Ile Lys Val Arg Ile Ser Leu
610 615 620
Lys Ser Ala Leu Gly Asp Lys Ala Tyr Glu Trp Asn Asp Asn Glu Met
625 630 635 640
Tyr Leu Phe Arg Ser Ser Val Ala Tyr Ala Met Arg Gln Tyr Phe Leu
645 650 655
Lys Val Lys Asn Gln Met Ile Leu Phe Gly Glu Glu Asp Val Arg Val
660 665 670
Ala Asn Leu Lys Pro Arg Ile Ser Phe Asn Phe Phe Val Thr Ala Pro
675 680 685
Lys Asn Val Ser Asp Ile Ile Pro Arg Thr Glu Val Glu Lys Ala Ile
690 695 700
Arg Met Ser Arg Ser Arg Ile Asn Asp Ala Phe Arg Leu Asn Asp Asn
705 710 715 720
Ser Leu Glu Phe Leu Gly Ile Gln Pro Thr Leu Gly Pro Pro Asn Gln
725 730 735
Pro Pro Val Ser Ile Trp Leu Ile Val Phe Gly Val Val Met Gly Val
740 745 750
Ile Val Val Gly Ile Val Ile Leu Ile Phe Thr Gly Ile Arg Asp Arg
755 760 765
Lys Lys Lys Asn Lys Ala Arg Ser Gly Glu Asn Pro Tyr Ala Ser Ile
770 775 780
Asp Ile Ser Lys Gly Glu Asn Asn Pro Gly Phe Gln Asn Thr Asp Asp
785 790 795 800
Val Gln Thr Ser Phe
805
<210>2
<211>5549
<212>DNA
<213>Artificial sequence
<220>
<223>pcDNA2004neo(-)
<400>2
gacggatcgg gagatctccc gatcccctat ggtcgactct cagtacaatc tgctctgatg 60
ccgcatagtt aagccagtat ctgctccctg cttgtgtgtt ggaggtcgct gagtagtgcg 120
cgagcaaaat ttaagctaca acaaggcaag gcttgaccga caattgcatg aagaatctgc 180
ttagggttag gcgttttgcg ctgcttcgct aggtggtcaa tattggccat tagccatatt 240
attcattggt tatatagcat aaatcaatat tggctattgg ccattgcata cgttgtatcc 300
atatcataat atgtacattt atattggctc atgtccaaca ttaccgccat gttgacattg 360
attattgact agttattaat agtaatcaat tacggggtca ttagttcata gcccatatat 420
ggagttccgc gttacataac ttacggtaaa tggcccgcct ggctgaccgc ccaacgaccc 480
ccgcccattg acgtcaataa tgacgtatgt tcccatagta acgccaatag ggactttcca 540
ttgacgtcaa tgggtggagt atttacggta aactgcccac ttggcagtac atcaagtgta 600
tcatatgcca agtacgcccc ctattgacgt caatgacggt aaatggcccg cctggcatta 660
tgcccagtac atgaccttat gggactttcc tacttggcag tacatctacg tattagtcat 720
cgctattacc atggtgatgc ggttttggca gtacatcaat gggcgtggat agcggtttga 780
ctcacgggga tttccaagtc tccaccccat tgacgtcaat gggagtttgt tttggcacca 840
aaatcaacgg gactttccaa aatgtcgtaa caactccgcc ccattgacgc aaatgggcgg 900
taggcgtgta cggtgggagg tctatataag cagagctcgt ttagtgaacc gtcagatcgc 960
ctggagacgc catccacgct gttttgacct ccatagaaga caccgggacc gatccagcct 1020
ccgcggccgg gaacggtgca ttggaagctt ggtaccggtg aattcggcgc gccgtcgacg 1080
atatcgatcg gaccgacgcg ttcgcgagcg gccgcaattc gctagcgtta acggatcctc 1140
gagtctagag tttaaaccgc tgatcagcct cgactgtgcc ttctagttgc cagccatctg 1200
ttgtttgccc ctcccccgtg ccttccttga ccctggaagg tgccactccc actgtccttt 1260
cctaataaaa tgaggaaatt gcatcgcatt gtctgagtag gtgtcattct attctggggg 1320
gtggggtggg gcaggacagc aagggggagg attgggaaga caatagcagg catgctgggg 1380
atgcggtggg ctctatggct tctgaggcgg aaagaaccag ctggggctct agggggtatc 1440
cccacgcgcc ctgtagcggc gcattaagcg cggcgggtgt ggtggttacg cgcagcgtga 1500
ccgctacact tgccagcgcc ctagcgcccg ctcctttcgc tttcttccct tcctttctcg 1560
ccacgttcgc cggctttccc cgtcaagctc taaatcgggg catcccttta gggttccgat 1620
ttagtgcttt acggcacctc gaccccaaaa aacttgatta gggtgatggt tcacgtagtg 1680
ggccatcgcc ctgatagacg gtttttcgcc ctttgacgtt ggagtccacg ttctttaata 1740
gtggactctt gttccaaact ggaacaacac tcaaccctat ctcggtctat tcttttgatt 1800
tataagggat tttggggatt tcggcctatt ggttaaaaaa tgagctgatt taacaaaaat 1860
ttaacgcgaa ttaattctgt ggaatgtgtg tcagttaggg tgtggaaagt ccccaggctc 1920
cccaggcagg cagaagtatg caaagcatgc atctcaatta gtcagcaacc aggtgtggaa 1980
agtccccagg ctccccagca ggcagaagta tgcaaagcat gcatctcaat tagtcagcaa 2040
ccatagtccc gcccctaact ccgcccatcc cgcccctaac tccgcccagt tccgcccatt 2100
ctccgcccca tggctgacta atttttttta tttatgcaga ggccgaggcc gcctctgcct 2160
ctgagctatt ccagaagtag tgaggaggct tttttggagg cctaggcttt tgcaaaaagc 2220
tcccgggagc ttggatatcc attttcggat ctgatcaaga gacaggatga ggatcgtttc 2280
gcatgattga acaagatgga ttgcacgcag gttctccggc cgcttgggtg gagaggctat 2340
tcggctatga ctgggcacaa cagacaatcg gctgctctga tgccgccgtg ttccggctgt 2400
cagcgcaggg gcgcccggtt ctttttgtca agaccgacct gtccggtgcc ctgaatgaac 2460
tgcaggacga ggcagcgcgg ctatcgtggc tggccacgac gggcgttcct tgcgcagctg 2520
tgctcgacgt tgtcactgaa gcgggaaggg actggctgct attgggcgaa gtgccggggc 2580
aggatctcct gtcatctcac cttgctcctg ccgagaaagt atccatcatg gctgatgcaa 2640
tgcggcggct gcatacgctt gatccggcta cctgcccatt cgaccaccaa gcgaaacatc 2700
gcatcgagcg agcacgtact cggatggaag ccggtcttgt cgatcaggat gatctggacg 2760
aagagcatca ggggctcgcg ccagccgaac tgttcgccag gctcaaggcg cgcatgcccg 2820
acggcgagga tctcgtcgtg acccatggcg atgcctgctt gccgaatatc atggtggaaa 2880
atggccgctt ttctggattc atcgactgtg gccggctggg tgtggcggac cgctatcagg 2940
acatagcgtt ggctacccgt gatattgctg aagagcttgg cggcgaatgg gctgaccgct 3000
tcctcgtgct ttacggtatc gccgctcccg attcgcagcg catcgccttc tatcgccttc 3060
ttgacgagtt cttctgagcg ggactctggg gttcggtgct acgagatttc gattccaccg 3120
ccgccttcta tgaaaggttg ggcttcggaa tcgttttccg ggacgccggc tggatgatcc 3180
tccagcgcgg ggatctcatg ctggagttct tcgcccaccc caacttgttt attgcagctt 3240
ataatggtta caaataaagc aatagcatca caaatttcac aaataaagca tttttttcac 3300
tgcattctag ttgtggtttg tccaaactca tcaatgtatc ttatcatgtc tgtataccgt 3360
cgacctctag ctagagcttg gcgtaatcat ggtcatagct gtttcctgtg tgaaattgtt 3420
atccgctcac aattccacac aacatacgag ccggaagcat aaagtgtaaa gcctggggtg 3480
cctaatgagt gagctaactc acattaattg cgttgcgctc actgcccgct ttccagtcgg 3540
gaaacctgtc gtgccagctg cattaatgaa tcggccaacg cgcggggaga ggcggtttgc 3600
gtattgggcg ctcttccgct tcctcgctca ctgactcgct gcgctcggtc gttcggctgc 3660
ggcgagcggt atcagctcac tcaaaggcgg taatacggtt atccacagaa tcaggggata 3720
acgcaggaaa gaacatgtga gcaaaaggcc agcaaaaggc caggaaccgt aaaaaggccg 3780
cgttgctggc gtttttccat aggctccgcc cccctgacga gcatcacaaa aatcgacgct 3840
caagtcagag gtggcgaaac ccgacaggac tataaagata ccaggcgttt ccccctggaa 3900
gctccctcgt gcgctctcct gttccgaccc tgccgcttac cggatacctg tccgcctttc 3960
tcccttcggg aagcgtggcg ctttctcaat gctcacgctg taggtatctc agttcggtgt 4020
aggtcgttcg ctccaagctg ggctgtgtgc acgaaccccc cgttcagccc gaccgctgcg 4080
ccttatccgg taactatcgt cttgagtcca acccggtaag acacgactta tcgccactgg 4140
cagcagccac tggtaacagg attagcagag cgaggtatgt aggcggtgct acagagttct 4200
tgaagtggtg gcctaactac ggctacacta gaaggacagt atttggtatc tgcgctctgc 4260
tgaagccagt taccttcgga aaaagagttg gtagctcttg atccggcaaa caaaccaccg 4320
ctggtagcgg tggttttttt gtttgcaagc agcagattac gcgcagaaaa aaaggatctc 4380
aagaagatcc tttgatcttt tctacggggt ctgacgctca gtggaacgaa aactcacgtt 4440
aagggatttt ggtcatgaga ttatcaaaaa ggatcttcac ctagatcctt ttaaattaaa 4500
aatgaagttt taaatcaatc taaagtatat atgagtaaac ttggtctgac agttaccaat 4560
gcttaatcag tgaggcacct atctcagcga tctgtctatt tcgttcatcc atagttgcct 4620
gactccccgt cgtgtagata actacgatac gggagggctt accatctggc cccagtgctg 4680
caatgatacc gcgagaccca cgctcaccgg ctccagattt atcagcaata aaccagccag 4740
ccggaagggc cgagcgcaga agtggtcctg caactttatc cgcctccatc cagtctatta 4800
attgttgccg ggaagctaga gtaagtagtt cgccagttaa tagtttgcgc aacgttgttg 4860
ccattgctac aggcatcgtg gtgtcacgct cgtcgtttgg tatggcttca ttcagctccg 4920
gttcccaacg atcaaggcga gttacatgat cccccatgtt gtgcaaaaaa gcggttagct 4980
ccttcggtcc tccgatcgtt gtcagaagta agttggccgc agtgttatca ctcatggtta 5040
tggcagcact gcataattct cttactgtca tgccatccgt aagatgcttt tctgtgactg 5100
gtgagtactc aaccaagtca ttctgagaat agtgtatgcg gcgaccgagt tgctcttgcc 5160
cggcgtcaat acgggataat accgcgccac atagcagaac tttaaaagtg ctcatcattg 5220
gaaaacgttc ttcggggcga aaactctcaa ggatcttacc gctgttgaga tccagttcga 5280
tgtaacccac tcgtgcaccc aactgatctt cagcatcttt tactttcacc agcgtttctg 5340
ggtgagcaaa aacaggaagg caaaatgccg caaaaaaggg aataagggcg acacggaaat 5400
gttgaatact catactcttc ctttttcaat attattgaag catttatcag ggttattgtc 5460
tcatgagcgg atacatattt gaatgtattt agaaaaataa acaaataggg gttccgcgca 5520
catttccccg aaaagtgcca cctgacgtc 5549
<210>3
<211>193
<212>PRT
<213>SARS-CoV
<400>3
Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Lys
1 5 10 15
Phe Pro Ser Val Tyr Ala Trp Glu Arg Lys Lys Ile Ser Asn Cys Val
20 25 30
Ala Asp Tyr Ser Val Leu Tyr Asn Ser Thr Phe Phe Ser Thr Phe Lys
35 40 45
Cys Tyr Gly Val Ser Ala Thr Lys Leu Asn Asp Leu Cys Phe Ser Asn
50 55 60
Val Tyr Ala Asp Ser Phe Val Val Lys Gly Asp Asp Val Arg Gln Ile
65 70 75 80
Ala Pro Gly Gln Thr Gly Val Ile Ala Asp Tyr Asn Tyr Lys Leu Pro
85 90 95
Asp Asp Phe Met Gly Cys Val Leu Ala Trp Asn Thr Arg Asn Ile Asp
100 105 110
Ala Thr Ser Thr Gly Asn Tyr Asn Tyr Lys Tyr Arg Tyr Leu Arg Hi s
115 120 125
Gly Lys Leu Arg Pro Phe Glu Arg Asp Ile Ser Asn Val Pro Phe Ser
130 135 140
Pro Asp Gly Lys Pro Cys Thr Pro Pro Ala Leu Asn Cys Tyr Trp Pro
145 150 155 160
Leu Asn Asp Tyr Gly Phe Tyr Thr Thr Thr Gly Ile Gly Tyr Gln Pro
165 170 175
Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu Asn Ala Pro Ala Thr
180 185 190
Val
<210>4
<211>240
<212>PRT
<213>Artificial sequence
<220>
<223>SARS-CoV S protein fragment S318-510 incuding additional sequence
s
<220>
<221>SIGNAL
<222>(1)..(21)
<223>
<220>
<221>BINDING
<222>(220)..(230)
<223>
<220>
<221>BINDING
<222>(235)..(240)
<223>
<220>
<221>PEPTIDE
<222>(22)..(214)
<223>
<400>4
Met Ala Cys Pro Gly Phe Leu Trp Ala Leu Val Ile Ser Thr Cys Leu
1 5 10 15
Glu Phe Ser Met Ala Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val
20 25 30
Phe Asn Ala Thr Lys Phe Pro Ser Val Tyr Ala Trp Glu Arg Lys Lys
35 40 45
Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Thr Phe
50 55 60
Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Ala Thr Lys Leu Asn Asp
65 70 75 80
Leu Cys Phe Ser Asn Val Tyr Ala Asp Ser Phe Val Val Lys Gly Asp
85 90 95
Asp Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Val Ile Ala Asp Tyr
100 105 110
Asn Tyr Lys Leu Pro Asp Asp Phe Met Gly Cys Val Leu Ala Trp Asn
115 120 125
Thr Arg Asn Ile Asp Ala Thr Ser Thr Gly Asn Tyr Asn Tyr Lys Tyr
130 135 140
Arg Tyr Leu Arg His Gly Lys Leu Arg Pro Phe Glu Arg Asp Ile Ser
145 150 155 160
Asn Val Pro Phe Ser Pro Asp Gly Lys Pro Cys Thr Pro Pro Ala Leu
165 170 175
Asn Cys Tyr Trp Pro Leu Asn Asp Tyr Gly Phe Tyr Thr Thr Thr Gly
180 185 190
Ile Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu
195 200 205
Asn Ala Pro Ala Thr Val Ser Arg Gly Pro Phe Glu Gln Lys Leu Ile
210 215 220
Ser Glu Glu Asp Leu Asn Met His Thr Gly His His His His His His
225 230 235 240
Claims (15)
1.一种衍生自原代人胚胎视网膜母细胞的人细胞，所述细胞在其基因组中包含编码腺病毒E1A和E1B的序列，特征在于所述细胞经工程化而表达人ACE2蛋白质。
2.权利要求1的人细胞，特征在于所述细胞是以保藏号ECACCno.96022940保藏的PER.C6细胞或其衍生物。
3.权利要求1或2的人细胞，特征在于所述人ACE2蛋白质被稳定表达。
4.一种生产冠状病毒的方法，所述方法包括如下步骤：
a)将编码人ACE2蛋白质的核酸分子提供给衍生自原代人胚胎视网膜母细胞的人细胞，所述细胞在其基因组中包含编码腺病毒E1A和E1B的序列，
b)将所述细胞在适于人ACE2蛋白质表达的条件下培养，
c)用冠状病毒感染所述细胞，和
d)从所述培养基或所述细胞中收获所述冠状病毒。
5.权利要求4的方法，特征在于所述冠状病毒选自SARS-CoV和HcoV-NL63组成的组。
6.权利要求4或5的方法，特征在于所述人细胞是以保藏号ECACC no.96022940保藏的PER.C6或其衍生物。
7.权利要求4-6任一项的方法，特征在于所述人ACE2蛋白质被稳定表达。
8.权利要求4-7任一项的方法，特征在于编码人ACE2蛋白质的核酸分子是由载体提供的。
9.权利要求4-8任一项的方法，特征在于所述人细胞能悬浮生长。
10.权利要求4-9任一项的方法，特征在于所述人细胞可以在无血清的条件下培养。
11.权利要求4-10任一项的方法，其进一步包括失活或减毒所收获的冠状病毒的步骤。
12.权利要求1-3任一项的人细胞在生产冠状病毒中的应用。
13.权利要求1-3任一项的人细胞在筛选抗冠状病毒的抗病毒剂中的应用。
14.一种鉴别能抑制冠状病毒感染和/或复制的分子的方法，所述方法包括如下步骤：
a)将权利要求1-3任一项的细胞与冠状病毒在有和无候选分子的条件下一起保温，和
b)确定所述候选分子的存在是否抑制冠状病毒感染和/或复制。
15.一种选择能降低冠状病毒对细胞的感染的抗病毒分子的方法，所述方法包括如下步骤：
a)将权利要求1-3任一项的细胞与冠状病毒的表面蛋白在有或无候选抗病毒分子的条件下接触，所述表面蛋白参与所述冠状病毒与由所述细胞表达的人ACE2蛋白质的结合，
b)测定所述细胞与所述表面蛋白之间的结合相互作用，和
c)选择与在无所述候选抗病毒分子的条件下的所述结合相互作用相比，使得该结合相互作用降低的候选抗病毒分子。
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| US70202905P | 2005-07-22 | 2005-07-22 | |
| US60/702,029 | 2005-07-22 | ||
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| EP05106768.4 | 2005-07-22 | ||
| PCT/EP2006/064489 WO2007010028A1 (en) | 2005-07-22 | 2006-07-21 | Cell line for producing coronaviruses |
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| CN101228267A true CN101228267A (zh) | 2008-07-23 |
| CN101228267B CN101228267B (zh) | 2013-01-23 |
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| CN2006800265222A Expired - Fee Related CN101228267B (zh) | 2005-07-22 | 2006-07-21 | 生产冠状病毒的细胞系 |
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| EP (1) | EP1907536B1 (zh) |
| JP (1) | JP5137829B2 (zh) |
| KR (1) | KR101274790B1 (zh) |
| CN (1) | CN101228267B (zh) |
| AT (1) | ATE463559T1 (zh) |
| AU (1) | AU2006271666B2 (zh) |
| CA (1) | CA2616221C (zh) |
| DK (1) | DK1907536T3 (zh) |
| WO (1) | WO2007010028A1 (zh) |
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| KR101206206B1 (ko) * | 2003-07-22 | 2012-11-29 | 크루셀 홀란드 비.브이. | 사스-코로나바이러스에 대한 결합분자 및 그것의 용도 |
| EP1907536B1 (en) | 2005-07-22 | 2010-04-07 | Crucell Holland B.V. | Cell line for producing coronaviruses |
| KR101485197B1 (ko) | 2006-09-07 | 2015-01-23 | 크루셀 홀란드 비.브이. | 인플루엔자 바이러스 ｈ5ｎ1을 중화시킬 수 있는 인간 결합분자 및 그것의 용도 |
| CN111273016B (zh) * | 2020-02-26 | 2021-06-15 | 浙江诺迦生物科技有限公司 | 一种基于s蛋白配体与ace2受体竞争法层析的冠状病毒快速检测的试剂盒 |
| WO2021207303A1 (en) * | 2020-04-07 | 2021-10-14 | Alsatech, Inc. | Immune stimulation against coronavirus infections |
| WO2021214467A1 (en) * | 2020-04-23 | 2021-10-28 | Cellbio | A diagnostic tool improvement comprising a pathogen binding molecule |
| CN111575242A (zh) * | 2020-06-04 | 2020-08-25 | 广东源心再生医学有限公司 | 一种用于COVID-19药物筛选的iPSC-nCoVN细胞模型及其建立和使用方法 |
| US20240035012A1 (en) * | 2020-08-21 | 2024-02-01 | Westlake University | Engineered ace2 oligomers and uses thereof |
| US20220226489A1 (en) | 2021-01-20 | 2022-07-21 | Singh Biotechnology, Llc | Therapeutics directed against coronavirus |
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| DK0833934T4 (da) * | 1995-06-15 | 2012-11-19 | Crucell Holland Bv | Pakningssystemer til human rekombinant adenovirus til anvendelse ved genterapi |
| US6855544B1 (en) * | 1999-04-15 | 2005-02-15 | Crucell Holland B.V. | Recombinant protein production in a human cell |
| DK1818408T3 (da) | 1999-05-17 | 2011-10-17 | Crucell Holland Bv | Rekombinant adenovirus af serotypen Ad11 |
| EP1103610A1 (en) * | 1999-11-26 | 2001-05-30 | Introgene B.V. | Production of vaccines from immortalised mammalian cell lines |
| FR2828405B1 (fr) | 2001-08-09 | 2005-06-24 | Virbac Sa | Vaccin anti-coronavirus |
| NZ538808A (en) | 2002-11-08 | 2008-03-28 | Crucell Holland Bv | Vaccines against west nile virus |
| WO2004111081A2 (en) | 2003-06-13 | 2004-12-23 | Crucell Holland B.V. | Antigenic peptides of sars coronavirus and uses thereof |
| WO2005012337A2 (en) | 2003-07-15 | 2005-02-10 | Crucell Holland B.V. | Antigenic peptides of sars coronavirus and uses thereof |
| WO2005012338A1 (en) | 2003-07-21 | 2005-02-10 | Crucell Holland B.V. | Antigenic peptides of sars coronavirus and uses thereof |
| KR101206206B1 (ko) | 2003-07-22 | 2012-11-29 | 크루셀 홀란드 비.브이. | 사스-코로나바이러스에 대한 결합분자 및 그것의 용도 |
| WO2005047459A2 (en) * | 2003-08-04 | 2005-05-26 | University Of Massachusetts | Sars nucleic acids, proteins, antibodies, and uses thereof |
| WO2005032487A2 (en) * | 2003-10-06 | 2005-04-14 | The Brigham And Women's Hospital, Inc. | Angiotensin-converting enzyme-2 as a receptor for the sars coronavirus |
| EP1907536B1 (en) | 2005-07-22 | 2010-04-07 | Crucell Holland B.V. | Cell line for producing coronaviruses |
-
2006
- 2006-07-21 EP EP06792538A patent/EP1907536B1/en active Active
- 2006-07-21 CA CA2616221A patent/CA2616221C/en active Active
- 2006-07-21 US US11/988,146 patent/US7888102B2/en active Active
- 2006-07-21 DK DK06792538.8T patent/DK1907536T3/da active
- 2006-07-21 WO PCT/EP2006/064489 patent/WO2007010028A1/en active Application Filing
- 2006-07-21 CN CN2006800265222A patent/CN101228267B/zh not_active Expired - Fee Related
- 2006-07-21 KR KR1020087001187A patent/KR101274790B1/ko active IP Right Grant
- 2006-07-21 AT AT06792538T patent/ATE463559T1/de active
- 2006-07-21 AU AU2006271666A patent/AU2006271666B2/en not_active Ceased
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| WO2007010028A1 (en) | 2007-01-25 |
| AU2006271666A1 (en) | 2007-01-25 |
| JP5137829B2 (ja) | 2013-02-06 |
| AU2006271666B2 (en) | 2011-04-07 |
| DK1907536T3 (da) | 2010-07-19 |
| KR101274790B1 (ko) | 2013-06-13 |
| JP2009502128A (ja) | 2009-01-29 |
| EP1907536A1 (en) | 2008-04-09 |
| CA2616221C (en) | 2011-07-05 |
| CA2616221A1 (en) | 2007-01-25 |
| US20090098530A1 (en) | 2009-04-16 |
| CN101228267B (zh) | 2013-01-23 |
| ATE463559T1 (de) | 2010-04-15 |
| EP1907536B1 (en) | 2010-04-07 |
| US7888102B2 (en) | 2011-02-15 |
| KR20080033270A (ko) | 2008-04-16 |
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