CN117396219A - 具有Kringle 5亚基的抗病毒蛋白 - Google Patents
具有Kringle 5亚基的抗病毒蛋白 Download PDFInfo
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Abstract
COVID‑19是由SARS‑CoV‑2病毒感染引起的,并迅速传播并感染了全世界。尽管冠状病毒刺突蛋白可以识别多种宿主细胞表面蛋白,但抑制刺突蛋白与称为GRP78的生存因子结合会导致SARS‑CoV‑2在肺和肾细胞中的附着、进入和复制显著减少。这种抑制作用是通过一种新型抑制剂来实现的,该抑制剂可有效阻断SARS‑CoV‑2刺突蛋白和整个病毒与表面结合的GRP78的结合。这些新型GRP78抑制剂还下调细胞因子(IL10、IL6)、免疫共抑制检查点蛋白(PD‑L1、B7H3、B7H4)并上调免疫共刺激蛋白(MHC‑II、CD‑86),从而导致在体外和体内降低受感染肺泡上皮细胞的免疫抑制性质。最后,这些新型GRP78抑制剂通过减少细胞表面纤溶酶的激活来抑制受感染肺细胞的纤溶亢进。
Description
优先权声明和引用并入
本申请要求2021年4月20日提交的美国专利申请序列号17235652的优先权,该专利申请通过引用并入本文,如同在本文中完整阐述一样。
相关技术的描述
COVID-19是“2019冠状病毒病”的缩写,是由一种名为SARS-CoV-2的冠状病毒感染引起的。这种病毒感染已被世界卫生组织宣布为大流行,并被疾病预防控制中心视为严重的公共卫生问题。COVID-19病例在全球范围内呈爆炸式增长,但迄今为止尚无获批的治疗方法。COVID-19可能会导致已有疾病的患者和老年人出现严重的呼吸道疾病,从而导致永久性肺损伤和死亡。
目前,两种抗疟疾药物氯喹和羟氯喹的使用都显示出在实验室中预防SARS-CoV-2病毒感染细胞的前景。最近,在使用羟氯喹和抗生素的少数针对COVID-19的初步临床试验中表明,接受治疗的患者血液中病毒数量的减少速度比未接受治疗的患者快得多。这些结果令人鼓舞,尽管心脏和神经损伤以及自杀念头的副作用是可以控制的,但它们仍然令人不安。这些研究还没有表明使用羟氯喹可以延长患者的寿命或更有可能康复。最后,在最近的一份报告中,另一种治疗方法Leronlimab(一种针对CCR5的抗体)在8名患者中显示出阳性结果。CCR5抑制剂已被证明可以减少COVID-19刺激的肺部炎症细胞因子风暴,从而为恢复提供更多时间。Leronlimab不是治疗方法或疫苗。同样,对治疗COVID-19的安全、有效的新药的需求迫切且尚未得到满足。
上述标签外疗法正在临床上用于治疗COVID-19患者,但其设计目的并不是特异性抑制SARS-CoV-2病毒的附着、进入和复制。尽管如此,这些标签外疗法已经显示出一些理想的反应。尽管一些结果看起来很有希望,但许多患者对这些疗法没有反应,世界各地仍有许多死亡发生。迫切需要专门针对SARS-CoV-2病毒感染的新药物。我们创造用于抗癌和抗免疫抑制的新型GRP78抑制剂的工作可能是急需的COVID-19新靶点和新疗法之一。
了解病毒和宿主细胞表面蛋白相互作用的机制有助于确定它们的趋向性、致病性并产生潜在的新抑制靶点。例如,最近的出版物描述了表面结合的GRP78在病毒进入和复制过程中的作用。GRP78被鉴定为柯萨奇病毒A9和登革热病毒的附着和进入的共同受体。此外,对于日本脑炎病毒(JEV)来说,细胞表面GRP78对于病毒进入很重要,对于病毒复制也至关重要。表面结合的GRP78还被认为是四种β冠状病毒(MERS-CoV、bCoV-HKU9、SARS-CoV和SARS-CoV-2)的附着因子。图1说明了冠状病毒如何使用GRP78作为辅助受体进行附着、内化和复制。肺气道细胞的病毒感染还会导致GRP78表面表达上调,从而导致受感染细胞的进一步附着和增强的病毒进入。
尽管冠状病毒刺突蛋白可以识别多种宿主细胞表面蛋白,但通过使用siRNA敲低、使用亚毒素A或抗体切割来抑制GRP78,会导致病毒附着、进入和复制显著减少。GRP78在人类气道受应激的上皮细胞和内皮细胞表面高表达。最近,研究表明,香烟烟雾增加了受应激的支气管上皮细胞表面GRP78的表达。由于事实证明,吸烟、吸电子烟、患有呼吸道疾病或年龄较大的人的COVID-19病情更为严重,因此我们怀疑该人群肺上皮细胞表面GRP78的表达明显较高。尽管仅表达GRP78不足以使非允许细胞易受MERS-CoV感染,但已表明GRP78对于病毒进入和复制至关重要。
发明内容
我发现A549腺癌人肺泡基底上皮细胞和VERO上皮细胞表面结合的GRP78上调免疫共抑制检查点蛋白PD-L1、B7H3、B7H4并下调免疫共刺激蛋白MHC-II和CD86。我还发现,表面结合的GRP78上调A549腺癌人肺泡上皮细胞上的细胞因子IL-10、IL6,从而导致免疫反应减弱。我创建了一类新型有效的抑制剂,可以特异性结合GRP78的N端结构域,阻断SARS-CoV-2病毒与GRP78的结合,并完全逆转肺上皮A549细胞和细胞因子的表达和免疫抑制表型。VERO上皮细胞(图1B)。应激的上皮细胞上调表面结合的GRP78,GRP78不仅充当SARS-COV-2病毒的共同受体,协助附着、进入和复制,而且还能减弱针对SARS-COV-2病毒和感染细胞的免疫反应。本发明的GRP78抑制剂可以显著减少SARS-COV-2病毒的附着、进入和复制,并在体外和体内降低受感染的肺泡上皮细胞的免疫抑制性质。
描述
德沃夏克博士发表说,肿瘤就像无法愈合的伤口。一个非常普遍的类比是,SARS-CoV-2感染也存在同样的机制,肺部感染就像无法愈合的伤口。病毒感染会对受感染的细胞产生巨大的压力,并增加GRP78的表达,就像肿瘤微环境(TME)中发生的那样。TME诱导促炎性、免疫抑制性肿瘤细胞,类似于在靶细胞上观察到的病毒感染情况。在共同待审的GRP78拮抗剂应用GRP78抑制剂中,Kr1Fc、K5Fc和K5可以阻断GRP78与细胞表面受体的相互作用,并降低肿瘤细胞的免疫抑制和炎症性质。我们现在首次证明,我们的GRP78抑制剂Kr1Fc、K5Fc和K5可以以nM效力阻断SARS-CoV-2刺突蛋白与GRP78的结合。此外,我们的GRP78抑制剂Kr1Fc和K5能够有效阻止整个活病毒、假型SARS-CoV-2附着和进入VERO肾上皮细胞。具体而言,共同待决的GRP78拮抗剂申请教导:
表面结合的GRP78抑制剂可阻断SARS-COV-2刺突蛋白的附着和进入。共同待审的GRP78拮抗剂应用教导了内皮细胞和癌细胞上的GRP78抑制剂。这些抑制剂现已针对SARS-COV-2病毒与GRP78和人肺细胞的结合进行了测试。一种先导抑制剂含有与人IgG1Fc结构域(Kr1Fc)融合的ROR1 kringle结构域,以高亲和力与GRP78的N末端结构域结合。本发明教导Kr1Fc、K5Fc和K5有效阻断SARS-COV-2刺突蛋白与GRP78的结合。所公开的GRP78抑制剂可有效阻断SARS-COV-2假型病毒的附着、进入和复制。
一种促进免疫耐受的新机制,且易于靶向。GRP78在应激细胞中的过度表达导致表面结合的GRP78大量增加。本发明教导人A549腺癌肺泡基底上皮细胞上表面结合的GRP78诱导A)细胞因子IL-10和IL-6、B)免疫共抑制检查点蛋白、PD-L1、B7H3、B7H4和的表达。C)抑制免疫共刺激蛋白、MHC-II和CD86的表达。通过用Kr1Fc阻断GRP78与表面蛋白的结合,可以逆转A549细胞的免疫抑制表型。在本发明中,抑制GRP78与SARS-COV-2刺突蛋白的结合将导致与SARS-COV-2感染相关的病毒载量、细胞因子风暴和免疫抑制的减少。
与GRP78 N端结构域结合的新型GRP78抑制剂可减少表面GRP78表达,而表面GRP78只在应激细胞上表达,而在正常细胞上不表达,因此比目前批准的其他抗病毒疗法更安全。本发明教导了与GRP78的N端结构域紧密结合的有效抑制剂,从而抑制SARS-CoV-2病毒的结合。在本发明中,表面结合的GRP78的抑制剂在CEREP受体结合和正常成纤维细胞增殖测定中是安全的。此前用于治疗COVID-19的疗法(如羟氯喹)与肺上皮细胞上的SARS-CoV-2受体ACE2结合较弱。事实上,ACE2在其他几种正常细胞上表达,并且羟氯喹具有如此弱的结合亲和力,这一事实支持了该药物在临床试验中发现的脱靶副作用。另一种被批准用于治疗SARS-CoV-2病毒的药物是瑞德西韦(Remdesivir)。瑞德西韦是一种腺苷类似物,可阻断病毒复制所必需的线粒体RNA聚合酶。然而,瑞德西韦对肠道和肺部有一些脱靶毒性,因此也必须谨慎使用。本发明教导在正常细胞表面不表达的GRP78是针对COVID-19的治疗的更安全且更有效的靶标。
本发明还教导,N端GRP78抑制剂通过抑制纤溶酶生成来阻断SARS-CoV-2病毒诱导的纤溶亢进和凝血病(coagulopat+hy)(“凝块风暴”)(图2)。重症COVID-19患者患有高血压、心脏病、糖尿病和癌症等已知会导致严重凝血病的合并症。97%的重症COVID-19患者在死亡前存在纤溶亢进,表现为血清D-二聚体水平升高。纤溶酶是纤维蛋白溶解亢进和D-二聚体水平的关键参与者,它还通过剪切其包膜蛋白上的弗林蛋白酶位点来增强SARS-CoV-2病毒的毒力和致病性。Kr1Fc、K5Fc和K5还可以阻断肺上皮和内皮细胞表面纤溶酶的激活,从而减少纤维蛋白溶解、D-二聚体形成和弗林蛋白酶位点裂解。我们的GRP78抑制剂不仅能显著阻断SARS-CoV-2病毒的附着、进入和复制,还能减少细胞因子风暴、抑制纤溶亢进并增强对SARS-CoV-2病毒的免疫监视(图2)。本发明教导N端结合GRP78抑制剂单独或与其他疗法组合将显著降低COVID-19的致病性。
附图的简要说明
图1是使用和不使用GRP78抑制剂时SARS-CoV-2病毒附着、进入和复制的示意图。
图2是我们的新型GRP78抑制剂抑制SARS-CoV-2病毒的示意图。
图3是Kr1Fc、K5Fc、Kr1和K5蛋白纯度、结构和与GRP78结合的分析。
图4A是示意图,显示N端GRP78抑制剂阻断GRP78与SARS-CoV-2刺突蛋白的结合。
图4B是显示N端GRP78抑制剂阻断GRP78与SARS-CoV-2刺突蛋白结合的图。
图5A是一系列图表,显示GRP78抑制剂阻断PE标记的SARS-CoV-2刺突蛋白与A549肺细胞的结合。
图5B是两个直方图,显示GRP78抑制剂阻断PE标记的SARS-CoV-2刺突蛋白与A549肺细胞的结合。
图6A是一系列图,显示GRP78抑制剂阻止SARS-CoV-2刺突蛋白-PE与VERO细胞结合。
图6B是两个直方图,显示GRP78抑制剂阻止SARS-CoV-2刺突蛋白-PE与VERO细胞结合。
图7A是一系列图,显示Kr1Fc和K5通过与VERO细胞预孵育或与刺突蛋白同时添加来阻止SARS-CoV-2刺突蛋白的结合。
图7B是两个直方图,显示Kr1Fc和K5通过与VERO细胞预孵育或与刺突蛋白同时添加来防止SARS-CoV-2刺突蛋白的结合。
图8A是一系列图,证明N末端GRP78抑制剂降低VERO细胞上表面结合的GRP78的表达。
图8B是两个直方图,证明N末端GRP78抑制剂降低VERO细胞上表面结合的GRP78的表达。
图9A是一系列图,证明N末端GRP78抑制剂降低A549肺细胞上表面结合的GRP78的表达。
图9B是两个图表直方图,证明N末端GRP78抑制剂降低A549肺细胞上表面结合的GRP78的表达。
图10A是示意图,显示VERO细胞上表面结合的GRP78表达(其被Kr1Fc和K5显著降低)对于SARS-CoV-2刺突蛋白内化至关重要。
图10B是一系列图,显示VERO细胞上表面结合的GRP78表达(其被Kr1Fc和K5显著降低)对于SARS-CoV-2刺突蛋白内化至关重要。
图10C是直方图,显示VERO细胞上表面结合的GRP78表达(其被Kr1Fc和K5显著降低)对于SARS-CoV-2刺突蛋白内化至关重要。
图11A是一张图,表明用N端GRP78结合蛋白Kr1Fc和K5抑制GRP78,有效且显著地抑制整个SARS-CoV-2假型病毒在VERO细胞上的附着和内化。
图11B是一张图,表明用N端GRP78结合蛋白Kr1Fc和K5抑制GRP78,有效且显著地抑制整个SARS-CoV-2假型病毒在VERO细胞上的附着和内化。
图12A是一系列图,其说明K5显著增强A549肺上由可溶性GRP78诱导的共抑制(PD-L1、B7H4)检查点蛋白和共刺激(CD86、MHC-II)蛋白表达细胞。
图12B是直方图,其说明K5显著增强A549肺细胞上由可溶性GRP78诱导的共抑制(PD-L1、B7H4)检查点蛋白和共刺激(CD86、MHC-II)蛋白表达。
图13A是一系列图,显示Kr1Fc显著增强可溶性GRP78诱导的共抑制(PD-L1,B7H4)检查点蛋白的表达和共刺激(CD86,MHC-II)蛋白表达。A549肺细胞。
图13A是柱状图,显示Kr1Fc显著增强A549肺上可溶性GRP78诱导的共抑制(PD-L1、B7H4)检查点蛋白的表达和共刺激(CD86、MHC-II)蛋白的表达细胞。
图14A和B是直方图,证明Kr1Fc和K5抑制可溶性GRP78诱导的来自A549肺细胞的IL10和IL6的细胞因子表达。
图15A是显示Kr1Fc和K5抑制VERO细胞表面上人纤溶酶原活化的示意图。
图15B是显示Kr1Fc和K5抑制VERO细胞表面上人纤溶酶原活化的直方图。
图16是显示每隔一天用Kr1Fc(60mg/kg)或K5(90mg/kg)处理的小鼠腹膜内没有表现出体重减轻或明显毒性的图。
图17是显示GRP78识别位点上的特定序列的细胞毒性和抗病毒活性的表格。
详细说明
我以前的出版物(通过引用并入)教导人纤溶酶原的第五个kringle结构域(K5)与表面GRP78结合以诱导肿瘤血管生成和肿瘤生长的抑制。然而,由于K5的作用机制未知且在小鼠和猴子中的半衰期较短(<20分钟),因此不被认为是良好的候选药物。通过确定可溶性GRP78如何与肿瘤细胞表面结合,鉴定出一种新型GRP78结合蛋白,称为受体酪氨酸激酶样受体-1(ROR1)。可以预见,ROR1的kringle结构域与K5非常相似(>70%)。ROR1kringle结构域Kr1与GRP78的结合比K5(Kd=0.6nM)紧密100倍(Kd=0.005nM)。本发明还显示ROR2与K5具有>70%的同源性并且将具有与ROR1 kringle结构域相似的活性。如图3所示,本发明公开了新型kringle融合蛋白,其含有ROR1 kringle结构域、Kr1和人IgG1Fc结构域。已证明在肽中添加IgG Fc结构域可以延长血浆半衰期。我们现已在Expi293FHEK细胞和ExpiCHO细胞中表达融合蛋白Kr1Fc和K5Fc,并通过Protein A柱纯化它们。重组Kr1Fc、Kr1、K5和K5Fc蛋白与作为第二纯化柱的苯甲脒-琼脂糖的结合表明kringle结构域正确折叠。在撰写本文时,我已表达并纯化了约600毫克Kr1Fc、2毫克K5Fc、10毫克Kr1和600毫克K5。通过引用并入的参考文献公开了用作抗癌剂的可溶性GRP78抑制剂Kr1Fc、K5Fc、Kr2Fc和Kr1。
结合抑制示例#1
GRP78抑制剂Kr1Fc、K5Fc和K5抑制SARS-CoV-2刺突蛋白与GRP78的结合。
现有技术描述了GRP78与SARS-CoV-2病毒的刺突蛋白结合。现有技术没有公开SARS-CoV-2刺突蛋白与GRP78的结合亲和力是多少。使用ELISA测定,本发明检查GRP78-HRP与板结合的SARS-CoV-2刺突蛋白的结合,Kd为293±35nM。为了确定Kr1Fc、K5Fc和K5是否可以阻断这种结合,本发明教导用SARS-CoV-2刺突蛋白(100nM)在4℃下过夜包被96孔板。然后用脱脂牛奶在室温下封闭板30分钟。然后将HRP标记的GRP78(200nM)添加到含有不同浓度的Kr1Fc、K5Fc、K5和阴性对照、未折叠Kr1Fc的板中。然后将板在室温下孵育2小时。最后,用PBS清洗孔,然后向每个孔中添加1-step ultra TMB-ELISA试剂,并在室温下孵育60分钟,然后在分光光度计上以450nM读数。图4显示Kr1Fc、K5Fc和K5抑制GRP78与SARS-CoV-2刺突蛋白的结合,IC50值分别为0.35nM、28.5nM和460nM。未折叠的Kr1Fc阴性对照未显示对SARS-CoV-2刺突蛋白与GRP78结合的抑制。本发明表明本发明的GRP78 N-末端结合抑制剂有效阻断GRP78和SARS-CoV-2刺突蛋白结合。
结合抑制示例#2
GRP78抑制剂Kr1Fc和K5在4℃下抑制SARS-CoV-2刺突蛋白与A549肺泡上皮腺癌细胞的结合。
在图5中,本发明检查了Kr1Fc和K5是否可以阻断PE标记的SARS-CoV-2刺突蛋白与A549肺细胞的结合。将A549细胞(50,000个细胞/100uL)添加至含PBS的Eppendorf管中。将不同浓度的GRP78抑制剂和50nM PE标记的SARS-CoV-2刺突蛋白添加到细胞中,并在4℃下孵育过夜,以阻止受体的内化。用PBS洗涤细胞2次,并在Guava PCA流式细胞仪上运行。使用的阴性对照是人IgG1-PE抗体。流式细胞术分析显示,SARS-CoV-2-PE刺突蛋白与52%的A549细胞结合,而对照IgG1-PE抗体与23%的细胞结合。100nM的Kr1Fc显著阻断SARS-CoV-2-PE刺突蛋白与A549肺上皮细胞的结合超过99%,而500nM的K5则阻断SARS-CoV-2-PE刺突蛋白与A549肺上皮细胞的结合70%左右。这些结果表明,GRP78对于SARS-CoV-2病毒与A549肺上皮细胞的结合非常重要。
结合抑制示例#3
GRP78抑制剂Kr1Fc和K5在37℃时抑制SARS-CoV-2刺突蛋白与VERO细胞的结合。
本发明检查N端GRP78抑制剂是否可以阻断SARS-CoV-2刺突蛋白与VERO猴上皮肾细胞的结合。已知VERO细胞高表达SARS-CoV-2受体ACE2,因此非常容易受到SARS-CoV-2病毒感染。本发明教导,用GRP78抑制剂预温育VERO细胞以及通过与SARS-CoV-2刺突蛋白同时添加GRP78抑制剂都会导致刺突蛋白结合的显著且有效的抑制。将PBS中的VERO细胞(50,000/100uL)添加至Eppendorf管中。将100nM的Kr1Fc或500nM的K5添加到一半的VERO细胞管中,预孵育6小时。添加50nM PE标记的SARS-CoV-2刺突蛋白之前。在装有细胞的另一半管中,与上面列出的GRP78抑制剂同时添加PE标记的SARS-CoV-2刺突蛋白。将细胞管在37℃下温和摇动孵育。24小时后,将细胞旋转并用PBS洗涤两次。将新鲜的PBS添加到细胞中,并在Guava PCA流式细胞仪上检测与VERO细胞结合的PE标记的SARS-CoV-2刺突蛋白的流式细胞术分析。在本发明中,GRP78抑制剂Kr1Fc和K5在与GRP78抑制剂预孵育6小时或不预孵育的情况下表现出对SARS-CoV-2刺突蛋白结合的抑制(图6和7)。100nM的Kr1Fc对SARS-CoV-2刺突蛋白与VERO细胞的结合具有超过90%的抑制作用。500nM的K5对SARS-CoV-2刺突蛋白与VERO细胞的结合具有>80%的抑制作用。GRP78抑制剂在VERO细胞上的预孵育会增强对SARS-CoV-2结合的抑制。
表面结合GRP78的内化示例#4
Kr1Fc和K5处理后,表面结合的GRP78显著减少。
在本发明中,将Kr1Fc(100nM)和K5(500nM)分别添加至含有50,000个A549细胞或50,000个VERO细胞的Eppendorf管中,一式三份。将细胞和GRP78抑制剂在37℃下孵育24小时。通过离心沉淀细胞并用PBS洗涤两次。然后每管添加1ul用PE(1mg/ml)标记的抗GRP78单克隆抗体。还将人IgG1-PE抗体的阴性对照添加到未处理细胞的试管中。抗GRP78-PE抗体在室温下孵育1小时后,用PBS洗涤细胞两次并通过Guava流式细胞仪分析表面结合的GRP78。图8表明,用GRP78抑制剂Kr1Fc和K5处理VERO细胞,显著降低了细胞表面GRP78的表达。图9显示用GRP78抑制剂、Kr1Fc和K5处理A549肺细胞使表面结合的GRP78的浓度显著降低了80%以上。比较A549和VERO细胞上表面结合GRP78的表达,很明显VERO细胞具有更高水平的表面结合GRP78。由于这些细胞更容易接受病毒感染,本发明和数据表明,对于感染性而言,不仅表面ACE2的水平而且GRP78的水平也很重要。由于这些GRP78抑制剂降低了表面结合的GRP78水平,这是否仅导致病毒结合的减少,还是GRP78也负责SARS-CoV-2刺突病毒的内化。
内化抑制示例#5
Kr1Fc和K5抑制VERO细胞中pHrodo-red标记的SARS-CoV-2刺突蛋白内化。
本发明检查了表面结合的GRP78抑制是否可以抑制SARS-CoV-2刺突蛋白的结合并阻止其内化。如图10A所示,SARS-CoV-2刺突蛋白用pHRodo-red染料标记,该染料在pH 7(细胞表面)时具有弱荧光,但在pH 4(细胞内部)时具有强荧光,从而可以进行检测刺突蛋白内化。将VERO细胞与GRP78抑制剂、Kr1Fc和K5预孵育6小时。6小时后,将Rodo-red标记的SARS-CoV-2刺突蛋白添加到VERO细胞中,并在37℃下温和振荡孵育24小时。然后将细胞沉淀,洗涤两次,并在Guava PCA流式细胞仪上进行流式细胞术分析,以检测内化刺突蛋白的抑制。在图10B中,本发明显示Rodo-red标记的SARS-CoV-2刺突蛋白在48小时内在约52%的VERO细胞中内化。37℃。当VERO细胞与GRP78抑制剂、Kr1Fc或K5预孵育时,Rodo-red标记的SARS-CoV-2刺突蛋白的内化被显著抑制90-95%,与Rodo-red标记的IgG1抗体阴性对照相似。在这两个例子中,A549和VERO细胞GRP78抑制剂可防止SARS-CoV-2刺突蛋白内化。
整个SARS-CoV-2病毒中和示例#6
GRP78抑制剂Kr1Fc和K5可中和VERO细胞的SARS-CoV-2假型病毒感染。
在本发明中,由IBT Bioservices(Rockville,MD)进行改良的SARS-CoV-2病毒测定。在该检测中,通过用编码荧光素酶蛋白的RNA替换SARS-CoV-2病毒的复制RNA片段来生成SARS-CoV-2假型病毒以进行检测。其余的结构蛋白(刺突蛋白、包膜蛋白、基质蛋白和核衣壳蛋白)保持完整。这使得SARS-CoV-2(rVSV-SARS-CoV-2(D614G))假型病毒能够附着并内化,但不能复制。本发明教导Kr1Fc和K5可以阻止完整的SARS-CoV-2假型病毒附着并进入VERO细胞。在图11A中,两种化合物表现出有效的活性,Kr1Fc的IC50值为3.5uM,K5的IC50值为47.4uM。该测定使用K5 0.5nM至500uM的八种稀释度和Kr1Fc 0.01nM至62uM的八种稀释度进行。将这些稀释液添加到96孔板中含有VERO细胞(每孔1x105个细胞)的一式三份孔中。根据本发明的孔在每个孔中以25,000-35,000相对光单位被SARS-CoV-2假型病毒感染。将板孵育24小时,洗涤附着的细胞,然后使用Bright-Glo Assay System Kit(Promega)读取每个孔的荧光素酶活性。还针对不含病毒的VERO细胞平行测定了测试化合物的毒性(图10B)。通过回归分析计算50%和90%有效中和浓度(IC50、IC90)和50%细胞死亡浓度(细胞毒性、CC50)值以证明功效。计算了选择性指数(SI90)(CC90除以IC90),它表示1log抑制的细胞毒性和抗病毒活性之间的安全窗,如图17所示。SI90值越高,抑制剂越有效和安全。
免疫抑制抑制示例#7
Kr1Fc、K5Fc和K5逆转sGRP78结合诱导的腺癌肺泡肺上皮细胞(A549)的免疫抑制表型。本发明解决了可溶性和表面结合的GRP78是否会增强肺细胞上的检查点蛋白表达,与已报道的树突状细胞相似,GRP78已被证明在病毒感染期间受到刺激。为了确定这一点,将sGRP78(5ug/ml)添加到A549细胞中,并在37C/5% CO2下+Kr1Fc培养3天。3天后,将细胞固定(未透化),用荧光标记抗体染色,并对共抑制剂检查点蛋白、PD-L1、B7H3、B7H4和共刺激蛋白MHC-II、CD86进行流式细胞术分析。本发明检查了在有和没有Kr1Fc、K5Fc和K5抑制剂的情况下表面GRP78的表达。我们选择5ug/ml sGRP78的浓度,因为已表明sGRP78在癌症和类风湿性关节炎患者中循环的浓度约为该浓度。图12和13显示sGRP78诱导A549细胞上免疫抑制性检查点蛋白PD-L1、B7H3、B7H4的表达显著增加,并且免疫刺激蛋白MHC-II和CD86的表达降低。Kr1Fc和K5完全逆转了这种免疫抑制表型。
细胞因子表达抑制实施例#8
此前,我们已经证明可溶性GRP78诱导肿瘤细胞上的细胞因子表达。在许多方面,病毒感染模仿肿瘤微环境,因此我们确定可溶性GRP78可以上调A549肺细胞上IL10和IL6的表达。在图14中,我们现在显示Kr1Fc和K5抑制来自A549肺细胞的可溶性GRP78诱导的IL10和IL6的细胞因子表达。将A549细胞(50,000)添加到含有完整DMEM培养基的Eppendorf管中。在一半管中,添加可溶性GRP78(5ug/ml)以及K5(500nM)或Kr1Fc(100nM)。使用IgG人抗体作为阴性对照。在37℃温和振荡下孵育3天后,将细胞离心并使用IL10或IL6 ELISA测定试剂盒(R&D Systems)测试上清液。每个试剂盒的方案均按照制造商的说明进行,并且在使用和使用GRP78抑制剂的A549细胞上的每种条件下每种细胞因子的pg/ml从标准曲线计算。使用Kr1Fc和K5 GRP78抑制剂观察到对A549细胞细胞因子表达的显著且剂量依赖性抑制。
纤溶酶原激活抑制实施例#9
Kr1Fc和K5阻断纤溶酶形成诱导的纤溶亢进。
患有糖尿病、高血压、肺癌和心脏病的人感染SARS-CoV-2病毒的风险更高,死亡的机会也更大。COVID-19导致死亡的主要原因是出血或出血性疾病,该疾病的特征之一是负责清除血栓的系统过度活跃(纤溶亢进)。这种异常凝血病是由导致纤溶酶的纤溶酶原水平升高引起的。最近的出版物表明,在导致COVID-19患者预后较差的所有合并症中,纤溶酶水平升高是一个常见因素。纤溶酶原通常作为非活性蛋白质在血液中循环。一旦发生损伤或病变(图2、图15A(红色)),纤溶酶原就会被激活为其活性形式,称为纤溶酶。然后,纤溶酶通过剪切纤维蛋白原,产生称为D-二聚体的纤维蛋白原片段,溶解病变处的血凝块。超过97%的重症COVID-19住院患者的D-二聚体水平升高。D-二聚体水平与体内检测到的病毒数量相关,并且随着COVID-19严重程度的增加而持续上升。在COVID-19幸存者中,D-二聚体水平降至对照水平。纤溶酶和D-二聚体水平高于正常水平可导致严重出血。一些出版物表明,纤溶酶原通过其kringle结构域之一kringle 5(K5)与表面结合的GRP78结合。事实上,GRP78与纤溶酶原的结合显著提高了其对纤溶酶的激活率。由于我们的GRP78抑制剂Kr1Fc、K5Fc和K5由纤溶酶原K5 kringle结构域或类似的kringle结构域(Kr1)组成,因此我们可以证明这些抑制剂可显著降低肺细胞上纤溶酶原向纤溶酶的激活超过70%(图15)。纤溶酶形成的减少应导致纤维蛋白溶解亢进和D-二聚体形成减少,从而减少重症COVID-19患者中观察到的出血性疾病。
安全概况示例#9
Kr1Fc和K5与受体和离子通道蛋白没有不良结合,也没有对原代人类细胞产生毒性。
为了确定可能的毒性,使用Kr1Fc(10uM)或K5(100uM)对75个受体和离子通道进行了受体结合谱测定,并对5个人类原代细胞系(从单一供体来源进行了验证)进行了细胞毒性测定。由CEREP/Eurofins确定。没有观察到特异性结合或毒性,表明Kr1Fc表现出安全、选择性的生化特征,并且不太可能在体内产生不良影响。
安全概况示例#10
在分别以60mg/kg和90mg/kg剂量处理GRP78抑制剂Kr1Fc和K5的小鼠中,没有观察到体重减轻或明显的毒性。
本发明检测了GRP78抑制剂Kr1Fc和K5对8周龄BALB/c小鼠的毒性。三组小鼠按每只动物的体重按10mL/kg的体积腹膜内(i.p.)给药。治疗组如下:
第1组接受载体(PBS pH 7.2)。
第2组每隔一天(qod)腹膜内注射60mg/kg Kr1Fc,直至第26天。
第3组每隔一天(qod)接受90mg/kg K5,直至第26天。
第1-5天每天对动物称重,然后每周两次称重,直到第26天。经常观察小鼠是否有任何不良、治疗相关(TR)副作用的明显迹象,并在观察时记录临床症状。按照方案监测个体体重,任何一次测量体重减轻超过30%或连续三次测量体重减轻超过25%的动物均被视为TR死亡而被安乐死。还根据查尔斯河发现服务协议(Charles River Discovery Servicesprotocol)监测组平均体重减轻。可接受的毒性定义为研究期间组平均体重(BW)损失低于20%,TR死亡人数不超过10%。如果死亡是由临床症状和/或尸检证明的治疗副作用引起的,则将死亡归类为TR。
图16显示,Kr1Fc和K5在按上述剂量给药的小鼠中没有表现出明显的毒性或体重减轻。这些结果支持了上述CEREP/Eurofins体外毒性测试,并表明本发明列出的GRP78抑制剂类型在临床研究中是安全的、低毒性的。
K5Fc、K5和Kr1Fc开发的化学、制造和控制(CMC)方面。
根据本发明,从业者将表达和纯化Kr1Fc、K5Fc、K5并进行CMC测定,以验证Kr1Fc、K5Fc和K5批次对体外和体内SARS-CoV-2病毒的纯度、效力和功效抑制研究。目前,Kr1Fc、K5Fc和K5在Expi293和ExpiCHO细胞中瞬时表达。由于需要正确折叠的Kringle结构域和Fc结构域的糖基化,哺乳动物细胞表达是必要的。根据本发明,将产生并储存表达Kr1Fc、K5Fc和K5的稳定CHO克隆,用于监管备案。根据本发明,从业者将验证Kr1Fc、K5Fc和K5批次的纯度、效力和身份的测定。为了验证Kr1Fc、K5Fc和K5的批次间质量,变性Kr1Fc的阴性对照和Kr1Fc的阳性标准批次被储存并在每次测定中用于比较。
统计分析:
根据本发明,化学、制造和控制(CMC)方面的测定由两个不同的研究人员在两个不同的场合一式三份地进行。计算所有测定的吸光度、密度和EC50值的平均平均值加上标准偏差。任何与我们的对照标准批次显著不同的复合批次(p<0.05,假设正态分布和等方差的学生双尾t检验)将不会用于进一步测试。
批次间纯度、效力和变异性:
根据本发明,Kr1Fc、K5Fc和K5批次的纯度通过对药物浓度进行280nm OD测量、用于药物纯度的考马斯染色SDSPAGE凝胶的光密度分析(GelQuant)和质谱分析(服务收费)来确定为了药品质量。这些测定用于确保Kr1Fc保持所需的质量。对于所有体外研究,阴性对照是Kr1Fc与变性、死亡的Kr1Fc以不同比例(10%至90%)混合,以定义每次测定的限度;对于阳性对照,留出一批Kr1Fc用于比较不同批次之间的所有测定。
根据本发明,使用Kr1Fc、或K5Fc、或K5与GRP78之间的直接结合ELISA测定来确定Kr1Fc、K5Fc和K5批次的效力。将PBS中100nM的全长his标记GRP78(StressMart)连接到镀镍96孔板(Pierce)。0.5至50nM之间的各种浓度的抑制剂在4C下结合。按照制造商的说明(Pierce),用10% BSA封闭板,并用含有0.05%去污剂的PBS清洗。最后,添加小鼠抗人Fc HRP标记的抗体,并用TMB ELISA(Sigma)试剂评估结合的Kr1Fc、K5Fc或K5的检测。对Kr1Fc、K5Fc和K5批次进行二次结合测定,测量SARS-COV-2刺突蛋白和GRP78之间的Kr1Fc竞争结合,如我们的结果中所述(图4)。
根据本发明,Kr1Fc批次的功能功效通过检查免疫共抑制检查点(PD-L1、B7H3、B7H4)和免疫共刺激(CD86、MHC-II)蛋白表达来确定。如图5所示,将sGRP78(5ug/ml)添加至肺上皮腺癌A549细胞中,并在37C/5% CO2下+Kr1Fc培养3天。3天后,用Versene去除细胞,固定,然后用荧光标记抗体染色并进行流式细胞术分析。
信噪比大于两倍且能够检测>10%杂质的测定,以及效力和功能测定的EC(50)值<
200nM EC(50)值的测定被认为是有效的。
在药物纯度和同一性方面,质谱法可以可靠地检测出低于5%的杂质。除功能检查点蛋白表达测定外,所有测定均满足两倍信噪比要求。另一种方法是使用Kr1Fc测试A549细胞信号通路中的蛋白质磷酸化。利用通过PI3K、SMAD2/3、STAT3的信号传导途径的蛋白质磷酸化测定在现有技术中是已知的。这些信号通路分析提供了一种快速、准确的方法来测试大量Kr1Fc的活性和功能。
根据本发明,GRP78抑制剂Kr1Fc、K5Fc和K5阻断SARS-CoV-2刺突蛋白结合和对肺上皮A549和VERO细胞的内化作用的功效已经确定和验证。
所公开的Kr1Fc、K5Fc和K5抑制剂有效阻断SARS-CoV-2刺突蛋白与GPR78的结合(图4A)。就像肿瘤一样,病毒感染会产生炎症、免疫逃避的微环境。通过引用并入的参考文献表明,应激细胞将GRP78重新定位至细胞表面。表面结合的GRP78通过上调共抑制检查点蛋白的表达和下调共刺激蛋白的表达来诱导免疫抑制。GRP78还会增加IL-10和IL-6等炎症细胞因子的表达。通过用我们的GRP78抑制剂阻断GRP78的活性以及对肺、肾上皮和内皮细胞表面的结合,实施本发明的人可以完全逆转人肺泡肺上皮腺癌A549细胞、VERO上皮和内皮细胞的免疫抑制和炎症性质。此外,研究表明,阻断GRP78的N端结构域可减少包括β冠状病毒在内的多种病毒的附着、进入和复制。因此,我们在这些研究中表明,我们的GRP78抑制剂与GRP78的N端结构域结合,将产生与siRNA或N端GRP78抗体类似的针对SARS-CoV-2病毒的效果。
根据本发明,Kr1Fc和K5针对完全假型SARS-CoV-2病毒(rVSV-SARS-CoV-2(D614G))的中和活性能够防止病毒附着并进入培养物中生长的VERO细胞。两种化合物表现出有效的活性,Kr1Fc的IC(50)值为3.448uM,K5的IC(50)值为47.35。将K5的0.5nM至500uM的八种稀释液和Kr1Fc的0.01nM至62uM的八种稀释液添加到含有细胞的一式三份孔中。根据本发明的孔以每孔25,000-35,000相对光单位被SARS-CoV2假型病毒感染。将板温育24小时,洗涤附着的细胞,然后使用Bright-Glo测定系统试剂盒(Promega)读取每个孔的荧光素酶活性。还针对不含病毒的VERO细胞平行测定了测试化合物的毒性。通过回归分析计算50%和90%有效中和浓度(IC50、IC90)和50%细胞死亡浓度(细胞毒性、CC50)值以证明功效。选择性指数(SI50)(CC50除以IC50)表示细胞毒性和抗病毒活性之间的安全窗,计算结果如表1所示。SI50值越高,抑制剂越有效和安全。
根据本发明,病毒附着的有效抑制是可证明的。GRP78在应激细胞和肿瘤细胞中是表面结合的,根据本发明,从业者可以将GRP78添加到A549和VERO细胞的培养基中以产生用于病毒附着和内化的细胞系。根据本发明,K5、K5Fc和Kr1Fc将使表面结合的GRP78减少>90%。根据本发明,用Kr1Fc处理的A549细胞观察到的免疫抑制的逆转证明了可以减少体内病毒病理学的反应。
根据本发明,Kr1Fc将在急性呼吸窘迫综合征致死小鼠模型(BALB/c小鼠)中抑制适应的SARS冠状病毒。SARS-COV-2病毒会造成一种高度致命的严重急性呼吸系统综合症。迄今为止,还没有直接批准用于治疗β冠状病毒感染的药物。造成这种情况的部分原因是缺乏合适的药物测试动物模型。研究人员正在用SARS病毒测试猕猴、狨猴、仓鼠、猫和雪貂的多种动物模型,但很少有模型能够模仿SARS-CoV-2病毒的致病性。最近,戴等人已经适应并表征了一种新的SARS-CoV毒株(v2163),该毒株以肺部为目标,对BALB/c小鼠具有高度致命性。该模型很大程度上模仿了人类的COVID-19疾病。由于费用低、易于操作且所需药物量最少,当根据本发明实践时,该模型证明了具有人SARS-CoV病毒的GRP78抑制剂。由于小鼠和人类GRP78 98%相同,这种性质的研究表明Kr1Fc药物将阻断GRP78在小鼠和人类中的活性,从而大大减少肺细胞的感染。
实验
根据本发明,Kr1Fc和K5的抗病毒活性是使用称为V2163的Urbani SARS-CoV的小鼠适应株来证明的。通过鼻内(i.n.)递送,给半雄性和半雌性BALB/c小鼠接种50uL含有104CCID50(细胞培养感染剂量50%终点)的SARS-CoV-V2163病毒。四组小鼠(每组10只小鼠)分别给予100mg/kg/天的K5、50mg/kg/天的Kr1Fc和PBS,pH 7.4阴性对照,以及本模型所用符合机构标准的阳性对照用于抗病毒研究。所有Kr1Fc和K5样品均在腹腔注射前16小时在肩胛骨之间腹腔注射、每日一次给药。未来7天的感染。每天观察小鼠,并在整个研究过程中测量组体重。在病毒暴露后第21天观察小鼠的死亡情况。体重下降超过初始体重30%的动物将被人道安乐死,安乐死当天被指定为死亡日。观察处死小鼠的肺的总体病理学和变色,并指定范围从0(正常出现的肺)到4(100%肺的最大李子色)的分数。将每个测试组的小鼠肺样本合并并在MEM溶液中均质化,并使用病毒产量测定法测定A)感染性病毒,B)细胞因子分析(IL-6、IL-1和IL-10)和免疫细胞浸润(NK)、巨噬细胞、T细胞和DC)。通过假设等方差和正态分布的对数变换值的方差分析,将病毒滴度、细胞因子浓度和免疫细胞数量与对照进行比较。与PBS阴性对照相比,Kr1Fc或K5治疗的存活率显著提高(p<0.05),并且肺部病毒诱导的CPE显著降低,为进一步研究奠定了基础。
如参考文献中所述,K5在小鼠和猴子中的半衰期约为20分钟,MTD大于660mg/kg。根据本发明的更有效的GRP78抑制剂Kr1Fc和K5Fc以及具有添加的Fc结构域的蛋白质的公开具有改善的半衰期并且可能优于单独的kringle结构域。此外,ACE2抑制剂和GRP78抑制剂的联合治疗可以表现出协同效应。
根据本发明,所描述的结论通过统计分析来证明。更具体地说,图形生成和统计分析是在GraphPad Prism 7.0软件上完成的。统计比较通过Student的双尾t检验与Bonferroni后检验进行双向方差分析,假设正态分布和等方差,其中差异在p<0.05时被认为是显著的。使用G*Power 3.1.9.4程序对两侧不配对样本功率分析进行Wilcoxon-Mann-Whitney测试的功率分析,用于确定所需的小鼠数量。假设变异系数等于1.5(如预计/预期的结果所示),组大小(n=10)能够检测到对照组和10mg/kg Kr1Fc治疗组之间转移瘤数量至少减少30%。数据),并使用双样本t检验对正态数据进行检验,功效为80%,显著性水平为0.05。通过Mann-Whitney成对比较或Kruskal-Wallis检验以及适用的Dunn多重比较检验来分析最大死亡日(MDD)、细胞因子值和总肺评分。原始存活数通过Fisher精确检验进行比较。使用Kaplan-Meier方法和对数秩检验进行生存曲线分析。当该分析显示治疗组之间存在显著差异时,通过Gehan-Breslow-Wilcoxon检验分析幸存者曲线的成对比较,并将相对显著性调整为Bonferroni校正的治疗比较次数的显著性阈值。假设等方差和正态分布,通过单向方差分析和纽曼-科伊尔斯多重比较检验来测试体重减轻百分比的差异。对于肺滴度数据,我们将进行KS检验以确保正态性,然后对非正态分布的组使用非参数Kruskal-Wallis检验和Dunn多重比较检验,并对非正态分布的组使用单向方差分析和Newman-Keuls多重比较检验正态分布的组。
附图详细说明
图1是使用和不使用GRP78抑制剂时SARS-CoV-2病毒附着、进入和复制的示意图。图1A显示压力诱导GRP78易位至细胞表面。1)SARS-CoV-2病毒附着在GRP78和ACE2上。2)GRP78增强SARS-CoV-2病毒进入肺上皮细胞。3)GRP78增加SARS-CoV-2的复制和分泌。图1B显示GRP78抑制剂可阻断大量SARS-CoV-2病毒结合并减少GRP78的表面表达,从而减少进入细胞的SARS-CoV-2病毒量。最后,细胞表面缺乏GRP78会抑制SARS-CoV-2病毒的附着、内化和复制。红色X表示阻断GRP78在细胞表面的结合可阻断病毒复制
图2是我们的GRP78抑制剂类抑制SARS-CoV-2病毒的示意图。本发明表明,N端GRP78抑制剂阻断1)SARS-CoV-2病毒的附着和进入,2)通过阻断肺细胞表面上的纤溶酶原转化为纤溶酶来减少纤维蛋白溶解亢进,3)通过减少肺细胞表面的检查点蛋白表达来逆转免疫抑制。肺和内皮细胞,4)通过减少IL10和IL6细胞因子表达来减少病毒诱导的细胞因子风暴。
图3是Kr1Fc、K5Fc、Kr1和K5蛋白质纯度、结构和结合的分析。图3A-D是SDS-PAGE分析图像,显示A)Kr1Fc、B)K5Fc、C)Kr1和D)K5蛋白在293F HEK细胞中表达。Kringle蛋白通过蛋白A-琼脂糖或苯甲脒-琼脂糖纯化。泳道标记为Mw:蛋白质标记,泳道1:还原条件,泳道2:非还原条件,M:表达培养基,F:流过物,W:洗涤,P:纯化的蛋白质。图3E是具有与人IgG1 Fc结构域融合的2个三环结构域的Kr1-Fc和K5Fc融合蛋白的图示。图3F是人GRP78区域的示意图,其中公开的GRP78蛋白抑制剂与本发明蛋白相互作用。GRP78示意图下方显示了已知和预测的病毒与GRP78蛋白的结合位点。(ATP酶结构域SBD:底物结合结构域,KDEL;4个残基C端肽)。
图4显示N端GRP78抑制剂阻断GRP78与SARS-CoV-2刺突蛋白的结合。图4A是在96孔板中使用全长SARS-CoV-2刺突蛋白、HRP标记的GRP78和GRP78抑制剂进行结合测定的示意图。图4B是显示N端GRP78抑制剂Kr1Fc、K5Fc和K5可以有效阻断GRP78与SARS-CoV-2刺突蛋白结合的数据的图。全长SARS-CoV-2刺突蛋白在4℃下过夜与96孔板结合。封闭和洗涤后,将HPR标记的GRP78和不同浓度的Kr1Fc、K5Fc、K5和阴性对照、未折叠的Kr1Fc添加到板中并孵育2小时。洗涤孔并添加TMB试剂并按照制造商方案测量吸光度。每个点是一式三份井的平均值。
图5显示GRP78抑制剂阻断PE标记的SARS-CoV-2刺突蛋白与A549肺细胞的结合。将SARS-CoV-2刺突蛋白-PE(50nM)添加到含有或不含有Kr1Fc(100nM)或K5(500nM)的50,000个A549肺细胞中。将细胞在4℃下孵育过夜,以阻止SARS-CoV-2刺突蛋白-PE的内化。用PBS洗涤细胞2次,并在Guava PCA流式细胞仪上运行。对照是人IgG1-PE Ab。图5A显示原始流式细胞术图,图5B是结合了SARS-CoV-2刺突蛋白-PE并与GRP78抑制剂竞争的A549细胞的直方图叠加分析,表明Kr1Fc和K5阻断SARS-CoV-2刺突蛋白-PE与A549肺细胞的结合分别超过99%和65%。
图6显示GRP78抑制剂阻止SARS-CoV-2刺突蛋白-PE与VERO细胞结合。使用VERO细胞是因为它们的ACE2高表达并且非常容易受到SARS-CoV-2病毒感染。将SARS-CoV-2刺突蛋白-PE(50nM)添加到50,000个含有和不含Kr1Fc(100nM)或K5(500nM)的VERO肾细胞中。将细胞在37℃下孵育过夜。然后用PBS洗涤细胞2次,并在Guava PCA流式细胞仪上运行。对照是人IgG1-PE Ab。图6A是点印迹流式细胞术分析,图6B是结合有和没有Kr1Fc和K5的SARS-CoV-2刺突蛋白-PE的VERO细胞的直方图叠加。从数据中可以清楚地看出,Kr1Fc(100nM)和K5(500nM)显著降低了SARS-CoV-2刺突蛋白-PE与VERO细胞表面的结合约50%。
图7显示,Kr1Fc和K5通过与VERO细胞预孵育或与刺突蛋白同时添加来防止SARS-CoV-2刺突蛋白的结合(图6)。图7A显示了SARS-CoV-2刺突蛋白-PE(50nM)与用或不用Kr1Fc(100nM)或K5(500nM)预孵育6小时的VERO细胞结合的点印迹流式细胞术分析和直方图叠加分析。Kr1或K5预孵育对SARS-CoV-2刺突蛋白-PE结合的抑制大于60%。这些数据表明,用GRP78抑制剂预孵育细胞可能会稍微更好地减少刺突蛋白结合。
图8证明N末端GRP78抑制剂减少VERO细胞上表面结合的GRP78的表达。为了帮助确定我们的GRP78抑制剂是否只是阻止SARS-CoV-2刺突蛋白与GRP78的结合,或者实际上从细胞表面去除GRP78,从而导致刺突蛋白结合和内化的表面结合GRP78减少,我们测量了表面的量Kr1Fc(100nM)和K5(500nM)处理后,VERO细胞上结合GRP78。图8A显示使用C端GRP78抗体-PE对VERO细胞表面结合的GRP78进行流式细胞术分析。该抗体尚未被证明可以抑制SARS-CoV-2刺突蛋白结合。图8B显示流式细胞术斑点印迹和直方图重叠分析Kr1Fc和K5使表面结合的GRP78减少超过50%。这表明这些N端GRP78抑制剂可能会从VERO细胞表面内化/去除GRP78,从而导致SARS-CoV-2刺突蛋白结合的结合位点减少。
图9证明N末端GRP78抑制剂降低A549肺细胞上表面结合的GRP78的表达。为了帮助确定我们的GRP78抑制剂是否可以从A549肺细胞表面(如VERO细胞)内化/去除GRP78,我们测量了Kr1Fc(100nM)和K5(500nM)处理后A549细胞上表面结合的GRP78的量。图9A显示A549细胞表面结合的GRP78的流式细胞术分析显示表面结合的GRP78的表达比VERO细胞低得多。再次说明为什么VERO细胞可能比A549细胞更容易受到感染。图9B显示流式细胞术点印迹和直方图重叠分析,Kr1Fc和K5分别使表面结合的GRP78从84%减少到60%。这表明这些N端GRP78抑制剂可能会从A540和VERO细胞表面内化/去除GRP78,从而导致SARS-CoV-2刺突蛋白结合的结合位点减少。
图10显示VERO细胞上表面结合的GRP78表达对于SARS-CoV-2刺突蛋白内化至关重要,Kr1Fc和K5显著降低了该表达。在图10A的测定中,使用pHrodo红色染料标记SARS-CoV-2刺突蛋白以测量内化。pHrodo染料在pH 7时(在细胞外部或与细胞结合)具有弱荧光,但在pH值约为5.5至4.5的细胞内部具有强荧光。这样可以测量VERO细胞上pHrodo红色标记的SARS-CoV-2刺突蛋白的内化。图10B显示了使用和不使用Kr1Fc和K5的VERO细胞上的SARS-CoV-2刺突蛋白-pHrodo内化的流式细胞术分析。从点印迹分析和图10C直方图叠加图来看,Kr1Fc(100nM)和K5(500nM)在VERO细胞中显著减少了SARS-CoV-2刺突蛋白pHrodo的内化超过95%。
图11表明,用N端GRP78结合蛋白Kr1Fc和K5抑制GRP78,可有效且显著地抑制整个SARS-CoV-2假型病毒在VERO细胞上的附着和内化。在本发明中,改良的SARS-CoV-2病毒测定由IBT Bioservices(马里兰州罗克维尔)进行。在该检测中,通过用编码荧光素酶蛋白的RNA替换SARS-CoV-2病毒的复制RNA片段来生成SARS-CoV-2假型病毒以进行检测。其余的结构蛋白(刺突蛋白、包膜蛋白、基质蛋白和核衣壳蛋白)保持完整。这使得SARS-CoV-2(rVSV-SARS-CoV-2(D614G))假型病毒能够附着并内化,但不能复制。本发明教导Kr1Fc和K5可以抑制完整的SARS-CoV-2假型病毒附着和进入VERO细胞。图11A显示了对SARS-CoV-2假型病毒感染性的有效、剂量依赖性和完全中和(99.9%),观察到Kr1Fc的IC50值为3.5uM,K5的IC50值为47.4uM。该测定使用K5 0.5nM至500uM的八种稀释度和Kr1Fc 0.01nM至62uM的八种稀释度进行。将这些稀释液添加到96孔板中含有VERO细胞(每孔1x105个细胞)的一式三份孔中。根据本发明的孔在每个孔中以25,000-35,000相对光单位被SARS-CoV-2假型病毒感染。将板孵育24小时,洗涤附着的细胞,然后使用Bright-Glo Assay System Kit(Promega)读取每个孔的荧光素酶活性。如图11B所示,还针对没有病毒的VERO细胞平行测定了测试化合物的毒性。Kr1Fc在高达2mM时没有表现出细胞毒性,K5在375uM的50%(CC50)细胞毒性细胞浓度下抑制VERO细胞生长。这些毒性数值比病毒抑制浓度至少高10倍,表明毒性不是病毒附着和进入抑制的作用机制。
图12A和B说明K5显著增强A549肺细胞上由可溶性GRP78诱导的共抑制(PD-L1、B7H4)检查点蛋白和共刺激(CD86、MHC-II)蛋白表达。检查点蛋白表达+/-sGRP78(5ug/m)和K5(500nM)的流式细胞术直方图。A549细胞孵育3天+/-sGRP78(5ug/ml)和K5(500nM)。然后将细胞固定并用所示的荧光标记抗体染色,并在Guava PCA上进行FAC分析。所有抗体均经过小鼠抗人抗体和PE标记。小鼠IgG-PE抗体(灰色)用作阴性对照。使用3次独立分析的平均值,其中A549细胞分裂数在5-10之间。ns:不显著,*p<0.05,**p<0.01,***p<0.005,****p<0.001。除非上下文另有说明,星号“*”对应于图中的星号。
图13A和B显示Kr1Fc显著增强A549肺细胞上由可溶性GRP78诱导的共抑制(PD-L1、B7H4)检查点蛋白的表达和共刺激(CD86、MHC-II)蛋白的表达。检查点蛋白表达+/-sGRP78(5ug/m)和Kr1Fc(100nM)的流式细胞术直方图。A549细胞孵育3天+/-sGRP78(5ug/ml)和Kr1Fc(100nM)。然后将细胞固定并用所示的荧光标记抗体染色,并在Guava PCA上进行FAC分析。所有抗体均经过小鼠抗人抗体和PE标记。小鼠IgG-PE抗体(灰色)用作阴性对照。使用3次独立分析的平均值,其中A549细胞分裂数在5-10之间。ns:不显著,*p<0.05,**p<0.01,***p<0.005,****p<0.001
图14A和B证明Kr1Fc和K5抑制来自A549肺细胞的可溶性GRP78诱导的IL10和IL6的细胞因子表达。将A549细胞(50,000)添加到含有完整DMEM培养基的Eppendorf管中。在一半管中,添加可溶性GRP78(5ug/ml)以及K5(500nM)或Kr1Fc(100nM)。使用IgG人抗体作为阴性对照。在37℃温和振荡下孵育3天后,将细胞离心并使用IL10或IL6ELISA测定试剂盒(R&DSystems)测试上清液。遵循每个试剂盒的方案,并从标准曲线计算使用和使用GRP78抑制剂的A549细胞每种条件下每种细胞因子的pg/ml。每行平均3口井。****p<0.001
图15显示Kr1Fc和K5抑制VERO细胞表面上人纤溶酶原的活化。在图15A中,左侧肺部未受损且血流有效且顺畅的示意图。右侧是因SARS-CoV-2病毒感染而受损的肺部。感染会引起严重的炎症和纤维蛋白溶解亢进,从而诱发微血栓和高水平的D-二聚体。红色纤溶酶原与纤溶酶反应是GRP78抑制剂通过抑制细胞表面纤溶酶活化来阻止微血栓和D-二聚体形成的过程。图15B显示Kr1和K5对VERO细胞上纤溶酶激活的显著抑制。在96孔板中,添加VERO细胞(每孔50,000个)并在37℃、5% CO2下孵育过夜。第二天,除去培养基并向每个孔中添加PBS。然后将GRP78抑制剂、Kr1Fc(100nM、10nM)和K5(500nM、50nM)加人纤溶酶原(100ng)添加到每个孔中。最后,按照制造商说明将纤溶酶底物VAL-Leu-Lys-pNA(S2251)添加到每个孔中,并在405nm处读取板以测量pNA形成,pNA形成与纤溶酶的酶活性成正比。如图表所示,Kr1Fc和K5显著抑制VERO细胞上纤溶酶原激活的Vmax。
图16显示每隔一天用Kr1Fc(60mg/kg)或K5(90mg/kg)治疗的小鼠,腹膜内没有表现出体重减轻或明显的毒性。Kr1Fc和K5对8周龄的BALB/c小鼠进行给药。三组小鼠按每只动物的体重按10mL/kg的体积腹膜内(i.p.)给药。治疗组为:1组用PBS处理,腹膜内注射。每隔一天一次,直到第22天;1组以60mg/kg腹膜内注射Kr1Fc治疗,每隔一天(qod)直至第22天;第1组每隔一天(qod)接受90mg/kg K5,直到第22天。在第1-5天每天对动物称重,然后每周两次称重,直到第22天。经常观察小鼠是否有任何不良反应的明显迹象。观察时记录治疗相关(TR)副作用和临床症状。按照方案监测个体体重,任何一次测量体重减轻超过30%或连续三次测量体重减轻超过25%的动物均被视为TR死亡而被安乐死。还根据查尔斯河发现服务协议监测组平均体重减轻。可接受的毒性定义为研究期间组平均体重(BW)损失低于20%,TR死亡人数不超过10%。如果死亡是由临床症状和/或尸检证明的治疗副作用引起的,则将死亡归类为TR。从图16可以清楚地看出,在按上述剂量给药的小鼠中,Kr1Fc和K5没有表现出明显的毒性或体重减轻。
图17是显示GRP78识别位点上特定序列的细胞毒性和抗病毒活性的表格。如下文更全面地描述,将病毒的序列比对与已知的GRP78结合三环序列进行比较,以鉴定可能的GRP78结合位点,从而能够预测哪些病毒将对我们通过阻断GRP78的N端结构域进行病毒抑制的治疗方法有反应。
使用本发明治疗时的治疗参数
严重的病毒性疾病是由于接触、细胞感染和病毒复制到病毒水平而导致的,病毒水平压倒了宿主的免疫系统,导致疾病的体征和症状。病毒不能自行制造新病毒,需要宿主细胞来制造新病毒。由于病毒暴露水平较低,这通常会导致身体的免疫系统在症状出现之前激活并攻击病毒。这导致病毒从宿主体内被清除。对于免疫反应有限和/或病毒暴露水平较高的人来说,宿主免疫系统很可能会被病毒载量压倒,患者就会生病。当病毒附着在细胞表面并被带入细胞内时,病毒感染就会传播。病毒将自己的DNA或RNA指令带入细胞进行复制并最终释放,只是为了一次又一次地重复这个过程,从而增加感染率,从而增加病毒载量,最终导致严重疾病。
众所周知,病毒表面有几种称为“刺突蛋白”的细胞结合蛋白,它们会寻找并附着在细胞表面。对于SARS-CoV和SARS-CoV-2病毒,这种附着可以附着在ACE2受体和其他辅助受体(如GRP78)上,这些受体存在于呼吸道肺和内皮细胞的细胞表面。然后这些受体将病毒物质运输到细胞中,在细胞中病毒物质被复制并从受感染的细胞中排出,重复这个过程。
使用GRP78识别位点选择和抑制病毒的方法。
据报道,表面结合的GRP78对于几种不同类型的病毒的附着和进入宿主细胞非常重要。在Elfiky的出版物中,他们预测冠状病毒SARS-CoV-2、NL63、229E、OC43和HKU1具有相似的GRP78识别/结合位点。其他出版物表明,表面结合的GRP78对于寨卡病毒、埃博拉病毒、中东呼吸综合征冠状病毒、柯萨奇病毒A9、登革热病毒、日本脑炎病毒(JEV)和流感病毒的附着和进入很重要,但尚未检查它们是否具有相同的GRP78结合序列。从我们之前的出版物中,我们证明了人纤溶酶原kringle 5的序列CYTTNPRKLYDYC与表面结合的GRP78紧密结合。
尽管Elfiky的预测使用了比K5序列更弱的GRP78结合序列PEP42(CTVALPGGYVRVC),但它仍然保留了我们之前在kringle 5结构折叠区域中显示的GRP78结合的一些重要氨基酸。在图17中,我们显示了病毒与我们已知的GRP78结合kringle序列相比的序列比对,以鉴定可能的GRP78结合位点。利用这种比对,我们可以预测哪些病毒会对我们通过阻断GRP78 N末端结构域进行病毒抑制的治疗方法产生反应。从这种比对中,我们现在可以预测SARS-CoV-2、NL63、229E、OC43、HKU1、MERS-CoV、埃博拉病毒、寨卡病毒、黄热病、西尼罗河病毒和甲型、乙型流感病毒将被我们的疗法抑制,因为到他们的GRP78结合。然而,SARS-CoV不包含拟议的GRP78结合序列,因此我们预测我们的GRP78抑制剂不会有效对抗这种病毒。为了证明这一预测是准确的,在实施例6中,我们可以证明我们的N端结合GRP78抑制剂Kr1Fc有效阻止SARS-CoV-2假病毒的附着和进入,但我们最近发现我们的GRP78抑制剂Kr1Fc,不能阻止感染SARS-CoV致命变种的小鼠病毒引起的死亡或体重减轻。
选择我们的目标人群进行GRP78抑制剂预防或治疗SARS-CoV-2和其他病毒感染的方法
65岁以下患有癌症、肥胖、心脏病、肺病和高血压等合并症的人比没有合并症的人感染SARS-CoV-2病毒的风险更高。同一人群的新冠病毒死亡率也高得多。对于65岁以上患有或不患有合并症的人来说,他们死于COVID19的几率也远高于65岁以下的人。由于这些合并症以及一般衰老过程对内皮、肺、呼吸和免疫细胞施加的压力,表面结合的GRP78的存在最近被认为是衰老和疾病进展的重要参与者。
随着衰老和合并症,细胞变得更加紧张,导致细胞表面结合的GRP78的一致和更高的表达。GRP78的较高表达允许更多的病毒结合和进入细胞(图1)。然后病毒复制和病毒颗粒的释放可以以更高的速率发生。由于GRP78受体增加,病毒结合、进入和复制增加的过程可以压倒免疫系统,导致发病率和死亡率增加。
治疗患有自身免疫性疾病的患者
患有自身免疫性疾病的患者没有功能齐全的免疫系统,据报道其表面结合的GRP78表达较高。目前旨在刺激免疫系统对抗SARS-CoV-2等病毒的治疗方法和疫苗对于这些容易出现不必要的病毒进展的患者来说效果要差得多。使用我们的GRP78抑制剂为这些患者提供预防和/或治疗支持,可以提供一定程度的感染保护,如果感染,将阻止新病毒附着、进入、复制和释放新病毒颗粒到患者体内。
治疗癌症患者
癌症患者,特别是肺癌和血源性癌症患者,已被证明在其下呼吸道和上呼吸道细胞以及内皮细胞上具有较高的表面结合GRP78表达。这些患者由于接受化疗,通常对疫苗和病原体的免疫反应降低。通过预防性地或在感染SARS-CoV-2病毒后,使用我们的GRP78抑制治疗这些患者,可以通过阻止病毒接触表面结合的GRP78受体来减少感染机会并降低病毒感染率。
治疗肥胖症患者。
肥胖患者有多种合并症,如高血压、糖尿病和血液循环不良,这些疾病可能导致肺和内皮细胞应激,导致表面表达的GRP78增加。表面表达的GRP78的增加使这群人面临SARS-CoV-2感染和死亡的高风险。使用我们的GRP78抑制剂通过表面结合的GRP78来阻断病毒感染量,我们可以大大减轻病毒感染的症状和严重程度。
治疗糖尿病患者
患有1型或2型糖尿病的患者已被证明在肾脏和内皮细胞上具有较高的表面结合GRP78表达。通过在这些患者中使用我们的GRP78抑制剂,病毒载量和SARS-CoV-2感染的机会应大大降低,从而允许正常的免疫攻击和消除病毒颗粒。
治疗心血管疾病患者
心血管疾病患者的一个标志是心脏组织内质应激增加,导致血管细胞上ACE2和表面结合的GRP78表达更高。尽管增加的ACE2表达允许增加SARS-CoV-2附着,但本发明教导SARS-CoV-2需要表面结合的GRP78来进行病毒进入,因此,通过用我们的GRP78抑制剂减少GRP78的表面表达,这应该导致以减少病毒感染和死亡率。
治疗高血压患者
研究表明,高血压患者的动脉细胞内质网表达的GRP78增加。GRP78表达的增加导致表面结合的GRP78的增加。如上所述,GRP78的表面表达允许SARS-CoV-2病毒在细胞中更高的附着、进入和复制。通过用我们的抑制剂减少表面结合的GRP78的表达,不仅可以降低病毒感染的风险,还可以减少慢性高血压的影响。
治疗65岁以上的患者
随着年龄的增长,炎症更加普遍,这导致肌肉和动脉细胞承受更大的压力,从而导致表面结合的GRP78的一致表达。很明显,SARS-CoV-2感染的严重程度随着年龄的增长而大幅增加。这种较高水平的GRP78受体允许SARS-CoV-2病毒更多地附着和进入细胞。使用GRP78抑制剂治疗65岁以上的患者将导致受应激的不健康细胞表面结合的GRP78减少。SARS-CoV-2病毒附着的受体越少,SARS-CoV-2感染的严重程度就越轻。
健康的年轻人(<60岁)很少出现SARS-CoV-2感染的严重症状。我们认为这是因为年轻健康人细胞表面结合的GRP78非常低,这降低了病毒附着的风险。这限制了感染的严重程度,并大大降低了儿童和年轻人的死亡率。因此,无需使用我们的GRP78抑制剂治疗该人群。
然而,这一理论也有例外。例如,流感病毒会感染年轻人和老年人,即使病毒含有GRP78结合位点并且其细胞上没有表面结合的GRP78。最近的出版物表明,受感染的细胞诱导表面GRP78表达,从而导致更多感染。在这些情况下,用GRP78抑制剂治疗将减少表面结合的GRP78,从而减少病毒载量并缩短感染时间。
治疗类型
对于我们的GRP78抑制剂,本发明展示了两种类型的治疗选择。第一个是使用我们的GRP78抑制剂治疗上述SARS-CoV-2感染后的患者。患有合并症的感染患者将受益于表面结合GRP78的减少,从而减少病毒附着和进入。
使用我们的GRP78抑制剂的第二种方法是预防性给药。对于上面列出的患有合并症的患者以及肺、呼吸道和动脉细胞表面结合GRP78表达增加的65岁以上患者,使用我们的GRP78抑制剂进行预防性治疗将降低SARS-CoV-2病毒感染和疾病进展的风险。我们预防性给予的GRP78抑制剂也可能有效保护医护人员、急救人员、前往高感染地区的人员和教师免受SARS-CoV-2感染。
联合治疗方案
本发明表明,我们的GRP78抑制剂可以与其他类型的疗法联合给予,以帮助减少病毒感染和由此产生的症状。例如:
-地塞米松等抗炎药已被证明可以减轻细胞因子炎症等症状,从而提高生存率,
-抗病毒药物,如瑞德西韦,已被证明可以阻止病毒复制,从而减少病毒性疾病。
-Baricitinib(JAK抑制剂)和Tocilzumab(IL6抑制剂)等免疫抑制剂尚未被证明对晚期疾病有效,但在早期至中期疾病中显示出希望。
-肝素等抗凝剂可显著减轻SARS-CoV-2感染引起的血栓风暴症状。
-SARS-CoV-2或流感疫苗等疫苗可能对主要毒株有效,但对不断进化的变种无效。通过同时使用疫苗和GRP78抑制剂,它们可能会更有效地治愈。
当前针对SARS-CoV-2病毒的疗法和疫苗存在的问题:
针对SARS-CoV-2病毒的疫苗旨在迫使免疫系统通过病毒表面的刺突蛋白或其他包膜蛋白攻击病毒。然后,身体就可以产生针对SARS-CoV-2病毒刺突蛋白的抗体,从而阻止SARS-CoV-2病毒附着并内化到宿主细胞中。目前,已经批准了三种针对SARS-CoV-2病毒刺突蛋白的疫苗。对于因合并症或其他药物治疗而免疫系统较弱的人来说,这些疫苗可能不那么有效。此外,SARS-CoV-2变体(B.1.351)感染已被证明对阿斯利康Covid-19疫苗对轻度至中度感染具有耐药性。这是抗病毒疫苗的根本问题,因为需要每年更新疫苗版本以对抗不断变化的变种。
针对SARS-CoV-2刺突蛋白的单克隆抗体已被FDA批准紧急使用。这些抗体已被证明对早期SARS-CoV-2感染患者有效。住院的患者没有出现任何改善。最后,与疫苗一样,这些疗法非常针对病毒刺突蛋白,并且变异体可能不会被抑制。
瑞德西韦是一种蛋白酶抑制剂,已被FDA批准使用。它对住院患者也失败了,也未能阻止死亡。如果在SARS-CoV-2病毒感染早期给予,可以减少住院时间和感染持续时间。
上面列出的是截至本发明撰写时FDA批准的唯一治疗COVID19疾病的疗法。然而,其他一些研究正在通过临床研究取得进展,显示出一些希望。Baricitinib是一种Janus激酶抑制剂,是一种免疫抑制剂。该疗法已被证明对吸氧但不通气的SARS-CoV-2病毒感染患者有效。同样,晚期新冠肺炎疾病也没有得到解决。Tocilizumab是一种抗IL-6的单克隆抗体。抑制IL-6可通过抑制炎症来治疗SARS-CoV-2感染症状,从而使免疫系统更好地发挥作用。接受托珠单抗治疗的晚期患者的结果是,接受通气和吸氧的患者出院时间均缩短了。
本发明教导了一种使用N端GRP78抑制剂治疗SARS-CoV-2感染患者的方法。与疫苗或当前的病毒治疗不同,我们的治疗针对的是细胞表面潜在的病毒感染,而不是病毒表面。通过抑制宿主细胞受体而不是病毒,突变体不会对GRP78抑制剂治疗产生耐药性。此外,由于GRP78抑制剂不依赖免疫系统清除或抑制病毒,因此免疫抑制患者仍然可以得到治疗。因此,晚期新冠肺炎患者、免疫系统受到抑制的患者或患有合并症的患者仍将对我们的GRP78抑制剂敏感,这将减少感染时间,从而减少住院时间和病毒载量。
如图17所示,图17是显示GRP78结合位点的蛋白质序列比较的表,比较显示选定的蛋白质序列(图17中以红色表示)与Kringle 5序列和第二个序列相同。类别(黄色)是类似类型的氨基酸。如果既没有红色也没有黄色,则得出结论不存在相似性。所有kringle和病毒序列比较均与Kringle 5进行比较。图17中的星号(*)在第3、8、12和18列中标记对GRP78结合重要的氨基酸。GRP78结合位点的蛋白质序列比较。C与Kringle 5序列相同,黄色是相似类型的氨基酸,白色是不相似的。所有Kringle和病毒序列比较均与Kringle 5进行比较。*标记对GRP78结合重要的氨基酸。
虽然已经结合其具体实施例描述了本发明,但是应当理解的是,它能够进行进一步的修改,并且本申请旨在覆盖本发明的任何变化、使用或修改,一般来说,本发明的原理,并且包括与本公开内容的偏离,这些偏离属于本发明所属领域内的已知或惯常实践,并且可以应用于上文阐述的基本特征,并且在这些权利要求的范围内如下应包括。
序列表
<110> 创意生物治疗有限责任公司
<120> 具有 Kringle 5 亚基的抗病毒蛋白
<130> CU-75247 DCB
<160> 189
<170> PatentIn版本 3.5
<210> 1
<211> 89
<212> PRT
<213> 人工序列
<220>
<223> 合成肽K5(3-89活性区)
<400> 1
Ser Glu Glu Asp Cys Met Phe Gly Asn Gly Lys Gly Tyr Arg Gly Lys
1 5 10 15
Arg Ala Thr Thr Val Thr Gly Thr Pro Cys Gln Asp Trp Ala Ala Gln
20 25 30
Glu Pro His Arg His Ser Ile Phe Thr Pro Glu Thr Asn Pro Arg Ala
35 40 45
Gly Leu Glu Lys Asn Tyr Cys Arg Asn Pro Asp Gly Asp Val Gly Gly
50 55 60
Pro Trp Cys Tyr Thr Thr Asn Pro Arg Lys Leu Tyr Asp Tyr Cys Asp
65 70 75 80
Val Pro Gln Cys Ala Ala Pro Lys Ser
85
<210> 2
<211> 317
<212> PRT
<213> 人工序列
<220>
<223> 合成肽K5(3-89活性区)frag-Fc
<400> 2
Ser Glu Glu Asp Cys Met Phe Gly Asn Gly Lys Gly Tyr Arg Gly Lys
1 5 10 15
Arg Ala Thr Thr Val Thr Gly Thr Pro Cys Gln Asp Trp Ala Ala Gln
20 25 30
Glu Pro His Arg His Ser Ile Phe Thr Pro Glu Thr Asn Pro Arg Ala
35 40 45
Gly Leu Glu Lys Asn Tyr Cys Arg Asn Pro Asp Gly Asp Val Gly Gly
50 55 60
Pro Trp Cys Tyr Thr Thr Asn Pro Arg Lys Leu Tyr Asp Tyr Cys Asp
65 70 75 80
Val Pro Gln Cys Ala Ala Pro Lys Ser Cys Asp Lys Thr His Thr Cys
85 90 95
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
100 105 110
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
115 120 125
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
130 135 140
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
145 150 155 160
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
165 170 175
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
180 185 190
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
195 200 205
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
210 215 220
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
225 230 235 240
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
245 250 255
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
260 265 270
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
275 280 285
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
290 295 300
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
305 310 315
<210> 3
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> 合成肽K5(57-81活性区)frag -Fc
<400> 3
Arg Asn Pro Asp Gly Asp Val Gly Gly Pro Trp Cys Tyr Thr Thr Asn
1 5 10 15
Pro Arg Lys Leu Tyr Asp Tyr Cys Lys Ser Cys Asp Lys Thr His Thr
20 25 30
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
35 40 45
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
50 55 60
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
65 70 75 80
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
85 90 95
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
100 105 110
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
115 120 125
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
130 135 140
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
145 150 155 160
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
165 170 175
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
180 185 190
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
195 200 205
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
210 215 220
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
225 230 235 240
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
245 250
<210> 4
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> 合成肽K5(57-81活性区w Ala sub Cys)frag -Fc
<400> 4
Arg Asn Pro Asp Gly Asp Val Gly Gly Pro Trp Ala Tyr Thr Thr Asn
1 5 10 15
Pro Arg Lys Leu Tyr Asp Tyr Ala Lys Ser Cys Asp Lys Thr His Thr
20 25 30
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
35 40 45
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
50 55 60
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
65 70 75 80
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
85 90 95
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
100 105 110
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
115 120 125
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
130 135 140
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
145 150 155 160
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
165 170 175
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
180 185 190
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
195 200 205
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
210 215 220
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
225 230 235 240
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
245 250
<210> 5
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> 合成肽K5(57-81活性区w Val sub Cys)frag-Fc
<400> 5
Arg Asn Pro Asp Gly Asp Val Gly Gly Pro Trp Val Tyr Thr Thr Asn
1 5 10 15
Pro Arg Lys Leu Tyr Asp Tyr Val Lys Ser Cys Asp Lys Thr His Thr
20 25 30
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
35 40 45
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
50 55 60
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
65 70 75 80
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
85 90 95
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
100 105 110
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
115 120 125
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
130 135 140
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
145 150 155 160
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
165 170 175
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
180 185 190
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
195 200 205
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
210 215 220
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
225 230 235 240
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
245 250
<210> 6
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> 合成肽K5(57-81活性区w Ile sub Cys)frag-Fc
<400> 6
Arg Asn Pro Asp Gly Asp Val Gly Gly Pro Trp Ile Tyr Thr Thr Asn
1 5 10 15
Pro Arg Lys Leu Tyr Asp Tyr Ile Lys Ser Cys Asp Lys Thr His Thr
20 25 30
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
35 40 45
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
50 55 60
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
65 70 75 80
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
85 90 95
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
100 105 110
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
115 120 125
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
130 135 140
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
145 150 155 160
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
165 170 175
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
180 185 190
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
195 200 205
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
210 215 220
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
225 230 235 240
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
245 250
<210> 7
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> 合成肽K5(57-81活性区w Leu sub Cys)frag-Fc
<400> 7
Arg Asn Pro Asp Gly Asp Val Gly Gly Pro Trp Leu Tyr Thr Thr Asn
1 5 10 15
Pro Arg Lys Leu Tyr Asp Tyr Leu Lys Ser Cys Asp Lys Thr His Thr
20 25 30
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
35 40 45
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
50 55 60
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
65 70 75 80
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
85 90 95
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
100 105 110
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
115 120 125
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
130 135 140
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
145 150 155 160
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
165 170 175
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
180 185 190
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
195 200 205
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
210 215 220
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
225 230 235 240
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
245 250
<210> 8
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> 合成肽K5(70-89活性区)frag-Fc
<400> 8
Tyr Thr Thr Asn Pro Arg Lys Leu Tyr Asp Tyr Cys Asp Val Pro Gln
1 5 10 15
Cys Ala Ala Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
20 25 30
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
35 40 45
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
50 55 60
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
65 70 75 80
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
85 90 95
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
100 105 110
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
115 120 125
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
130 135 140
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
145 150 155 160
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
165 170 175
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
180 185 190
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
195 200 205
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
210 215 220
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
225 230 235 240
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
245 250
<210> 9
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> 合成肽K5(70-89活性区具有Ala sub Cys)frag-Fc
<400> 9
Tyr Thr Thr Asn Pro Arg Lys Leu Tyr Asp Tyr Ala Asp Val Pro Gln
1 5 10 15
Ala Ala Ala Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
20 25 30
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
35 40 45
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
50 55 60
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
65 70 75 80
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
85 90 95
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
100 105 110
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
115 120 125
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
130 135 140
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
145 150 155 160
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
165 170 175
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
180 185 190
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
195 200 205
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
210 215 220
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
225 230 235 240
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
245 250
<210> 10
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> 合成肽K5(70-89活性区具有Val sub Cys)frag-Fc
<400> 10
Tyr Thr Thr Asn Pro Arg Lys Leu Tyr Asp Tyr Val Asp Val Pro Gln
1 5 10 15
Val Ala Ala Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
20 25 30
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
35 40 45
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
50 55 60
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
65 70 75 80
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
85 90 95
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
100 105 110
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
115 120 125
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
130 135 140
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
145 150 155 160
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
165 170 175
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
180 185 190
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
195 200 205
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
210 215 220
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
225 230 235 240
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
245 250
<210> 11
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> 合成肽K5(70-89活性区具有Ile sub Cys)frag-Fc
<400> 11
Tyr Thr Thr Asn Pro Arg Lys Leu Tyr Asp Tyr Ile Asp Val Pro Gln
1 5 10 15
Ile Ala Ala Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
20 25 30
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
35 40 45
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
50 55 60
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
65 70 75 80
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
85 90 95
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
100 105 110
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
115 120 125
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
130 135 140
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
145 150 155 160
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
165 170 175
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
180 185 190
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
195 200 205
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
210 215 220
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
225 230 235 240
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
245 250
<210> 12
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> 合成肽K5(70-89活性区具有Leu sub Cys)frag-Fc
<400> 12
Tyr Thr Thr Asn Pro Arg Lys Leu Tyr Asp Tyr Leu Asp Val Pro Gln
1 5 10 15
Leu Ala Ala Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
20 25 30
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
35 40 45
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
50 55 60
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
65 70 75 80
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
85 90 95
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
100 105 110
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
115 120 125
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
130 135 140
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
145 150 155 160
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
165 170 175
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
180 185 190
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
195 200 205
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
210 215 220
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
225 230 235 240
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
245 250
<210> 13
<211> 246
<212> PRT
<213> 人工序列
<220>
<223> 合成肽K5(74-89活性区)frag-Fc
<400> 13
Pro Arg Lys Leu Tyr Asp Tyr Cys Asp Val Pro Gln Cys Ala Ala Pro
1 5 10 15
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
20 25 30
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
35 40 45
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
50 55 60
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
65 70 75 80
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
85 90 95
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
100 105 110
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
115 120 125
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
130 135 140
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
145 150 155 160
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
165 170 175
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
180 185 190
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
195 200 205
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
210 215 220
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
225 230 235 240
Ser Leu Ser Pro Gly Lys
245
<210> 14
<211> 246
<212> PRT
<213> 人工序列
<220>
<223> 合成肽K5(74-89活性区w Ala sub Cys)frag-Fc
<400> 14
Pro Arg Lys Leu Tyr Asp Tyr Ala Asp Val Pro Gln Ala Ala Ala Pro
1 5 10 15
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
20 25 30
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
35 40 45
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
50 55 60
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
65 70 75 80
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
85 90 95
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
100 105 110
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
115 120 125
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
130 135 140
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
145 150 155 160
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
165 170 175
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
180 185 190
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
195 200 205
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
210 215 220
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
225 230 235 240
Ser Leu Ser Pro Gly Lys
245
<210> 15
<211> 246
<212> PRT
<213> 人工序列
<220>
<223> 合成肽K5(74-89活性区w Val sub Cys)frag-Fc
<400> 15
Pro Arg Lys Leu Tyr Asp Tyr Val Asp Val Pro Gln Val Ala Ala Pro
1 5 10 15
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
20 25 30
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
35 40 45
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
50 55 60
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
65 70 75 80
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
85 90 95
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
100 105 110
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
115 120 125
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
130 135 140
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
145 150 155 160
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
165 170 175
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
180 185 190
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
195 200 205
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
210 215 220
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
225 230 235 240
Ser Leu Ser Pro Gly Lys
245
<210> 16
<211> 246
<212> PRT
<213> 人工序列
<220>
<223> 合成肽K5(74-89活性区w Ile sub Cys)frag-Fc
<400> 16
Pro Arg Lys Leu Tyr Asp Tyr Ile Asp Val Pro Gln Ile Ala Ala Pro
1 5 10 15
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
20 25 30
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
35 40 45
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
50 55 60
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
65 70 75 80
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
85 90 95
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
100 105 110
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
115 120 125
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
130 135 140
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
145 150 155 160
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
165 170 175
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
180 185 190
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
195 200 205
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
210 215 220
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
225 230 235 240
Ser Leu Ser Pro Gly Lys
245
<210> 17
<211> 246
<212> PRT
<213> 人工序列
<220>
<223> 合成肽K5(74-89活性区w Leu sub Cys)frag-Fc
<400> 17
Pro Arg Lys Leu Tyr Asp Tyr Leu Asp Val Pro Gln Leu Ala Ala Pro
1 5 10 15
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
20 25 30
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
35 40 45
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
50 55 60
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
65 70 75 80
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
85 90 95
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
100 105 110
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
115 120 125
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
130 135 140
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
145 150 155 160
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
165 170 175
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
180 185 190
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
195 200 205
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
210 215 220
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
225 230 235 240
Ser Leu Ser Pro Gly Lys
245
<210> 18
<211> 237
<212> PRT
<213> 人工序列
<220>
<223> 合成肽K5(74-80活性区)frag-Fc
<400> 18
Pro Arg Lys Leu Tyr Asp Tyr Lys Ser Cys Asp Lys Thr His Thr Cys
1 5 10 15
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
20 25 30
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
35 40 45
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
50 55 60
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
65 70 75 80
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
85 90 95
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
100 105 110
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
115 120 125
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
130 135 140
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
145 150 155 160
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
165 170 175
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
180 185 190
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
195 200 205
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
210 215 220
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
225 230 235
<210> 19
<211> 93
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(1-93活性区)frag
<400> 19
Gly Ser Asn Lys Asn His Lys Cys Tyr Asn Ser Thr Gly Val Asp Tyr
1 5 10 15
Arg Gly Thr Val Ser Val Thr Lys Ser Gly Arg Gln Cys Gln Pro Trp
20 25 30
Asn Ser Gln Tyr Pro His Thr His Thr Phe Thr Ala Leu Arg Phe Pro
35 40 45
Glu Leu Asn Gly Gly His Ser Tyr Cys Arg Asn Pro Gly Asn Gln Lys
50 55 60
Glu Ala Pro Trp Cys Phe Thr Leu Asp Glu Asn Phe Lys Ser Asp Leu
65 70 75 80
Cys Asp Ile Pro Ala Cys Asp Ser Lys Asp Ser Asp Ile
85 90
<210> 20
<211> 317
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(3-91活性区)frag-Fc
<400> 20
Asn Lys Asn His Lys Cys Tyr Asn Ser Thr Gly Val Asp Tyr Arg Gly
1 5 10 15
Thr Val Ser Val Thr Lys Ser Gly Arg Gln Cys Gln Pro Trp Asn Ser
20 25 30
Gln Tyr Pro His Thr His Thr Phe Thr Ala Leu Arg Phe Pro Glu Leu
35 40 45
Asn Gly Gly His Ser Tyr Cys Arg Asn Pro Gly Asn Gln Lys Glu Ala
50 55 60
Pro Trp Cys Phe Thr Leu Asp Glu Asn Phe Lys Ser Asp Leu Cys Asp
65 70 75 80
Ile Pro Ala Cys Asp Ser Lys Asp Ser Cys Asp Lys Thr His Thr Cys
85 90 95
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
100 105 110
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
115 120 125
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
130 135 140
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
145 150 155 160
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
165 170 175
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
180 185 190
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
195 200 205
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
210 215 220
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
225 230 235 240
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
245 250 255
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
260 265 270
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
275 280 285
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
290 295 300
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
305 310 315
<210> 21
<211> 262
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(58-91活性区)frag-Fc
<400> 21
Arg Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Cys Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Cys Asp Ile Pro Ala Cys Asp Ser Lys
20 25 30
Asp Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
35 40 45
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
50 55 60
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
65 70 75 80
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
85 90 95
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
100 105 110
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
115 120 125
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
130 135 140
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
145 150 155 160
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
165 170 175
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
180 185 190
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
195 200 205
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
210 215 220
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
225 230 235 240
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
245 250 255
Ser Leu Ser Pro Gly Lys
260
<210> 22
<211> 262
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(58-91活性区具有Ala sub Cys)frag-Fc
<400> 22
Arg Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Ala Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Ala Asp Ile Pro Ala Ala Asp Ser Lys
20 25 30
Asp Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
35 40 45
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
50 55 60
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
65 70 75 80
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
85 90 95
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
100 105 110
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
115 120 125
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
130 135 140
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
145 150 155 160
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
165 170 175
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
180 185 190
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
195 200 205
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
210 215 220
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
225 230 235 240
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
245 250 255
Ser Leu Ser Pro Gly Lys
260
<210> 23
<211> 262
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(58-91活性区具有Val sub Cys)frag-Fc
<400> 23
Arg Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Val Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Val Asp Ile Pro Ala Val Asp Ser Lys
20 25 30
Asp Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
35 40 45
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
50 55 60
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
65 70 75 80
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
85 90 95
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
100 105 110
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
115 120 125
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
130 135 140
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
145 150 155 160
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
165 170 175
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
180 185 190
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
195 200 205
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
210 215 220
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
225 230 235 240
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
245 250 255
Ser Leu Ser Pro Gly Lys
260
<210> 24
<211> 262
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(58-91活性区具有Ile sub Cys)frag-Fc
<400> 24
Arg Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Ile Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Ile Asp Ile Pro Ala Ile Asp Ser Lys
20 25 30
Asp Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
35 40 45
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
50 55 60
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
65 70 75 80
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
85 90 95
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
100 105 110
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
115 120 125
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
130 135 140
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
145 150 155 160
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
165 170 175
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
180 185 190
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
195 200 205
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
210 215 220
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
225 230 235 240
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
245 250 255
Ser Leu Ser Pro Gly Lys
260
<210> 25
<211> 262
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(58-91活性区具有Leu sub Cys)frag-Fc
<400> 25
Arg Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Leu Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Leu Asp Ile Pro Ala Leu Asp Ser Lys
20 25 30
Asp Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
35 40 45
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
50 55 60
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
65 70 75 80
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
85 90 95
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
100 105 110
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
115 120 125
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
130 135 140
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
145 150 155 160
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
165 170 175
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
180 185 190
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
195 200 205
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
210 215 220
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
225 230 235 240
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
245 250 255
Ser Leu Ser Pro Gly Lys
260
<210> 26
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(58-80活性区)frag-Fc
<400> 26
Arg Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Cys Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Cys Asp Lys Thr His Thr Cys Pro Pro
20 25 30
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
35 40 45
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
50 55 60
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
65 70 75 80
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
85 90 95
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
100 105 110
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
115 120 125
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
130 135 140
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
145 150 155 160
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
165 170 175
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
180 185 190
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
195 200 205
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
210 215 220
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
225 230 235 240
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
245 250
<210> 27
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(58-80活性区w Ala sub Cys)frag-Fc
<400> 27
Arg Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Ala Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Cys Asp Lys Thr His Thr Cys Pro Pro
20 25 30
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
35 40 45
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
50 55 60
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
65 70 75 80
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
85 90 95
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
100 105 110
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
115 120 125
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
130 135 140
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
145 150 155 160
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
165 170 175
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
180 185 190
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
195 200 205
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
210 215 220
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
225 230 235 240
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
245 250
<210> 28
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(58-80活性区w Val sub Cys)frag-Fc
<400> 28
Arg Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Val Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Cys Asp Lys Thr His Thr Cys Pro Pro
20 25 30
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
35 40 45
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
50 55 60
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
65 70 75 80
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
85 90 95
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
100 105 110
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
115 120 125
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
130 135 140
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
145 150 155 160
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
165 170 175
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
180 185 190
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
195 200 205
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
210 215 220
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
225 230 235 240
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
245 250
<210> 29
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(58-80活性区w Ile sub Cys)frag-Fc
<400> 29
Arg Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Ile Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Cys Asp Lys Thr His Thr Cys Pro Pro
20 25 30
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
35 40 45
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
50 55 60
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
65 70 75 80
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
85 90 95
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
100 105 110
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
115 120 125
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
130 135 140
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
145 150 155 160
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
165 170 175
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
180 185 190
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
195 200 205
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
210 215 220
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
225 230 235 240
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
245 250
<210> 30
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(58-80活性区w Leu sub Cys)frag-Fc
<400> 30
Arg Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Leu Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Cys Asp Lys Thr His Thr Cys Pro Pro
20 25 30
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
35 40 45
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
50 55 60
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
65 70 75 80
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
85 90 95
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
100 105 110
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
115 120 125
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
130 135 140
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
145 150 155 160
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
165 170 175
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
180 185 190
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
195 200 205
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
210 215 220
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
225 230 235 240
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
245 250
<210> 31
<211> 239
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(70-80活性区)frag-Fc
<400> 31
Phe Thr Leu Asp Glu Asn Phe Lys Ser Asp Leu Cys Asp Lys Thr His
1 5 10 15
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
20 25 30
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
35 40 45
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
50 55 60
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
65 70 75 80
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
85 90 95
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
100 105 110
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
115 120 125
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
130 135 140
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
145 150 155 160
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
165 170 175
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
180 185 190
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
195 200 205
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
210 215 220
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
225 230 235
<210> 32
<211> 236
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(73-80活性区)frag-Fc
<400> 32
Asp Glu Asn Phe Lys Ser Asp Leu Cys Asp Lys Thr His Thr Cys Pro
1 5 10 15
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
20 25 30
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
35 40 45
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
50 55 60
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
65 70 75 80
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
85 90 95
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
100 105 110
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
115 120 125
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
130 135 140
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
145 150 155 160
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
165 170 175
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
180 185 190
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
195 200 205
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
210 215 220
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
225 230 235
<210> 33
<211> 85
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(1-85活性区)frag
<400> 33
Gly Arg Tyr His Gln Cys Tyr Asn Gly Ser Gly Met Asp Tyr Arg Gly
1 5 10 15
Thr Ala Ser Thr Thr Lys Ser Gly His Gln Cys Gln Pro Trp Ala Leu
20 25 30
Gln His Pro His Ser His His Leu Ser Ser Thr Asp Phe Pro Glu Leu
35 40 45
Gly Gly Gly His Ala Tyr Cys Arg Asn Pro Gly Gly Gln Met Glu Gly
50 55 60
Pro Trp Cys Phe Thr Gln Asn Lys Asn Val Arg Met Glu Leu Cys Asp
65 70 75 80
Val Pro Ser Cys Ser
85
<210> 34
<211> 316
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(1-85活性区)frag-Fc
<400> 34
Gly Arg Tyr His Gln Cys Tyr Asn Gly Ser Gly Met Asp Tyr Arg Gly
1 5 10 15
Thr Ala Ser Thr Thr Lys Ser Gly His Gln Cys Gln Pro Trp Ala Leu
20 25 30
Gln His Pro His Ser His His Leu Ser Ser Thr Asp Phe Pro Glu Leu
35 40 45
Gly Gly Gly His Ala Tyr Cys Arg Asn Pro Gly Gly Gln Met Glu Gly
50 55 60
Pro Trp Cys Phe Thr Gln Asn Lys Asn Val Arg Met Glu Leu Cys Asp
65 70 75 80
Val Pro Ser Cys Ser Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
85 90 95
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
100 105 110
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
115 120 125
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
130 135 140
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
145 150 155 160
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
165 170 175
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
180 185 190
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
195 200 205
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
210 215 220
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
225 230 235 240
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
245 250 255
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
260 265 270
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
275 280 285
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
290 295 300
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
305 310 315
<210> 35
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(56-85活性区)frag-Fc
<400> 35
Arg Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Cys Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu Cys Asp Val Pro Ser Cys Ser Pro Lys
20 25 30
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
35 40 45
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
50 55 60
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
65 70 75 80
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
85 90 95
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
100 105 110
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
115 120 125
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
130 135 140
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
145 150 155 160
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
165 170 175
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
180 185 190
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
195 200 205
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
210 215 220
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
225 230 235 240
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
245 250 255
Leu Ser Pro Gly Lys
260
<210> 36
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(56-85活性区w Ala sub Cys)frag-Fc
<400> 36
Arg Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Ala Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu Ala Asp Val Pro Ser Ala Ser Pro Lys
20 25 30
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
35 40 45
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
50 55 60
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
65 70 75 80
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
85 90 95
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
100 105 110
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
115 120 125
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
130 135 140
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
145 150 155 160
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
165 170 175
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
180 185 190
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
195 200 205
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
210 215 220
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
225 230 235 240
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
245 250 255
Leu Ser Pro Gly Lys
260
<210> 37
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(56-85活性区w Val sub Cys)frag-Fc
<400> 37
Arg Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Val Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu Val Asp Val Pro Ser Val Ser Pro Lys
20 25 30
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
35 40 45
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
50 55 60
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
65 70 75 80
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
85 90 95
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
100 105 110
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
115 120 125
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
130 135 140
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
145 150 155 160
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
165 170 175
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
180 185 190
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
195 200 205
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
210 215 220
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
225 230 235 240
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
245 250 255
Leu Ser Pro Gly Lys
260
<210> 38
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(56-85活性区w Ile sub Cys)frag-Fc
<400> 38
Arg Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Ile Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu Ile Asp Val Pro Ser Ile Ser Pro Lys
20 25 30
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
35 40 45
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
50 55 60
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
65 70 75 80
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
85 90 95
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
100 105 110
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
115 120 125
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
130 135 140
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
145 150 155 160
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
165 170 175
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
180 185 190
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
195 200 205
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
210 215 220
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
225 230 235 240
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
245 250 255
Leu Ser Pro Gly Lys
260
<210> 39
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(56-85活性区w Leu sub Cys)frag-Fc
<400> 39
Arg Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Leu Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu Leu Asp Val Pro Ser Leu Ser Pro Lys
20 25 30
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
35 40 45
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
50 55 60
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
65 70 75 80
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
85 90 95
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
100 105 110
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
115 120 125
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
130 135 140
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
145 150 155 160
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
165 170 175
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
180 185 190
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
195 200 205
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
210 215 220
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
225 230 235 240
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
245 250 255
Leu Ser Pro Gly Lys
260
<210> 40
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(68-85活性区)frag-Fc
<400> 40
Phe Thr Gln Asn Lys Asn Val Arg Met Glu Leu Cys Asp Val Pro Ser
1 5 10 15
Cys Ser Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
20 25 30
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
35 40 45
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
50 55 60
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
65 70 75 80
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
85 90 95
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
100 105 110
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
115 120 125
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
130 135 140
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
145 150 155 160
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
165 170 175
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
180 185 190
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
195 200 205
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
210 215 220
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
225 230 235 240
Lys Ser Leu Ser Leu Ser Pro Gly Lys
245
<210> 41
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(68-85 活性区w Ala sub Cys)frag-Fc
<400> 41
Phe Thr Gln Asn Lys Asn Val Arg Met Glu Leu Ala Asp Val Pro Ser
1 5 10 15
Ala Ser Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
20 25 30
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
35 40 45
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
50 55 60
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
65 70 75 80
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
85 90 95
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
100 105 110
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
115 120 125
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
130 135 140
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
145 150 155 160
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
165 170 175
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
180 185 190
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
195 200 205
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
210 215 220
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
225 230 235 240
Lys Ser Leu Ser Leu Ser Pro Gly Lys
245
<210> 42
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(68-85 活性区w Val sub Cys)frag-Fc
<400> 42
Phe Thr Gln Asn Lys Asn Val Arg Met Glu Leu Val Asp Val Pro Ser
1 5 10 15
Val Ser Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
20 25 30
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
35 40 45
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
50 55 60
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
65 70 75 80
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
85 90 95
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
100 105 110
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
115 120 125
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
130 135 140
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
145 150 155 160
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
165 170 175
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
180 185 190
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
195 200 205
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
210 215 220
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
225 230 235 240
Lys Ser Leu Ser Leu Ser Pro Gly Lys
245
<210> 43
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(68-85活性区w Ile sub Cys)frag-Fc
<400> 43
Phe Thr Gln Asn Lys Asn Val Arg Met Glu Leu Ile Asp Val Pro Ser
1 5 10 15
Ile Ser Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
20 25 30
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
35 40 45
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
50 55 60
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
65 70 75 80
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
85 90 95
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
100 105 110
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
115 120 125
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
130 135 140
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
145 150 155 160
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
165 170 175
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
180 185 190
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
195 200 205
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
210 215 220
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
225 230 235 240
Lys Ser Leu Ser Leu Ser Pro Gly Lys
245
<210> 44
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(68-85活性区w Leu sub Cys)frag-Fc
<400> 44
Phe Thr Gln Asn Lys Asn Val Arg Met Glu Leu Leu Asp Val Pro Ser
1 5 10 15
Leu Ser Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
20 25 30
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
35 40 45
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
50 55 60
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
65 70 75 80
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
85 90 95
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
100 105 110
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
115 120 125
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
130 135 140
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
145 150 155 160
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
165 170 175
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
180 185 190
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
195 200 205
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
210 215 220
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
225 230 235 240
Lys Ser Leu Ser Leu Ser Pro Gly Lys
245
<210> 45
<211> 241
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(68-79活性区w Lys sub Cys)frag-Fc
<400> 45
Phe Thr Gln Asn Lys Asn Val Arg Met Glu Leu Lys Ser Cys Asp Lys
1 5 10 15
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
20 25 30
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
35 40 45
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
50 55 60
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
65 70 75 80
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
85 90 95
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
100 105 110
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
115 120 125
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
130 135 140
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
145 150 155 160
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
165 170 175
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
180 185 190
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
195 200 205
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
210 215 220
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
225 230 235 240
Lys
<210> 46
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(58-81活性区w Ala sub Cys和w Lys
sub Cys)frag
<400> 46
Arg Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Ala Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Lys
20
<210> 47
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(58-81活性区w Val sub Cys和w Lys
sub Cys)frag
<400> 47
Arg Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Val Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Lys
20
<210> 48
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(58-81活性区w Ile sub Cys和w Lys
sub Cys)frag
<400> 48
Arg Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Ile Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Lys
20
<210> 49
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(58-81活性区w Leu sub Cys和w Lys
sub Cys)frag
<400> 49
Arg Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Leu Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Lys
20
<210> 50
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(58-80活性区w Ala sub Cys)frag
<400> 50
Arg Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Ala Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu
20
<210> 51
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(58-80活性区w Val sub Cys)frag
<400> 51
Arg Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Val Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu
20
<210> 52
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(58-80活性区w Ile sub Cys)frag
<400> 52
Arg Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Ile Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu
20
<210> 53
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(58-80活性区w Leu sub Cys)frag
<400> 53
Arg Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Leu Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu
20
<210> 54
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(58-69活性区w Lys sub Cys)frag
<400> 54
Arg Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Lys
1 5 10
<210> 55
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(58-68活性区)frag
<400> 55
Arg Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp
1 5 10
<210> 56
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(70-81活性区w Lys sub Cys)frag
<400> 56
Phe Thr Leu Asp Glu Asn Phe Lys Ser Asp Leu Lys
1 5 10
<210> 57
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(70-80活性区)frag
<400> 57
Phe Thr Leu Asp Glu Asn Phe Lys Ser Asp Leu
1 5 10
<210> 58
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(71-80活性区)frag
<400> 58
Thr Leu Asp Glu Asn Phe Lys Ser Asp Leu
1 5 10
<210> 59
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(72-80活性区)frag
<400> 59
Leu Asp Glu Asn Phe Lys Ser Asp Leu
1 5
<210> 60
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(73-80活性区)frag
<400> 60
Asp Glu Asn Phe Lys Ser Asp Leu
1 5
<210> 61
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr1(73-79活性区)frag
<400> 61
Asp Glu Asn Phe Lys Ser Asp
1 5
<210> 62
<211> 79
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(6-84活性区)frag
<400> 62
Cys Tyr Asn Gly Ser Gly Met Asp Tyr Arg Gly Thr Ala Ser Thr Thr
1 5 10 15
Lys Ser Gly His Gln Cys Gln Pro Trp Ala Leu Gln His Pro His Ser
20 25 30
His His Leu Ser Ser Thr Asp Phe Pro Glu Leu Gly Gly Gly His Ala
35 40 45
Tyr Cys Arg Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Cys Phe Thr
50 55 60
Gln Asn Lys Asn Val Arg Met Glu Leu Cys Asp Val Pro Ser Cys
65 70 75
<210> 63
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(56-79活性区w Ala sub Cys和Lys sub
Cys)frag
<400> 63
Arg Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Ala Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu Lys
20
<210> 64
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(56-79活性区w Val sub Cys和Lys sub
Cys)frag
<400> 64
Arg Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Val Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu Lys
20
<210> 65
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(56-79活性区w Ile sub Cys和Lys sub
Cys)
<400> 65
Arg Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Ile Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu Lys
20
<210> 66
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(56-79活性区w Leu sub Cys和Lys sub
Cys)frag
<400> 66
Arg Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Leu Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu Lys
20
<210> 67
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(56-78活性区w Ala sub Cys)frag
<400> 67
Arg Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Ala Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu
20
<210> 68
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(56-78活性区w Val sub Cys)frag
<400> 68
Arg Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Val Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu
20
<210> 69
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(56-78活性区w Ile sub Cys)frag
<400> 69
Arg Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Ile Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu
20
<210> 70
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(56-78活性区w Leu sub Cys)frag
<400> 70
Arg Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Leu Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu
20
<210> 71
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(56-67活性区具有Lys sub Cys)frag
<400> 71
Arg Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Lys
1 5 10
<210> 72
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(56-66活性区)frag
<400> 72
Arg Asn Pro Gly Gly Gln Met Glu Gly Pro Trp
1 5 10
<210> 73
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(68-79活性区w Lys sub Cys)frag
<400> 73
Phe Thr Gln Asn Lys Asn Val Arg Met Glu Leu Lys
1 5 10
<210> 74
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(68-78活性区)frag
<400> 74
Phe Thr Gln Asn Lys Asn Val Arg Met Glu Leu
1 5 10
<210> 75
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(69-78活性区)frag
<400> 75
Thr Gln Asn Lys Asn Val Arg Met Glu Leu
1 5 10
<210> 76
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(70-78活性区)frag
<400> 76
Gln Asn Lys Asn Val Arg Met Glu Leu
1 5
<210> 77
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(70-77活性区)frag
<400> 77
Gln Asn Lys Asn Val Arg Met Glu
1 5
<210> 78
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-81活性区w Ala sub Cys和w
Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<400> 78
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Ala Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Lys
20
<210> 79
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-81活性区w Val sub Cys和w
Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<400> 79
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Val Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Lys
20
<210> 80
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-81活性区w Ile sub Cys和w
Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<400> 80
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Ile Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Lys
20
<210> 81
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-81活性区w Leu sub Cys和w
Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<400> 81
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Leu Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Lys
20
<210> 82
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-81活性区w Ala sub Cys和w
Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Arg
<400> 82
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Ala Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Lys
20
<210> 83
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-81活性区w Val sub Cys和w
Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Arg
<400> 83
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Val Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Lys
20
<210> 84
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-81活性区w Ile sub Cys和w
Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Arg
<400> 84
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Ile Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Lys
20
<210> 85
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-81活性区w Leu sub Cys和w
Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Arg
<400> 85
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Leu Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Lys
20
<210> 86
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-81活性区w Ala sub Cys和w
Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Arg
<400> 86
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Ala Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Lys
20
<210> 87
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-81活性区w Val sub Cys和w
Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Arg
<400> 87
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Val Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Lys
20
<210> 88
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-81活性区w Ile sub Cys和w
Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Arg
<400> 88
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Ile Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Lys
20
<210> 89
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-81活性区w Leu sub Cys和w
Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Arg
<400> 89
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Leu Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu Lys
20
<210> 90
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-81活性区w Ala sub Cys和w
Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<220>
<221> VARIANT
<222> (23)..(23)
<223> Xaa是连接至N-epsilon-MPA的Lys
<400> 90
Xaa Pro Gly Asn Gln Lys Glu Ala Pro Trp Ala Phe Thr Leu Asp Glu
1 5 10 15
Asn Phe Lys Ser Asp Leu Xaa
20
<210> 91
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-81活性区w Val sub Cys和w
Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<220>
<221> VARIANT
<222> (23)..(23)
<223> Xaa是连接至N-epsilon-MPA的Lys
<400> 91
Xaa Pro Gly Asn Gln Lys Glu Ala Pro Trp Val Phe Thr Leu Asp Glu
1 5 10 15
Asn Phe Lys Ser Asp Leu Xaa
20
<210> 92
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-81活性区w Ile sub Cys和w
Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<220>
<221> VARIANT
<222> (23)..(23)
<223> Xaa是连接至N-epsilon-MPA的Lys
<400> 92
Xaa Pro Gly Asn Gln Lys Glu Ala Pro Trp Ile Phe Thr Leu Asp Glu
1 5 10 15
Asn Phe Lys Ser Asp Leu Xaa
20
<210> 93
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-81活性区w Leu sub Cys和w
Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<220>
<221> VARIANT
<222> (23)..(23)
<223> Xaa是连接至N-epsilon-MPA的Lys
<400> 93
Xaa Pro Gly Asn Gln Lys Glu Ala Pro Trp Leu Phe Thr Leu Asp Glu
1 5 10 15
Asn Phe Lys Ser Asp Leu Xaa
20
<210> 94
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-80活性区w Ala sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<400> 94
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Ala Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu
20
<210> 95
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-80活性区w Val sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<400> 95
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Val Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu
20
<210> 96
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-80活性区w Ile sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<400> 96
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Ile Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu
20
<210> 97
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-80活性区w Leu sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<400> 97
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Leu Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu
20
<210> 98
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-80活性区w Ala sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Arg
<400> 98
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Ala Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu
20
<210> 99
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-80活性区w Val sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Arg
<400> 99
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Val Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu
20
<210> 100
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-80活性区w Ile sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Arg
<400> 100
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Ile Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu
20
<210> 101
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-80活性区w Leu sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Arg
<400> 101
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Leu Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu
20
<210> 102
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-80活性区)
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Arg
<400> 102
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Ala Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu
20
<210> 103
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-80活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Arg
<400> 103
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Val Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu
20
<210> 104
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-80活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Arg
<400> 104
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Ile Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu
20
<210> 105
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-80活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Arg
<400> 105
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Leu Phe Thr Leu Asp
1 5 10 15
Glu Asn Phe Lys Ser Asp Leu
20
<210> 106
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-69活性区w Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<400> 106
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Lys
1 5 10
<210> 107
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-69活性区w Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Arg
<400> 107
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Lys
1 5 10
<210> 108
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-69活性区w Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Arg
<400> 108
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Lys
1 5 10
<210> 109
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-69活性区w Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<220>
<221> VARIANT
<222> (12)..(12)
<223> Xaa是连接至N-epsilon-MPA的Lys
<400> 109
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp Xaa
1 5 10
<210> 110
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-68活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<400> 110
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp
1 5 10
<210> 111
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-68活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Arg
<400> 111
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp
1 5 10
<210> 112
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(58-68活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Arg
<400> 112
Xaa Asn Pro Gly Asn Gln Lys Glu Ala Pro Trp
1 5 10
<210> 113
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(70-81活性区w Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Phe
<400> 113
Xaa Thr Leu Asp Glu Asn Phe Lys Ser Asp Leu Lys
1 5 10
<210> 114
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(70-81活性区w Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Phe
<400> 114
Xaa Thr Leu Asp Glu Asn Phe Lys Ser Asp Leu Lys
1 5 10
<210> 115
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(70-81活性区w Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Phe
<400> 115
Xaa Thr Leu Asp Glu Asn Phe Lys Ser Asp Leu Lys
1 5 10
<210> 116
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(70-81活性区w Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Phe
<220>
<221> VARIANT
<222> (12)..(12)
<223> Xaa是连接至N-epsilon-MPA的Lys
<400> 116
Xaa Thr Leu Asp Glu Asn Phe Lys Ser Asp Leu Xaa
1 5 10
<210> 117
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(70-80活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Phe
<400> 117
Xaa Thr Leu Asp Glu Asn Phe Lys Ser Asp Leu
1 5 10
<210> 118
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(70-80活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Phe
<400> 118
Xaa Thr Leu Asp Glu Asn Phe Lys Ser Asp Leu
1 5 10
<210> 119
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(70-80活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Phe
<400> 119
Xaa Thr Leu Asp Glu Asn Phe Lys Ser Asp Leu
1 5 10
<210> 120
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(71-80活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Thr
<400> 120
Xaa Leu Asp Glu Asn Phe Lys Ser Asp Leu
1 5 10
<210> 121
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(71-80活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Thr
<400> 121
Xaa Leu Asp Glu Asn Phe Lys Ser Asp Leu
1 5 10
<210> 122
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(71-80活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Thr
<400> 122
Xaa Leu Asp Glu Asn Phe Lys Ser Asp Leu
1 5 10
<210> 123
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(72-80活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Leu
<400> 123
Xaa Asp Glu Asn Phe Lys Ser Asp Leu
1 5
<210> 124
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(72-80活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Leu
<400> 124
Xaa Asp Glu Asn Phe Lys Ser Asp Leu
1 5
<210> 125
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(72-80活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Leu
<400> 125
Xaa Asp Glu Asn Phe Lys Ser Asp Leu
1 5
<210> 126
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(73-80活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Asp
<400> 126
Xaa Glu Asn Phe Lys Ser Asp Leu
1 5
<210> 127
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(73-80活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Asp
<400> 127
Xaa Glu Asn Phe Lys Ser Asp Leu
1 5
<210> 128
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(73-80活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Asp
<400> 128
Xaa Glu Asn Phe Lys Ser Asp Leu
1 5
<210> 129
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(73-79活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Asp
<400> 129
Xaa Glu Asn Phe Lys Ser Asp
1 5
<210> 130
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(73-79活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Asp
<400> 130
Xaa Glu Asn Phe Lys Ser Asp
1 5
<210> 131
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(73-79活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Asp
<400> 131
Xaa Glu Asn Phe Lys Ser Asp
1 5
<210> 132
<211> 85
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(1-85活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Gly
<400> 132
Xaa Arg Tyr His Gln Cys Tyr Asn Gly Ser Gly Met Asp Tyr Arg Gly
1 5 10 15
Thr Ala Ser Thr Thr Lys Ser Gly His Gln Cys Gln Pro Trp Ala Leu
20 25 30
Gln His Pro His Ser His His Leu Ser Ser Thr Asp Phe Pro Glu Leu
35 40 45
Gly Gly Gly His Ala Tyr Cys Arg Asn Pro Gly Gly Gln Met Glu Gly
50 55 60
Pro Trp Cys Phe Thr Gln Asn Lys Asn Val Arg Met Glu Leu Cys Asp
65 70 75 80
Val Pro Ser Cys Ser
85
<210> 133
<211> 85
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(1-85活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Gly
<400> 133
Xaa Arg Tyr His Gln Cys Tyr Asn Gly Ser Gly Met Asp Tyr Arg Gly
1 5 10 15
Thr Ala Ser Thr Thr Lys Ser Gly His Gln Cys Gln Pro Trp Ala Leu
20 25 30
Gln His Pro His Ser His His Leu Ser Ser Thr Asp Phe Pro Glu Leu
35 40 45
Gly Gly Gly His Ala Tyr Cys Arg Asn Pro Gly Gly Gln Met Glu Gly
50 55 60
Pro Trp Cys Phe Thr Gln Asn Lys Asn Val Arg Met Glu Leu Cys Asp
65 70 75 80
Val Pro Ser Cys Ser
85
<210> 134
<211> 85
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Kr2(1-85活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Gly
<400> 134
Xaa Arg Tyr His Gln Cys Tyr Asn Gly Ser Gly Met Asp Tyr Arg Gly
1 5 10 15
Thr Ala Ser Thr Thr Lys Ser Gly His Gln Cys Gln Pro Trp Ala Leu
20 25 30
Gln His Pro His Ser His His Leu Ser Ser Thr Asp Phe Pro Glu Leu
35 40 45
Gly Gly Gly His Ala Tyr Cys Arg Asn Pro Gly Gly Gln Met Glu Gly
50 55 60
Pro Trp Cys Phe Thr Gln Asn Lys Asn Val Arg Met Glu Leu Cys Asp
65 70 75 80
Val Pro Ser Cys Ser
85
<210> 135
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-79活性区w Ala sub Cys和Lys
sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<400> 135
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Ala Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu Lys
20
<210> 136
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-79活性区w Val sub Cys和Lys
sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<400> 136
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Val Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu Lys
20
<210> 137
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-79活性区w Ile sub Cys和Lys
sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<400> 137
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Ile Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu Lys
20
<210> 138
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-79活性区w Leu sub Cys和Lys
sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<400> 138
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Leu Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu Lys
20
<210> 139
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-79活性区w Ala sub Cys和Lys
sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Arg
<400> 139
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Ala Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu Lys
20
<210> 140
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-79活性区w Val sub Cys和Lys
sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Arg
<400> 140
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Val Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu Lys
20
<210> 141
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-79活性区w Ile sub Cys和Lys
sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Arg
<400> 141
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Ile Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu Lys
20
<210> 142
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-79活性区w Leu sub Cys和Lys
sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Arg
<400> 142
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Leu Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu Lys
20
<210> 143
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-79活性区w Ala sub Cys和Lys
sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Arg
<400> 143
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Ala Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu Lys
20
<210> 144
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-79活性区w Val sub Cys和Lys
sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Arg
<400> 144
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Val Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu Lys
20
<210> 145
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-79活性区w Ile sub Cys和Lys
sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Arg
<400> 145
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Ile Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu Lys
20
<210> 146
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-79活性区w Leu sub Cys和Lys
sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Arg
<400> 146
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Leu Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu Lys
20
<210> 147
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-79活性区w Ala sub Cys和Lys
sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<220>
<221> VARIANT
<222> (24)..(24)
<223> Xaa是连接至N-epsilon-MPA的Lys
<400> 147
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Ala Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu Xaa
20
<210> 148
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-79活性区w Val sub Cys和Lys
sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<220>
<221> VARIANT
<222> (24)..(24)
<223> Xaa是连接至N-epsilon-MPA的Lys
<400> 148
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Val Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu Xaa
20
<210> 149
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-79活性区w Ile sub Cys和Lys
sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<220>
<221> VARIANT
<222> (24)..(24)
<223> Xaa是连接至N-epsilon-MPA的Lys
<400> 149
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Ile Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu Xaa
20
<210> 150
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-79活性区w Leu sub Cys和Lys
sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<220>
<221> VARIANT
<222> (24)..(24)
<223> Xaa是连接至N-epsilon-MPA的Lys
<400> 150
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Leu Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu Xaa
20
<210> 151
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-78活性区w Ala sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<400> 151
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Ala Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu
20
<210> 152
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-78活性区w Val sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<400> 152
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Val Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu
20
<210> 153
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-78活性区w Ile sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<400> 153
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Ile Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu
20
<210> 154
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-78活性区w Leu sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<400> 154
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Leu Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu
20
<210> 155
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-78活性区w Ala sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Arg
<400> 155
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Ala Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu
20
<210> 156
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-78活性区w Val sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Arg
<400> 156
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Val Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu
20
<210> 157
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-78活性区w Ile sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Arg
<400> 157
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Ile Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu
20
<210> 158
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-78活性区w Leu sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Arg
<400> 158
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Leu Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu
20
<210> 159
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-78活性区w Ala sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Arg
<400> 159
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Ala Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu
20
<210> 160
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-78活性区w Val sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Arg
<400> 160
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Val Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu
20
<210> 161
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-78活性区w Ile sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Arg
<400> 161
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Ile Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu
20
<210> 162
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-78活性区w Leu sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Arg
<400> 162
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Leu Phe Thr Gln Asn
1 5 10 15
Lys Asn Val Arg Met Glu Leu
20
<210> 163
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-67活性区w Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<400> 163
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Lys
1 5 10
<210> 164
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-67活性区w Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Arg
<400> 164
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Lys
1 5 10
<210> 165
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-67活性区w Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Arg
<400> 165
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Lys
1 5 10
<210> 166
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-67活性区w Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<220>
<221> VARIANT
<222> (12)..(12)
<223> Xaa是连接至N-epsilon-MPA的Lys
<400> 166
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp Xaa
1 5 10
<210> 167
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-66活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Arg
<400> 167
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp
1 5 10
<210> 168
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-66活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Arg
<400> 168
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp
1 5 10
<210> 169
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(56-66活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Arg
<400> 169
Xaa Asn Pro Gly Gly Gln Met Glu Gly Pro Trp
1 5 10
<210> 170
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(68-79活性区w Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Phe
<400> 170
Xaa Thr Gln Asn Lys Asn Val Arg Met Glu Leu Lys
1 5 10
<210> 171
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(68-79活性区w Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Phe
<400> 171
Xaa Thr Gln Asn Lys Asn Val Arg Met Glu Leu Lys
1 5 10
<210> 172
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(68-79活性区w Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Phe
<400> 172
Xaa Thr Gln Asn Lys Asn Val Arg Met Glu Leu Lys
1 5 10
<210> 173
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(68-79活性区w Lys sub Cys)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Phe是NAc-Phe
<220>
<221> VARIANT
<222> (12)..(12)
<223> Xaa是连接至N-epsilon-MPA的Lys
<400> 173
Xaa Thr Gln Asn Lys Asn Val Arg Met Glu Leu Xaa
1 5 10
<210> 174
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(68-78活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Phe
<400> 174
Xaa Thr Gln Asn Lys Asn Val Arg Met Glu Leu
1 5 10
<210> 175
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(68-78活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Phe
<400> 175
Xaa Thr Gln Asn Lys Asn Val Arg Met Glu Leu
1 5 10
<210> 176
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(68-78活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Phe
<400> 176
Xaa Thr Gln Asn Lys Asn Val Arg Met Glu Leu
1 5 10
<210> 177
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(69-78活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Thr
<400> 177
Xaa Gln Asn Lys Asn Val Arg Met Glu Leu
1 5 10
<210> 178
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(69-78活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Thr
<400> 178
Xaa Gln Asn Lys Asn Val Arg Met Glu Leu
1 5 10
<210> 179
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(69-78活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Thr
<400> 179
Xaa Gln Asn Lys Asn Val Arg Met Glu Leu
1 5 10
<210> 180
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(70-78活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Gln
<400> 180
Xaa Asn Lys Asn Val Arg Met Glu Leu
1 5
<210> 181
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(70-78活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Gln
<400> 181
Xaa Asn Lys Asn Val Arg Met Glu Leu
1 5
<210> 182
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(70-78活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Gln
<400> 182
Xaa Asn Lys Asn Val Arg Met Glu Leu
1 5
<210> 183
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(70-77活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Gln
<400> 183
Xaa Asn Lys Asn Val Arg Met Glu
1 5
<210> 184
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(70-77活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Gln
<400> 184
Xaa Asn Lys Asn Val Arg Met Glu
1 5
<210> 185
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr2(70-77活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Gln
<400> 185
Xaa Asn Lys Asn Val Arg Met Glu
1 5
<210> 186
<211> 93
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(1-93活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至NAc的Gly
<400> 186
Xaa Ser Asn Lys Asn His Lys Cys Tyr Asn Ser Thr Gly Val Asp Tyr
1 5 10 15
Arg Gly Thr Val Ser Val Thr Lys Ser Gly Arg Gln Cys Gln Pro Trp
20 25 30
Asn Ser Gln Tyr Pro His Thr His Thr Phe Thr Ala Leu Arg Phe Pro
35 40 45
Glu Leu Asn Gly Gly His Ser Tyr Cys Arg Asn Pro Gly Asn Gln Lys
50 55 60
Glu Ala Pro Trp Cys Phe Thr Leu Asp Glu Asn Phe Lys Ser Asp Leu
65 70 75 80
Cys Asp Ile Pro Ala Cys Asp Ser Lys Asp Ser Asp Ile
85 90
<210> 187
<211> 93
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(1-93活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA的Gly
<400> 187
Xaa Ser Asn Lys Asn His Lys Cys Tyr Asn Ser Thr Gly Val Asp Tyr
1 5 10 15
Arg Gly Thr Val Ser Val Thr Lys Ser Gly Arg Gln Cys Gln Pro Trp
20 25 30
Asn Ser Gln Tyr Pro His Thr His Thr Phe Thr Ala Leu Arg Phe Pro
35 40 45
Glu Leu Asn Gly Gly His Ser Tyr Cys Arg Asn Pro Gly Asn Gln Lys
50 55 60
Glu Ala Pro Trp Cys Phe Thr Leu Asp Glu Asn Phe Lys Ser Asp Leu
65 70 75 80
Cys Asp Ile Pro Ala Cys Asp Ser Lys Asp Ser Asp Ile
85 90
<210> 188
<211> 93
<212> PRT
<213> 人工序列
<220>
<223> 合成肽Mod-Kr1(1-93活性区)frag
<220>
<221> VARIANT
<222> (1)..(1)
<223> Xaa是连接至MPA-AEEA的Gly
<400> 188
Xaa Ser Asn Lys Asn His Lys Cys Tyr Asn Ser Thr Gly Val Asp Tyr
1 5 10 15
Arg Gly Thr Val Ser Val Thr Lys Ser Gly Arg Gln Cys Gln Pro Trp
20 25 30
Asn Ser Gln Tyr Pro His Thr His Thr Phe Thr Ala Leu Arg Phe Pro
35 40 45
Glu Leu Asn Gly Gly His Ser Tyr Cys Arg Asn Pro Gly Asn Gln Lys
50 55 60
Glu Ala Pro Trp Cys Phe Thr Leu Asp Glu Asn Phe Lys Ser Asp Leu
65 70 75 80
Cys Asp Ile Pro Ala Cys Asp Ser Lys Asp Ser Asp Ile
85 90
<210> 189
<211> 91
<212> PRT
<213> 人工序列
<220>
<223> 合成肽K5(1-91活性区)frag
<400> 189
Gly Ser Ser Glu Glu Asp Cys Met Phe Gly Asn Gly Lys Gly Tyr Arg
1 5 10 15
Gly Lys Arg Ala Thr Thr Val Thr Gly Thr Pro Cys Gln Asp Trp Ala
20 25 30
Ala Gln Glu Pro His Arg His Ser Ile Phe Thr Pro Glu Thr Asn Pro
35 40 45
Arg Ala Gly Leu Glu Lys Asn Tyr Cys Arg Asn Pro Asp Gly Asp Val
50 55 60
Gly Gly Pro Trp Cys Tyr Thr Thr Asn Pro Arg Lys Leu Tyr Asp Tyr
65 70 75 80
Cys Asp Val Pro Gln Cys Ala Ala Pro Asp Ile
85 90
Claims (17)
1.一种治疗方法,包括向有需要的人施用有效剂量的抗病毒剂,用于预防和抑制使用表面结合的GRP78进行附着、进入和复制的病毒(如SARS-CoV-2病毒、SARS-CoV-2病毒)的病毒感染。冠状病毒、MER-CoV病毒、日本脑炎病毒、柯萨奇病毒、登革热病毒和甲型和乙型流感病毒。
2.根据权利要求1所述的抗病毒剂,包括:
GRP78拮抗剂或药学上可接受的盐:
其中所述GRP78拮抗剂选自由纤溶酶kringle 5片段、附着于免疫球蛋白的纤溶酶kringle 5片段、ROR1 kringle片段、附着于免疫球蛋白的ROR1 kringle片段、ROR2kringle片段和ROR2 kringle片段组成的组附着在免疫球蛋白上。
3.根据权利要求2所述的抗病毒剂,其中所述纤溶酶原kringle 5片段包含SEQ ID NO:1及其组合。
4.权利要求2的抗病毒剂,其中附着于免疫球蛋白的纤溶酶kringle 5片段选自由SEQID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:5、SEQ ID NO:5、SEQ IDNO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6,SEQ ID NO:7,SEQ ID NO:8,SEQ ID NO:9,SEQ ID NO:10,SEQ ID NO:11,SEQ ID NO:12,SEQ ID NO:13,SEQ ID NO:SEQID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、及其组合。
5.根据权利要求2所述的抗病毒剂,其中所述ROR1 kringle片段具有SEQ ID NO:19及其组合。
6.根据权利要求2所述的抗病毒剂,其中连接至免疫球蛋白的所述ROR1 kringle片段选自由SEQ ID NO:20、SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ ID NO:23组成的组。N0:24、SEQ ID N0:25、SEQ ID N0:26、SEQ ID N0:27、SEQ ID N0:28、SEQ ID N0:29、SEQID N0:30、SEQ ID N0:31、SEQ ID N0:32及其组合。
7.根据权利要求2所述的抗病毒剂,其中所述ROR2 kringle是SEQ ID NO:33及其组合。
8.权利要求2的抗病毒剂,其中连接至免疫球蛋白的ROR2 kringle片段选自由SEQ IDNO:34、SEQ ID NO:35、SEQ ID NO:36、SEQ ID NO:37、SEQ ID NO:37组成的组。SEQ ID NO:38、SEQ ID NO:39、SEQ ID NO:40、SEQ ID NO:41、SEQ ID NO:42、SEQ ID NO:43、SEQ IDNO:44、SEQ ID NO:45及其组合。
9.权利要求2的抗病毒剂,其中所述GRP78拮抗剂结合N端GRP78结构域并与GRP78拮抗剂竞争以诱导GRP78内化。
10.一种抗病毒剂,包括:
GRP78拮抗剂或药学上可接受的盐:
其中所述GRP78拮抗剂选自由纤溶酶kringle 5片段、附着于免疫球蛋白的纤溶酶kringle 5片段、ROR1 kringle片段、附着于免疫球蛋白的ROR1 kringle片段、ROR2kringle片段和ROR2 kringle片段组成的组附着在免疫球蛋白上。
11.(当前修正)权利要求10的抗病毒剂,其中所述纤溶酶kringle 5片段包含SEQ IDNO:1及其组合。
12.根据权利要求10所述的抗病毒剂,其中附着于免疫球蛋白的纤溶酶kringle 5片段选自由SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:5、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6,SEQ ID NO:7,SEQ ID NO:8,SEQID NO:9,SEQ ID NO:10,SEQ ID NO:11,SEQ ID NO:12,SEQ ID NO:13,SEQ ID NO:SEQ IDNO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、及其组合。
13.根据权利要求10所述的抗病毒剂,其中所述ROR1 kringle片段具有SEQ ID NO:19及其组合。
14.根据权利要求10所述的抗病毒剂,其中连接至免疫球蛋白的所述ROR1 kringle片段选自由SEQ ID NO:20、SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ ID NO:23组成的组。NO:24、SEQ ID NO:25、SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29、SEQ ID NO:30、SEQ ID NO:31、SEQ ID NO:32及其组合。
15.根据权利要求10所述的抗病毒剂,其中所述ROR2 kringle片段是SEQ ID NO:33及其组合。
16.根据权利要求10所述的抗病毒剂,其中连接至免疫球蛋白的所述ROR2 kringle片段选自由SEQ ID NO:34、SEQ ID NO:35、SEQ ID NO:36、SEQ ID NO:37、SEQ ID NO:37组成的组。SEQ ID NO:38、SEQ ID NO:39、SEQ ID NO:40、SEQ ID NO:41、SEQ ID NO:42、SEQ IDNO:43、SEQ ID NO:44、SEQ ID NO:45及其组合。
17.权利要求10的抗病毒剂,其中所述GRP78拮抗剂结合N端GRP78结构域并与GRP78拮抗剂竞争以诱导GRP78内化。
Applications Claiming Priority (4)
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US202063012900P | 2020-04-20 | 2020-04-20 | |
US17/235,652 US20210324047A1 (en) | 2020-04-20 | 2021-04-20 | Antivirus proteins having a kringle 5 subunit |
US17/235,652 | 2021-04-20 | ||
PCT/US2021/055329 WO2022216316A1 (en) | 2020-04-20 | 2021-10-16 | Antivirus proteins having a kringle 5 subunit |
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CN117396219A true CN117396219A (zh) | 2024-01-12 |
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US (1) | US20210324047A1 (zh) |
EP (1) | EP4319878A1 (zh) |
JP (1) | JP2024513507A (zh) |
CN (1) | CN117396219A (zh) |
AU (1) | AU2021439258A1 (zh) |
IL (1) | IL307542A (zh) |
WO (1) | WO2022216316A1 (zh) |
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CA2743057C (en) * | 2008-11-07 | 2019-11-26 | Research Development Foundation | Compositions and methods for the inhibition of cripto/grp78 complex formation and signaling |
US20190076431A1 (en) * | 2016-03-17 | 2019-03-14 | University Of Southern California | Src inhibitor to block cell surface grp78 expression |
US10905750B2 (en) * | 2017-11-10 | 2021-02-02 | Donald J. Davidson | GRP78 antagonist that block binding of receptor tyrosine kinase orphan receptors as immunotherapy anticancer agents |
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2021
- 2021-04-20 US US17/235,652 patent/US20210324047A1/en active Pending
- 2021-10-16 AU AU2021439258A patent/AU2021439258A1/en active Pending
- 2021-10-16 JP JP2023562275A patent/JP2024513507A/ja active Pending
- 2021-10-16 IL IL307542A patent/IL307542A/en unknown
- 2021-10-16 CN CN202180096923.XA patent/CN117396219A/zh active Pending
- 2021-10-16 EP EP21936227.4A patent/EP4319878A1/en active Pending
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US20210324047A1 (en) | 2021-10-21 |
JP2024513507A (ja) | 2024-03-25 |
EP4319878A1 (en) | 2024-02-14 |
IL307542A (en) | 2023-12-01 |
AU2021439258A1 (en) | 2023-10-26 |
AU2021439258A9 (en) | 2023-11-02 |
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