CN114685643A - 一种人glp-1多肽变体及其应用 - Google Patents
一种人glp-1多肽变体及其应用 Download PDFInfo
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- CN114685643A CN114685643A CN202011601861.7A CN202011601861A CN114685643A CN 114685643 A CN114685643 A CN 114685643A CN 202011601861 A CN202011601861 A CN 202011601861A CN 114685643 A CN114685643 A CN 114685643A
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Abstract
本申请涉及一种人GLP‑1多肽变体，所述的人GLP‑1多肽变体与SEQ ID NO：2所示的人GLP‑1多肽的氨基酸序列相比，包含至少2个氨基酸突变，所述至少2个氨基酸突变选自位于下组的氨基酸位置处：W31、K26、Q23和/或Y19。本申请所述的人GLP‑1多肽变体可用于构建融合蛋白或免疫缀合物。本申请还提供了所述人GLP‑1多肽变体或融合蛋白或免疫缀合物在预防和/或治疗疾病或病症中的应用。
Description
技术领域
本申请涉及生物医药领域，具体的涉及一种人GLP-1多肽变体及其应用。
背景技术
胰高血糖素样肽(glucagon-like peptide-1，GLP-1)是一种由小肠上皮L-细胞分泌的肠促胰素，在健康的个体中，GLP-1能响应机体营养物质的摄取，促进胰岛素释放并抑制胰高血糖素分泌。在患有II型糖尿病的患者中，输入超生理剂量的GLP-1可恢复内源性胰岛素分泌，降低血糖。
由于二肽酰二肽酶IV的酶解和肾脏的清除作用，天然GLP-1的血浆半衰期短。尽管已经开发了几种修饰以延长半衰期的GLP-1R激动剂(如度拉糖肽Dulaglutide)用于治疗II型糖尿病，但仍需开发有效的长期治疗并维持最低限度的副作用的方案。
发明内容
本申请提供了一种人GLP-1多肽变体，其中与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列包含至少2个氨基酸突变，所述至少2个氨基酸突变位于下列选自下组的氨基酸位置处：W31、K26、Q23和Y19。本申请还提供了包含所述人GLP-1多肽变体的融合蛋白或免疫缀合物，所述融合蛋白或免疫缀合物具有以下至少一种性质：(1)能够与GLP-1受体结合，(2)能够激活GLP-1受体，从而提高cAMP水平，(3)较长的血液半衰期，(4)较高的体内外稳定性，(5)较高的血药浓度和(6)能够降低血糖。
一方面，本申请提供了一种人GLP-1多肽变体，其中与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列包含至少2个氨基酸突变，所述至少2个氨基酸突变位于下列选自下组的氨基酸位置处：W31、K26、Q23和Y19。
在某些实施方式中，所述人GLP-1多肽变体具有人GLP-1的至少部分活性。
在某些实施方式中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列包含选自下组的氨基酸位置处的至少2个突变：W31、K26和Y19。
在某些实施方式中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列包含选自下组的氨基酸位置处的至少2个突变：W31、K26和Q23。
在某些实施方式中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列包含W31和K26氨基酸位置处的突变。
在某些实施方式中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列包含W31和Q23氨基酸位置处的突变。
在某些实施方式中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列包含W31和Y19氨基酸位置处的突变。
在某些实施方式中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列包含K26和Q23氨基酸位置处的突变。
在某些实施方式中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列包含K26和Y19氨基酸位置处的突变。
在某些实施方式中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列包含W31、K26和Y19氨基酸位置处的突变。
在某些实施方式中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列包含W31、K26和Q23氨基酸位置处的突变。
在某些实施方式中，所述的人GLP-1多肽变体的所述W31处包含氨基酸取代，所述的氨基酸取代为W31Y、W31K、W31R或W31A。例如，所述的氨基酸取代为W31Y、W31K或W31R。又例如，所述的氨基酸取代为W31Y。
在某些实施方式中，所述的人GLP-1多肽变体的所述Y19处包含氨基酸取代，所述的氨基酸取代为选自下组的任意一种氨基酸取代：Y19A、Y19L、Y19T、Y19F、Y19I、Y19V和Y19S。
在某些实施方式中，所述的人GLP-1多肽变体的所述Q23处包含氨基酸取代，所述的氨基酸取代为选自下组的任意一种氨基酸取代：Q23E、Q23T、Q23S和Q23N。
在某些实施方式中，所述的人GLP-1多肽变体的所述K26处包含氨基酸取代，所述的氨基酸取代包括为K26R。
在某些实施方式中，所述的人GLP-1多肽变体包含SEQ ID NO:29、31-53和61-71中任一项所示的氨基酸序列。在某些实施方式中，所述的人GLP-1多肽变体包含SEQ ID NO:29、32-53和61-71中任一项所示的氨基酸序列。在某些实施方式中，所述的融合蛋白或免疫缀合物包含SEQ ID NO:29所示的氨基酸序列。在某些实施方式中，所述的融合蛋白或免疫缀合物包含SEQ ID NO:32-53中任一项所示的氨基酸序列。在某些实施方式中，所述的融合蛋白或免疫缀合物包含SEQ ID NO:61-71中任一项所示的氨基酸序列。
另一方面，本申请提供了一种融合蛋白或免疫缀合物，其包含所述的人GLP-1多肽变体。
在某些实施方式中，所述的融合蛋白或免疫缀合物还包含免疫球蛋白Fc区。
在某些实施方式中，所述的融合蛋白或免疫缀合物的所述免疫球蛋白Fc区为源自IgG的Fc区。
在某些实施方式中，所述的融合蛋白或免疫缀合物的所述免疫球蛋白Fc区为源自IgG4的Fc区。
在某些实施方式中，所述免疫球蛋白Fc区包含SEQ ID NO:139-143中任一项所示的氨基酸序列。
在某些实施方式中，所述人GLP-1多肽变体与所述免疫球蛋白Fc区框内融合。
在某些实施方式中，所述融合蛋白或免疫缀合物包含连接肽。
在某些实施方式中，所述人GLP-1多肽变体与所述免疫球蛋白Fc区通过所述连接肽连接。
在某些实施方式中，所述连接肽包含SEQ ID NO:144-149中任一项所示的氨基酸序列。
在某些实施方式中，所述人GLP-1多肽变体、所述连接肽与所述免疫球蛋白Fc区框内融合。
在某些实施方式中，所述的融合蛋白或免疫缀合物包含SEQ ID NO:96、98-120和128-138中任一项所示的氨基酸序列。在某些实施方式中，所述的融合蛋白或免疫缀合物包含SEQ ID NO:96、97-120和128-138中任一项所示的氨基酸序列。在某些实施方式中，所述的融合蛋白或免疫缀合物包含SEQ ID NO:96所示的氨基酸序列。在某些实施方式中，所述的融合蛋白或免疫缀合物包含SEQ ID NO:99-122中任一项所示的氨基酸序列。在某些实施方式中，所述的融合蛋白或免疫缀合物包含SEQ ID NO:128-138中任一项所示的氨基酸序列。
另一方面，本申请提供了一种分离的核酸分子，其编码权所述的人GLP-1多肽变体或所述的融合蛋白或免疫缀合物。
另一方面，本申请提供了一种载体，其包含所述的分离的核酸分子。
另一方面，本申请提供了一种细胞，其包含或表达所述的人GLP-1多肽变体、所述的融合蛋白或免疫缀合物、所述的分离的核酸分子或所述的载体。
另一方面，本申请提供了一种药物组合物，其包含所述的人GLP-1多肽变体、所述的融合蛋白或免疫缀合物、所述的分离的核酸分子、所述的载体或所述的细胞，以及任选地药学上可接受的佐剂。
另一方面，本申请提供了所述的人GLP-1多肽变体或所述的融合蛋白或免疫缀合物用于制备药物的用途，所述药物用于预防和/或治疗代谢性疾病或病症。
另一方面，本申请提供了预防和/或治疗代谢性疾病或病症的方法，所述方法包括施用所述的人GLP-1多肽变体或所述的融合蛋白或免疫缀合物。
另一方面，本申请提供了所述的人GLP-1多肽变体或所述的融合蛋白或免疫缀合物，其用于预防和/或治疗代谢性疾病或病症。
在某些实施方式中，所述代谢性疾病或病症包括GLP-1相关代谢性病症。
在某些实施方式中，所述代谢性疾病或病症包括糖尿病。
另一方面，本申请提供了增加或促进有需要的受试者中胰岛素表达的方法，所述方法包括向所述受试者施用有效量的所述的人GLP-1多肽变体或所述的融合蛋白或免疫缀合物。
另一方面，本申请提供了所述的人GLP-1多肽变体或所述的融合蛋白或免疫缀合物，其用于增加或促进有需要的受试者中胰岛素表达。
另一方面，本申请提供了所述的人GLP-1多肽变体或所述的融合蛋白或免疫缀合物在制备药物中的用途，所述药物用于增加或促进有需要的受试者中胰岛素表达。
本领域技术人员能够从下文的详细描述中容易地洞察到本申请的其它方面和优势。下文的详细描述中仅显示和描述了本申请的示例性实施方式。如本领域技术人员将认识到的，本申请的内容使得本领域技术人员能够对所公开的具体实施方式进行改动而不脱离本申请所涉及发明的精神和范围。相应地，本申请的附图和说明书中的描述仅仅是示例性的，而非为限制性的。
附图说明
本申请所涉及的发明的具体特征如所附权利要求书所显示。通过参考下文中详细描述的示例性实施方式和附图能够更好地理解本申请所涉及发明的特点和优势。对附图简要说明如下：
图1显示的是融合蛋白GM-WY和GM-FY与GLP-1受体的结合活性。
图2显示的是融合蛋白GM-WY与GLP-1受体的结合活性。
图3显示的是融合蛋白GM-WR和GM-FH与GLP-1受体的结合活性。
图4显示的是融合蛋白GM-WY、GM-QN、GM-QT、GM-QS、GM-YL、GM-YT和GM-YF与GLP-1受体的结合活性。
图5显示的是融合蛋白GM-WY、GM-YI、GM-YV、GM-YS、GM-QE和GM-YA与GLP-1受体的结合活性
图6显示的是融合蛋白GM-FT、GM-FN、GM-FS和GM-FQ与GLP-1受体的结合活性。
图7显示的是融合蛋白GM-FE、GM-FV、GM-FK和GM-FI与GLP-1受体的结合活性
图8显示的是融合蛋白GM-WY、GM-KRFY、GM-KRWY和GM-KRWYFY与GLP-1受体的结合活性。
图9显示的是融合蛋白GM-WY、GM-KRQN、GM-KRQT、GM-KRQS、GM-KRYL、GM-KRYT和GM-KRYF与GLP-1受体的结合活性。
图10显示的是融合蛋白GM-KRWY、GM-KRYI、GM-KRYV、GM-KRYS、GM-KRQE、和GM-KRYA与GLP-1受体的结合活性。
图11显示的是融合蛋白GM-WY、GM-WYQN、GM-WYQS和GM-WYQT与GLP-1受体的结合活性。
图12显示的是融合蛋白GM-WY、GM-WYYL、GM-WYYT、GM-WYYF、GM-WYYI、GM-WYYV和GM-WYYS与GLP-1受体的结合活性。
图13显示的是融合蛋白GM-WYYA和GM-WYQE与GLP-1受体的结合活性。
图14显示的是融合蛋白GM-WYYA在6h(A)和24h(B)对cAMP/PKA信号通路的激活作用。
图15显示的是融合蛋白GM-WYQE在6h(A)和24h(B)对cAMP/PKA信号通路的激活作用。
图16显示的是融合蛋白GM-WYFL和GM-WY与GLP-1受体的结合活性。
图17显示的是融合蛋白GM-WIFL、GM-WA、GM-WL和GM-WLFL与GLP-1受体的结合活性。
图18显示的是融合蛋白GM-KRWYYF、GM-KRWYYL、GM-KRWYYT、GM-KRWYQN、GM-KRWYQT和GM-KRWYQS与GLP-1受体的结合活性。
图19显示的是融合蛋白GM-KRWYYI、GM-KRWYYV、GM-KRWYYS、GM-KRWYQE和GM-KRWYYA与GLP-1受体的结合活性。
图20显示的是融合蛋白GM-KRWYYA和GM-KRWYQN与GLP-1受体的结合活性。
图21显示的是融合蛋白GM-KRWY和GM-KRWYQE在6h(A)和24h(B)对cAMP/PKA信号通路的激活作用。
图22显示的是融合蛋白GM-KRWYYA和GM-KRWYYL在6h(A)和24h(B)对cAMP/PKA信号通路的激活作用。
图23显示的是融合蛋白GM-KRWYYS和GM-KRWYYI在6h(A)和24h(B)对cAMP/PKA信号通路的激活作用。
图24显示的是融合蛋白GM-KRWYYT和GM-KRWYQN在6h(A)和24h(B)对cAMP/PKA信号通路的激活作用。
图25显示的是融合蛋白GM-KRWYQT和GM-KRWYQS在6h(A)和24h(B)对cAMP/PKA信号通路的激活作用。
图26显示的是融合蛋白GM-KRWYYA和GM-KRWYQN在6h(A)和24h(B)对cAMP/PKA信号通路的激活作用。
图27显示的是融合蛋白GM-KRWY的药代动力学效果。
图28显示的是融合蛋白GM-KRWYYL、GM-KRWYYI和GM-KRWYYA的药代动力学效果。
图29显示的是融合蛋白GM-KRWYQN、GM-KRWYQE和GM-KRWYYA的药代动力学效果。
图30A-30B显示的是融合蛋白GM-KRWY在口服糖耐量试验中的降血糖活性。
图31A-31B显示的是融合蛋白GM-KRWYQE和GM-KRWYYA在口服糖耐量试验中的降血糖活性。
图32显示的是本申请中氨基酸序列的编号示例。
具体实施方式
以下由特定的具体实施例说明本申请发明的实施方式，熟悉此技术的人士可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。
术语定义
在本申请中，术语“GLP-1”通常是指胰高血糖素样肽-1(glucagon like peptide1)。天然GLP-1分子在体内经过加工，切割了前6个氨基酸，因此本领域习惯将GLP-1的氨基酸序列的N端第一个氨基酸定为第7位，C端最后一个氨基酸定为第37位。经过加工的肽可以在体内得到进一步修饰，去除C端的甘氨酸残基并以酰胺基替代。GLP-1通常有两种生物活性形式，分别为GLP-1(7-37)OH和GLP-1(7-36)NH2。本申请所述的“GLP-1”包含天然的、人工合成的或经修饰的GLP-1蛋白，还包含完整的GLP-1蛋白或其功能性片段，以及不同生物活性形式的GLP-1蛋白。例如，野生型的人GLP-1可包含如SEQ ID NO:1所示的氨基酸序列，其N末端的氨基酸残基H记为第7位。因此，本申请的术语“K26”通常是指从GLP-1蛋白N端第7位的H起算，第26位氨基酸的位置，在SEQ ID NO:1所示的氨基酸序列中，第26位的氨基酸为K；术语“W31”通常是指从GLP-1蛋白N端第7位的H起算，第31位氨基酸的位置，在SEQ ID NO:1所示的氨基酸序列中，第31位的氨基酸为W。
所述人GLP-1可以被改造，改造后的GLP-1的变体可以具有改造前的人GLP-1的至少部分活性。例如，示例性的野生型人GLP-1改造后的氨基酸序列可以如SEQ ID NO:2所示。
在本申请中，术语“人GLP-1的至少部分活性”通常是指具有人GLP-1蛋白的一种或多种活性，或具有人GLP-1蛋白的至少20％(例如，至少25％、30％、35％、40％、45％、或50％或更高)的活性。所述“人GLP-1的至少部分活性”的人GLP-1可以是野生型的，如，SEQ IDNO:1所示的氨基酸序列。所述“人GLP-1的至少部分活性”中的人GLP-1可以是野生型人GLP-1改造后的GLP-1变体，如，SEQ ID NO:2所示的氨基酸序列。例如，本申请的人GLP-1多肽变体可以具有氨基酸序列如SEQ ID NO:1所示的人GLP-1的至少部分活性。在另一些情形中，本申请的人GLP-1多肽变体可以具有氨基酸序列如SEQ ID NO:2所示的人GLP-1的至少部分活性。
所述活性不要求与人GLP-1蛋白具有相同水平的活性，可以是高于、相近或低于人GLP-1蛋白的活性。在某些情形中，“人GLP-1的至少部分活性”可以指选自下组中的一种或多种：与GLP-1受体结合的活性、激活GLP-1受体的活性、激活腺苷酸环化酶、促进细胞内环磷酸腺苷(cAMP)水平升高的活性、正性调节细胞内Ca2+水平的活性、刺激胰岛素分泌的活性、增加肝糖原储存量的活性、延缓胃排空的活性、抑制胃动力的活性、降低食欲的活性、抑制β细胞凋亡的活性、抑制餐后胰高血糖素的分泌的活性、缓解低血糖的活性和减轻体重的活性。例如，其可以通过检测与GLP-1受体结合的能力、cAMP的表达水平来检测。所述“人GLP-1的至少部分活性”可以是包含人GLP-1的融合蛋白(例如，与Fc区的融合蛋白)的至少部分活性。
在本申请中，术语“GLP-1R”通常是指胰高血糖素样肽-1受体(glucagon likepeptide 1receptor)。GLP-1R与GLP-1结合可激活信号级联反应，导致腺苷酸环化酶的激活和细胞内cAMP水平的增加。本申请所述GLP-1R可包括天然GLP-1R的全长分子、变体、片段、合成物，只要保留GLP-1R的活性即可。例如，本申请所述GLP-1R可包含NCBI数据库登录号为NP_002053.3所示的氨基酸序列。
在本申请中，术语“多肽”通常是指由通过酰胺键(也称为肽键)线性连接的单体(氨基酸)构成的分子。术语“多肽”可以是具有两个或更多个氨基酸的任意链，并且不指特定长度的产物。本申请所述多肽包括肽、二肽、三肽、寡肽、蛋白质、氨基酸链或任何其它用于指具有两个或更多个氨基酸的链，而且术语“多肽”可以代替这些术语中任一个或与其交换使用。术语“多肽”还可以指多肽的表达后修饰的产物，包括但不限于糖基化、乙酰化、磷酸化、酰化、通过已知的保护性/封闭性基团衍生化、蛋白水解分裂、或通过非天然存在的氨基酸修饰。多肽可以自天然的生物学来源衍生或通过重组技术生成。
在本申请中，术语“变体”通常是指与天然生物活性蛋白质具有序列同源性的蛋白质分子。本申请所述的多肽变体包括通过添加(包含插入)、缺失、修饰和/或取代一个或多个氨基酸残基而具有改变的氨基酸序列的多肽，其同时保留亲本序列的至少一种治疗和/或生物活性而与亲本序列不同。例如，变体可与亲本蛋白具有至少0％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％或99％的序列同一性。变体可以天然存在或者是非天然存在的。可以使用本领域已知的技术来生成非天然存在的变体。多肽变体可以包含保守的或非保守的氨基酸替代、删除或添加。
在本申请中，术语“突变”通常包括对序列(核酸或氨基酸序列)的任何类型的改变或修饰，包括氨基酸或核苷酸的缺失、截短、失活、破坏、取代或易位。在本申请中，氨基酸突变可以是氨基酸取代，术语“取代”通常是指用不同的“替换”氨基酸残基来替换预先确定的亲本氨基酸序列中的至少一个氨基酸残基。该一个或多个被替换的氨基酸残基可以是“天然存在的氨基酸残基”(即由遗传密码编码)。
在本申请中，术语“铰链区”通常是指免疫球蛋白重链CHl和CH2功能区之间的区域。铰链区通常来源于IgG，例如，可来源于IgG1、IgG2、IgG3或IgG4。
在本申请中，术语“融合蛋白”通常是指包含或者由下述这样的多肽组成的更长的多肽，所述多肽的氨基酸序列可以直接或间接地(通过连接子，例如，连接肽)融合至一异源多肽(例如，前一多肽或其结构域无关的多肽)的氨基酸序列。在某些情形中，融合蛋白可以包含所述多肽变体，以及与所述多肽变体直接或间接连接(例如，通过连接肽连接)的免疫球蛋白Fc区。例如，所述连接肽可以为GS、GAP、G4S、(G4S)2、(G4S)3或(G4S)4。
在本申请中，术语“免疫缀合物”通常是指多肽或蛋白质和感兴趣的活性物质(例如，蛋白质、核酸、药物或标记分子等)直接或间接连接(例如，通过连接子共价连接)而形成的缀合物。
在本申请中，术语“免疫球蛋白”通常是指基本上由免疫球蛋白基因编码的一个或多个多肽组成的蛋白质。公认的人免疫球蛋白基因包括κ、λ、α(IgA1和IgA2)、γ(IgG1、IgG2、IgG3、IgG4)、δ、ε和μ恒定区基因，以及众多的免疫球蛋白可变区基因。全长免疫球蛋白“轻链”(约25KD和214个氨基酸)的NH2-末端(约110个氨基酸)由可变区基因编码，COOH-末端由κ或λ恒定区基因编码。一般来说，免疫球蛋白可以是约150,000道尔顿的异四聚体糖蛋白，其由两条相同的轻链(L)和两条相同的重链(H)组成。天然的免疫球蛋白基本上由经由免疫球蛋白铰链区连接的两个Fab分子和Fc区组成。
在本申请中，术语“Fc区”通常是指免疫球蛋白重链的C端区域，所述C端区域可以通过木瓜蛋白酶消化完整的抗体而产生。Fc区可以是天然序列Fc区或变体Fc区。免疫球蛋白的Fc区通常包含2个恒定域(CH2结构域和CH3结构域)，且任选地可以包含CH4结构域。
在本申请中，术语“框内融合”通常是指两个或多个开放阅读框(ORF)以保持原始ORF正确阅读框的方式连接以形成连续更长的ORF。因此，得到的重组融合蛋白是含有对应于由原始ORF编码的多肽的两个或更多个区段的单个蛋白质。
在本申请中，术语“核酸分子”通常是指从其天然环境中分离的或人工合成的任何长度的分离形式的核苷酸、脱氧核糖核苷酸或核糖核苷酸或其类似物。
在本申请中，术语“载体”通常是指能够在合适的宿主细胞中自我复制的核酸分子，其将插入的核酸分子转移到宿主细胞中和/或宿主细胞之间。所述载体可包括主要用于将DNA或RNA插入细胞中的载体、主要用于复制DNA或RNA的载体，以及主要用于DNA或RNA的转录和/或翻译的表达的载体。所述载体还可以包括具有多种上述功能的载体。所述载体可以是当引入合适的宿主细胞时能够转录并翻译成多肽的多核苷酸。通常，通过培养包含所述载体的合适的宿主细胞，所述载体可以产生期望的表达产物。
在本申请中，术语“细胞”通常是指可以或已经含有包括本申请所述的核酸分子的质粒或载体，或者能够表达本申请所述的抗体或其抗原结合片段的个体细胞，细胞系或细胞培养物。所述宿主细胞可以包括单个宿主细胞的子代。由于天然的，意外的或故意的突变，子代细胞与原始亲本细胞在形态上或在基因组上可能不一定完全相同，但能够表达本申请所述的抗体或其抗原结合片段即可。所述宿主细胞可以通过使用本申请所述的载体体外转染细胞而得到。所述宿主细胞可以是原核细胞(例如大肠杆菌)，也可以是真核细胞(例如酵母细胞，例如COS细胞，中国仓鼠卵巢(CHO)细胞，HeLa细胞，HEK293细胞，COS-1细胞，NS0细胞或骨髓瘤细胞)。所述重组宿主细胞不仅包括某种特定的细胞，还包括这些细胞的后代。
在本申请中，术语“代谢性疾病或病症”通常是指破坏体内正常代谢过程，使得机体无法正常利用和/或贮存能量的疾病或病症。所述代谢性疾病或病症可以是指糖类代谢障碍的疾病、脂肪类代谢障碍的疾病和/或细胞线粒体障碍的疾病。所述代谢性疾病或病症可以是与饮食、毒素或感染相关的，也可以是遗传性疾病。所述代谢性疾病或病症可以包括由缺少代谢相关的酶、或代谢相关的酶功能异常引起的疾病或病症。本申请所述代谢性疾病或病症可以选自糖尿病、肥胖症和其他GLP-1相关代谢性病症。
在申请中，“度拉糖肽(dulaglutide)”通常是指一种包含GLP-1类似物的异源融合蛋白质，由GLP-1类似物(氨基酸序列如SEQ ID NO: 2所示)与源自人IgG4的Fc区(氨基酸序列如SEQ ID NO: 143所示)通过小分子肽(氨基酸序列如SEQ ID NO: 148所示)共价连接形成。度拉糖肽也可称为杜拉鲁肽或度拉鲁肽，商品名为
或度
度拉糖肽包含如SEQ ID NO: 4所示的氨基酸序列(参见PCT专利WO2009009562和美国专利US7452966)。
在本申请中， 术语“包含”通常是指包括明确指定的特征， 但不排除其他要素。
在本申请中，术语“约”通常是指在指定数值以上或以下0.5％-10％的范围内变动，例如在指定数值以上或以下0.5％、 1％、 1.5％、2％、2.5％、3％、3.5％、4％、4.5％、5％、5.5％、6％、6.5％、7％、7.5％、8％、8.5％、9％、9.5％、或10％的范围内变动。
发明详述
多肽变体
一方面，本申请提供了一种人GLP-1多肽变体，其具有人GLP-1的至少部分活性。在某些情形中，人GLP-1多肽变体可以具有选自下组中的一种或多种活性：与GLP-1受体结合的活性、激活GLP-1受体的活性、激活腺苷酸环化酶、促进细胞内环磷酸腺苷(cAMP)水平升高的活性、正性调节细胞内Ca2+水平的活性、刺激胰岛素分泌的活性、增加肝糖原储存量的活性、延缓胃排空的活性、抑制胃动力的活性、降低食欲的活性、抑制β细胞凋亡的活性、抑制餐后胰高血糖素的分泌的活性、缓解低血糖的活性和减轻体重的活性。例如，其可以通过检测与GLP-1受体结合的能力、cAMP的表达水平来检测。所述人GLP-1多肽变体的活性可以为人GLP-1活性的至少20％(例如，至少25％、30％、35％、40％、45％、或50％或更高)。
与SEQ ID NO: 2所示的氨基酸序列相比：HGEGTFTSDVSSYLEEQAAKEFIAWLVKGGG(SEQ ID NO: 2)，所述人GLP-1多肽变体的氨基酸序列可包含至少2个氨基酸突变，例如，可包含2个、3个、4个或更多个氨基酸突变。例如，与SEQ ID NO: 2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含2-4个(例如，2-3个、3个或2个)氨基酸取代。所述至少2个氨基酸突变可以位于选自下组的氨基酸位置处：K26、W31、Y19和Q23。
在本申请中，所述氨基酸位置“Xn”是指在相应于SEQ ID NO: 1或SEQ ID NO: 2所示的氨基酸序列中第n位的残基X处发生氨基酸取代，其中n为正整数(对于GLP-1，n从7开始起算)，X为任意氨基酸残基的缩写。例如，氨基酸位置“W31”表示相应于SEQ ID NO:1或SEQID NO: 2所示的氨基酸序列的第31位氨基酸的位置。对于SEQ ID NO: 2所示的氨基酸序列，氨基酸残基X和位置n的对应关系如图32所示。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含选自下组的氨基酸位置处的至少2个突变：W31、K26和Y19。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含选自下组的氨基酸位置处的至少2个突变：W31、K26和Q23。
例如，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含W31和K26氨基酸位置处的2个氨基酸突变。例如，所述人GLP-1多肽变体的氨基酸序列有2个氨基酸突变，可以位于W31和K26氨基酸位置处。例如，所述人GLP-1多肽变体可包含SEQ ID NO:29所示的氨基酸序列。
例如，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含W31和Y19氨基酸位置处的2个氨基酸突变。例如，所述人GLP-1多肽变体的氨基酸序列有2个氨基酸突变，可以位于W31和Y26氨基酸位置处。例如，所述人GLP-1多肽变体可包含SEQ ID NO:47-53中任一项所示的氨基酸序列。
例如，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含W31和Q23氨基酸位置处的2个氨基酸突变。例如，所述人GLP-1多肽变体的氨基酸序列有2个氨基酸突变，可以位于W31和Q23氨基酸位置处。例如，所述人GLP-1多肽变体可包含SEQ ID NO:43-46中任一项所示的氨基酸序列。
例如，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含K26和Y19氨基酸位置处的2个氨基酸突变。例如，所述人GLP-1多肽变体的氨基酸序列有2个氨基酸突变，可以位于K26和Y19氨基酸位置处。例如，所述人GLP-1多肽变体可包含SEQ ID NO:36-42中任一项所示的氨基酸序列。
例如，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含K26和Q23氨基酸位置处的2个氨基酸突变。例如，所述人GLP-1多肽变体的氨基酸序列有2个氨基酸突变，可以位于K26和Q23氨基酸位置处。例如，所述人GLP-1多肽变体可包含SEQ ID NO:32-35中任一项所示的氨基酸序列。
例如，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含Y19和Q23氨基酸位置处的2个氨基酸突变。例如，所述人GLP-1多肽变体的氨基酸序列有2个氨基酸突变，可以位于Y19和Q23氨基酸位置处。
例如，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含W31、K26和Y19氨基酸位置处的3个氨基酸突变。例如，所述人GLP-1多肽变体的氨基酸序列有3个氨基酸突变，可以位于W31、K26和Y19氨基酸位置处。
例如，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含W31、K26和Q23氨基酸位置处的3个氨基酸突变。例如，所述人GLP-1多肽变体的氨基酸序列有3个氨基酸突变，可以位于W31、K26和Q23氨基酸位置处。
例如，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含Y19、K26和Q23氨基酸位置处的3个氨基酸突变。例如，所述人GLP-1多肽变体的氨基酸序列有3个氨基酸突变，可以位于Y19、K26和Q23氨基酸位置处。
例如，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含W31、Y19和Q23氨基酸位置处的3个氨基酸突变。例如，所述人GLP-1多肽变体的氨基酸序列有3个氨基酸突变，可以位于W31、Y19和Q23氨基酸位置处。
例如，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含W31、K26、Y19和Q23氨基酸位置处的4个氨基酸突变。例如，所述人GLP-1多肽变体的氨基酸序列有4个氨基酸突变，可以位于W31、K26、Y19和Q23氨基酸位置处。
在本申请中，所述氨基酸突变可以包含氨基酸取代。所述氨基酸突变使所述GLP-1多肽变体仍具有人GLP-1(例如，氨基酸序列如SEQ ID NO:1或2中任一项所示的人GLP-1蛋白)的至少部分活性。所述氨基酸突变可以使所述GLP-1多肽变体的融合蛋白仍具有人GLP-1(例如，氨基酸序列如SEQ ID NO:1或2中任一项所示的人GLP-1蛋白)的融合蛋白的至少部分活性。所述氨基酸突变可以使所述GLP-1多肽变体与Fc区的融合蛋白仍具有人GLP-1(例如，氨基酸序列如SEQ ID NO:1或2中任一项所示的人GLP-1蛋白)与Fc区的融合蛋白的至少部分活性。
在本申请中，所述K26处可以包含氨基酸取代，所述氨基酸取代可以为K26R。
在本申请中，所述W31处可以包含氨基酸取代，所述氨基酸取代可以为W31Y、W31A、W31R或W31K。在本申请中，所述W31处可以包含氨基酸取代，所述氨基酸取代可以为W31Y、W31K或W31R。例如，所述W31处可以包含氨基酸取代，所述氨基酸取代可以为W31Y。
在本申请中，所述Y19处可以包含氨基酸取代，所述氨基酸取代可以为Y19A、Y19L、Y19T、Y19F、Y19I、Y19V或Y19S。
在本申请中，所述Q23处可以包含氨基酸取代，所述氨基酸取代可以为Q23E、Q23T、Q23S或Q23N。
在本申请中，氨基酸取代“XnY”是指相应于SEQ ID NO:1或SEQ ID NO:2所示的氨基酸序列中第n位的残基X被取代为氨基酸残基Y，其中n为正整数(对于GLP-1，n从7开始起算)，X和Y分别独立地为任意氨基酸残基的缩写，且X不同于Y。例如，氨基酸取代“W31Y”是指相应于SEQ ID NO:1或SEQ ID NO:2所示的氨基酸序列中第31位的氨基酸残基W被取代为氨基酸残基Y。
在本申请中，与SEQ ID NO:1或SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含至少2个氨基酸取代，所述氨基酸取代可以选自下组：1)K26R，2)选自W31Y、W31R、W31K和W31A中的任意一个，3)选自Y19A、Y19L、Y19T、Y19F、Y19I、Y19V和Y19S中的任意一个，和4)选自Q23N、Q23T、Q23S和Q23E中的任意一个。
例如，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含选自下组的至少2个氨基酸突变：1)K26R，2)选自W31Y、W31R和W31K和W31A中的任意一个，和3)选自Y19A、Y19L、Y19T、Y19F、Y19I、Y19V和Y19S中的任意一个。
例如，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含选自下组的至少2个氨基酸突变：1)K26R，2)选自W31Y、W31R和W31K和W31A中的任意一个，和3)选自Q23N、Q23T、Q23S和Q23E中的任意一个。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含W31和K26氨基酸位置处的2个氨基酸取代，所述K26处的氨基酸取代可以为K26R，且所述W31处的氨基酸取代可以为W31Y、W31R和W31K和W31A。例如，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含W31Y和K26R的氨基酸取代。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含氨基酸取代W31Y。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含氨基酸取代K26R。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含氨基酸取代Q23E。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含氨基酸取代Y19A。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含氨基酸取代W31Y和Q23E。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含氨基酸取代W31Y和Y19A。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含氨基酸取代W31Y和K26R。例如，所述人GLP-1多肽变体可包含SEQ ID NO：29、31和61-71中任一项所示的氨基酸序列。又例如，所述人GLP-1多肽变体可包含SEQ IDNO：29和61-71中任一项所示的氨基酸序列。
例如，所述人GLP-1多肽变体的氨基酸序列的氨基酸取代可以为W31Y和K26R，例如，所述人GLP-1多肽变体可包含SEQ ID NO：29所示的氨基酸序列。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含氨基酸取代Q23E和K26R。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含氨基酸取代Y19A和K26R。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含氨基酸取代K26R，W31处的氨基酸取代和Q23处的氨基酸取代。在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含氨基酸取代K26R，氨基酸取代W31Y和Q23处的氨基酸取代。例如，所述GLP-1多肽变体可包含SEQ IDNO：61-64中任一项所示的氨基酸序列。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含氨基酸取代K26R，氨基酸取代W31Y和Y19处的氨基酸取代。例如，所述GLP-1多肽变体可包含SEQ ID NO：65-71中任一项所示的氨基酸序列。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含氨基酸取代K26R，氨基酸取代W31Y和氨基酸取代Q23N。例如，所述GLP-1多肽变体可包含SEQ ID NO：61所示的氨基酸序列。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含氨基酸取代K26R，氨基酸取代W31Y和氨基酸取代Q23T。例如，所述GLP-1多肽变体可包含SEQ ID NO：62所示的氨基酸序列。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含氨基酸取代K26R，氨基酸取代W31Y和氨基酸取代Q23S。例如，所述GLP-1多肽变体可包含SEQ ID NO：63所示的氨基酸序列。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含氨基酸取代K26R，氨基酸取代W31Y和氨基酸取代Q23E。例如，所述人GLP-1多肽变体可包括SEQ ID NO:64所示的氨基酸序列。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含氨基酸取代K26R，氨基酸取代W31Y和氨基酸取代Y19A。例如，所述人GLP-1多肽变体可包括SEQ ID NO:71所示的氨基酸序列。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含氨基酸取代K26R，氨基酸取代W31Y和氨基酸取代Y19L。例如，所述GLP-1多肽变体可包含SEQ ID NO:66所示的氨基酸序列。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含氨基酸取代K26R，氨基酸取代W31Y和氨基酸取代Y19T。例如，所述GLP-1多肽变体可包含SEQ ID NO:67所示的氨基酸序列。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含氨基酸取代K26R，氨基酸取代W31Y和氨基酸取代Y19F。例如，所述GLP-1多肽变体可包含SEQ ID NO:65所示的氨基酸序列。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含氨基酸取代K26R，氨基酸取代W31Y和氨基酸取代Y19I。例如，所述GLP-1多肽变体可包含SEQ ID NO:68所示的氨基酸序列。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含氨基酸取代K26R，氨基酸取代W31Y和氨基酸取代Y19V。例如，所述GLP-1多肽变体可包含SEQ ID NO:69所示的氨基酸序列。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含氨基酸取代K26R，氨基酸取代W31Y和氨基酸取代Y19S。例如，所述GLP-1多肽变体可包含SEQ ID NO:70所示的氨基酸序列。
本申请中，所述人GLP-1多肽变体可以包含SEQ ID NO:153所示的氨基酸序列:HGEGTFTSDVSSX19LEEX23AAX26EFIAX31LVKGGG；其中，X19＝Y、A、L、T、F、I、V或S；X23＝Q、E、T、S或N；X26＝K或R；X31＝W、A、R、K或Y。其中，X19＝Y、X23＝Q、X26＝K和X31＝W全部不同时存在，或X19＝Y、X23＝Q、X26＝K和X31＝W中的至少三种不同时存在。
在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体可以包含SEQ ID NO:153所示的氨基酸序列:HGEGTFTSDVSSX19LEEX23AAX26EFIAX31LVKGGG，其中，与SEQ ID NO：2所示的氨基酸相比，可包含在X19、X23、X26和/或X31处中至少2个的氨基酸取代，其中，X19处的氨基酸Y可被取代为A、L、T、F、I、V或S；X23处的氨基酸Q可被取代为E、T、S或N；X26处的氨基酸K可被取代为R；X31处的氨基酸W可被取代为Y、K、R或A。
本申请中，所述人GLP-1多肽变体可以包含SEQ ID NO:150所示的氨基酸序列:HGEGTFTSDVSSX19LEEX23AAREFIAYLVKGGG；其中，X19＝Y、A、L、T、F、I、V或S；X23＝Q、E、T、S或N。其中，X19＝Y和X23＝Q不同时存在。在本申请中，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体可以包含SEQ ID NO:150所示的氨基酸序列:HGEGTFTSDVSSX19LEEX23AAREFIAYLVKGGG，其中，所述人GLP-1多肽变体可包含在X19和X23处的氨基酸取代，其中，X19处的氨基酸Y可被取代为A、L、T、F、I、V或S；X23处的氨基酸Q可被取代为E、T、S或N。
本申请中，所述人GLP-1多肽变体的氨基酸序列可以包含SEQ ID NO:151所示的氨基酸序列:HGEGTFTSDVSSYLEEX23AAREFIAYLVKGGG；其中，X23＝E、T、S或N。在本申请中，所述人GLP-1多肽变体的氨基酸序列可以包含SEQ ID NO:151所示的氨基酸序列，与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含在X23处的氨基酸取代，其中X23处的氨基酸Q可被取代为E、T、S或N。
本申请中，所述人GLP-1多肽变体的氨基酸序列可以包含SEQ ID NO:152所示的氨基酸序列:HGEGTFTSDVSSX19LEEQAAREFIAYLVKGGG；其中，X19＝A、L、T、F、I、V或S。在本申请中，所述人GLP-1多肽变体的氨基酸序列可以包含SEQ ID NO:151所示的氨基酸序列，与SEQID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列可包含在X19处的氨基酸取代，其中，X19处的氨基酸Y可被取代为A、L、T、F、I、V或S。
融合蛋白或免疫缀合物
另一方面，本申请提供一种融合蛋白或免疫缀合物，所述融合蛋白或免疫缀合物可包含本申请所述人GLP-1多肽变体。在本申请中，所述融合蛋白或免疫缀合物可包含1个、2个或以上(例如，3个、4个、5个)所述的人GLP-1多肽变体。
在本申请中，所述融合蛋白或免疫缀合物还可包含免疫球蛋白Fc区。本申请所述的免疫球蛋白Fc区可以包括免疫球蛋白的重链恒定区2(CH2)和重链恒定区3(CH3)，通常不含有来自该抗体的两个抗原结合区(Fab片段)。此外，本申请的免疫球蛋白Fc区可以包含全部或部分的Fc区，只要其具有与天然蛋白相似的生理活性。本申请的Fc区可以包括来自IgA、IgD、IgE、IgG及IgM的Fc区。例如，所述Fc区可以为源自IgG的Fc区。所述Fc区可以源自人IgG。例如，所述Fc区可以为源自IgG1、IgG2、IgG3或IgG4的Fc区。例如，所述Fc区可以源自人IgG4。
在本申请中，所述融合蛋白或免疫缀合物的Fc区还可包含免疫球蛋白铰链区。所述铰链区可以源自IgG。所述铰链区可以源自人IgG。例如，所述铰链区可以为源自IgG1、IgG2、IgG3或IgG4的铰链区。例如，所述铰链区可以位于所述GLP-1多肽变体的C端，例如，所述铰链区可以位于所述Fc区CH2的N端。
例如，所述Fc区可包含SEQ ID N:139-143所示的氨基酸序列。例如，所述融合蛋白或免疫缀合物的所述Fc区可以包含SEQ ID NO:142或143所示的氨基酸序列。又例如，所述Fc区可以包含SEQ ID NO:143所示的氨基酸序列。
在本申请中，所述GLP-1多肽变体的一端可以直接或间接地连接至所述Fc区的一端。例如，通过框内融合。在某些情形中，所述GLP-1多肽变体的C端可以直接或间接地连接至所述Fc区的N端。
在本申请中，所述融合蛋白或免疫缀合物可包含所述GLP-1多肽变体和免疫球蛋白Fc区。在某些情形中，所述GLP-1多肽变体和所述Fc可以通过连接子(例如，连接肽)连接。例如，所述连接肽可以选自GS、GAP、G4S、(G4S)2、(G4S)3或(G4S)4。例如，所述连接肽可包含SEQ ID NO:144-149中任一项所示的氨基酸序列。
在本申请中，所述融合蛋白或免疫缀合物自N端至C端，可依次包含本申请所述的任GLP-1多肽变体、所述连接肽和所述Fc区。所述融合蛋白或免疫缀合物自N端至C端，可依次包含本申请所述的任GLP-1多肽变体、所述连接肽(G4S)3(氨基酸序列如SEQ ID NO:148)和源自IgG4的Fc区(氨基酸序列如SEQ ID NO:143)例如，本申请所述的融合蛋白或免疫缀合物可包含SEQ ID NO:96、98-120和128-138中任一项所示的氨基酸序列。
本申请所述的融合蛋白或免疫缀合物具有生物学活性。生物学活性指体内或体外结合并激活GLP-lR并引起反应的能力。所述反应包括但是不限于胰岛素的分泌、胰高血糖素的抑制、抑制食欲、体重减轻、诱导过饱、抑制凋亡、诱导胰腺β细胞增殖及胰腺β细胞分化。对有代表性的一些融合蛋白测试体外和体内活性。
本申请所述的融合蛋白或免疫缀合物能偶与实施例2反映了基于本申请所述融合蛋白与人类GLP-lR相互作用能力，例如，使用ELISA法检测的。实施例3反映了本申请所述融合蛋白对GLP-1R的体外活化能力，GLP-1R的活化引起腺苷酸环化酶的活化，该酶的活化又诱导cAMP反应元件结合蛋白(CREB)驱动的报告基因的表达，例如，使用荧光素酶报告基因的荧光强度来体现，或利用cAMP表达量来体现。实施例4反映了所述融合蛋白具有较长的血液半衰期。实施例5反映了本申请所述融合蛋白的能够降低升高的血糖水平。
在本申请中，所述人GLP-1多肽变体命名为GLP-1-XX，其中，“XX”代表氨基酸取代，例如，对于人GLP-1多肽变体GLP-WY，表示与SEQ ID NO:2所示的氨基酸序列相比，人GLP-1多肽变体GLP-WY的氨基酸突变为：第31位的氨基酸残基W被氨基酸残基Y取代；对于人GLP-1多肽变体GLP-KRWYYA，表示与SEQ ID NO:2所示的氨基酸序列相比，人GLP-1多肽变体GLP-KRWYYA的氨基酸突变为：第19位的氨基酸残基Y被氨基酸残基A取代，第26位的氨基酸残基K被氨基酸残基R取代，以及第31位的氨基酸残基W被氨基酸残基Y取代。
在本申请中，所述人GLP-1多肽变体和Fc区的融合蛋白的命名为GM-XX，其中，“XX”代表人GLP-1多肽变体中的相应的氨基酸取代。
核酸分子、载体、细胞和制备方法
在另一个方面，本申请还提供了分离的一种或多种核酸分子，所述一种或多种核酸分子可编码本申请所述的多肽变体或者所述的融合蛋白或免疫缀合物。例如，所述一种或多种核酸分子中的每一个核酸分子可以编码完整的多肽变体或者所述的融合蛋白或免疫缀合物，也可以编码其中的一部分。
本申请所述的核酸分子可以为分离的。例如，其可以是通过以下方法产生或合成的：(i)在体外扩增的，例如通过聚合酶链式反应(PCR)扩增产生的，(ii)通过克隆重组产生的，(iii)纯化的，例如通过酶切和凝胶电泳分级分离，或者(iv)合成的，例如通过化学合成。在某些实施方式中，所述分离的核酸是通过重组DNA技术制备的核酸分子。重组DNA和分子克隆技术包括由Sambrook,J.,Fritsch,E.F.和Maniatis,T.Molecular Cloning:ALaboratory Manual；Cold Spring Harbor Laboratory Press:Cold Spring Harbor,(1989)(Maniatis)和由T.J.Silhavy,M.L.Bennan和L.W.Enquist,Experiments with GeneFusions,Cold Spring Harbor Laboratory,Cold Spring Harbor,N.Y.(1984)以及由Ausubel,F.M.等，Current Protocols in Molecular Biology,pub.by GreenePublishing Assoc.and Wiley-Interscience(1987)描述的那些技术。简而言之，可从基因组DNA片段、cDNA和RNA制备所述核酸，所有这些核酸可直接从细胞中提取或通过各种扩增方法(包括但不限于PCR和RT-PCR)重组产生。
在另一个方面，本申请提供了一种或多种载体，其包含所述的核酸分子。例如，所述载体中可包含一种或多种所述核酸分子。此外，所述载体中还可包含其他基因，例如允许在适当的宿主细胞中和在适当的条件下选择该载体的标记基因。此外，所述载体还可包含允许编码区在适当宿主中正确表达的表达控制元件。这样的控制元件为本领域技术人员所熟知的，例如，可包括启动子、核糖体结合位点、增强子和调节基因转录或mRNA翻译的其他控制元件等。本申请所述的一种或多种核酸分子可以与所述表达控制元件可操作地连接。
所述载体可以包括，例如质粒、粘粒、病毒、噬菌体或者在例如遗传工程中通常使用的其他载体。例如，所述载体为表达载体。
在另一方面，本申请提供了一种细胞，所述细胞可包含本申请所述的一种或多种核酸分子和/或本申请所述的一种或多种载体。在某些实施方式中，每种或每个宿主细胞可包含一个或一种本申请所述的核酸分子或载体。在某些实施方式中，每种或每个宿主细胞可包含多个(例如，2个或以上)或多种(例如，2种或以上)本申请所述的核酸分子或载体。例如，可将本申请所述的载体引入所述细胞中，例如原核细胞(例如，细菌细胞)、CHO细胞、NS0细胞、HEK293T细胞或HEK293A细胞，或者其他真核细胞，如来自植物的细胞、真菌或酵母细胞等。可通过本领域已知的方法将本申请所述的载体引入所述细胞中，例如电穿孔、脂质体转染等。
在另一个方面，本申请提供了制备本申请所述多肽变体、所述融合蛋白或免疫缀合物的方法。所述方法可包括，在使得所述多肽变体、所述融合蛋白或免疫缀合物表达的条件下，培养本申请所述的细胞。例如，可通过使用适当的培养基、适当的温度和培养时间等，这些方法是本领域普通技术人员所了解的。
在某些情形中，所述方法还可包括收获(例如分离和/或纯化)，本申请所述多肽变体、所述融合蛋白或免疫缀合物的步骤。例如，可以采用蛋白G-琼脂糖或蛋白A-琼脂糖进行亲和层析，还可通过凝胶电泳和/或高效液相色谱等来纯化和分离本申请所述多肽变体、所述融合蛋白或免疫缀合物。
药物组合物和用途
另一方面，本申请提供了一种药物组合物，所述药物组合物包含所述的人GLP-1多肽变体，所述融合蛋白或免疫缀合物，所述的核酸分子，所述的载体，或所述的细胞，以及任选地药学上可接受的佐剂。
例如，所述药学上可接受的佐剂可以包括缓冲剂、抗氧化剂、防腐剂、低分子量多肽、蛋白质、亲水聚合物、氨基酸、糖、螯合剂、反离子、金属复合物和/或非离子表面活性剂等。
在本申请中，所述药物组合物可被配制用于口服给药，静脉内给药，肌肉内给药，在肿瘤部位的原位给药，吸入，直肠给药，阴道给药，经皮给药或通过皮下储存库给药。
本申请所述的药物组合物可以用于治疗代谢性疾病或病症。所述药物组合物可以用于治疗糖尿病(例如高血糖症、I型糖尿病、II型糖尿病、葡萄糖耐量受损、非胰岛素依赖型糖尿病、MODY(青年人的成年发病型糖尿病)、妊娠期糖尿病和/或用于降低糖化血红蛋白(HbAlC))、糖尿病前期、高血压、高血糖和/或血脂异常(或者这些代谢风险因素的组合)。糖尿病的急性症状包括尿产生过量、所导致的代偿性口渴和流体摄取增多、视力模糊、原因不明的体重降低、嗜睡和能量代谢改变。糖尿病的慢性高血糖症与大血管和微血管并发症相关，所述并发症可导致多种器官(尤其是眼(尤其以糖尿病视网膜病的形式)、肾(以糖尿病性肾病的形式)、神经(以糖尿病神经病变的形式)、心脏和血管)的长期损伤、功能障碍和在一些情况下的最终衰竭。所述药物组合物还可用于治疗体重增加、促进体重降低、减少过多体重和/或治疗肥胖症(例如通过控制食欲、进食、食物摄取、热量摄取和/或能量消耗)(包括病态肥胖)以及相关疾病、异常和健康状况(包括但不限于肥胖相关炎症、肥胖相关胆囊病和肥胖引起的睡眠呼吸暂停)。例如，所述代谢性疾病或病症可以选自糖尿病、肥胖和其他GLP-1相关代谢性病症。
所述药物组合物的给药频率和剂量可以通过多个相关因素被确定，该因素包括要被治疗的疾病类型，给药途径，病人年龄，性别，体重和疾病的严重程度以及作为活性成分的药物类型。由于所述药物组合物具有优良的体内功效和浓度的持续时间，它可以显著地减少所述药物的给药频率和剂量。
另一方面，本申请还提供了以下实施方案：
1.人GLP-1多肽变体，其中与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列包含至少2个氨基酸突变，所述至少2个氨基酸突变位于选自下组的氨基酸位置处：W31、K26、Q23和Y19。
2.根据实施方案1所述的人GLP-1多肽变体，其具有人GLP-1的至少部分活性。
3.根据实施方案1-2中任一项所述的人GLP-1多肽变体，其中与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列包含选自下组的氨基酸位置处的至少2个突变：W31、K26和Y19。
4.根据实施方案1-3中任一项所述的人GLP-1多肽变体，其中与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列包含选自下组的氨基酸位置处的至少2个突变：W31、K26和Q23。
5.根据实施方案1-4中任一项所述的人GLP-1多肽变体，其中与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列包含W31和K26氨基酸位置处的突变。
6.根据实施方案1-5中任一项所述的人GLP-1多肽变体，其中与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列包含W31和Q23氨基酸位置处的突变。
7.根据实施方案1-6中任一项所述的人GLP-1多肽变体，其中与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列包含W31和Y19氨基酸位置处的突变。
8.根据实施方案1-7中任一项所述的人GLP-1多肽变体，其中与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列包含K26和Q23氨基酸位置处的突变。
9.根据实施方案1-8中任一项所述的人GLP-1多肽变体，其中与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列包含K26和Y19氨基酸位置处的突变。
10.根据实施方案1-9中任一项所述的人GLP-1多肽变体，其中所述W31处包含氨基酸取代，所述氨基酸取代为W31Y、W31R、W31K或W31A。
11.根据实施方案1-10中任一项所述的人GLP-1多肽变体，其中所述Y19处包含氨基酸取代，所述氨基酸取代为选自下组的任意一种氨基酸取代：Y19A、Y19L、Y19T、Y19F、Y19I、Y19V和Y19S。
12.根据实施方案1-11中任一项所述的人GLP-1多肽变体，其中所述Q23处包含氨基酸取代，所述氨基酸取代为选自下组的任意一种氨基酸取代：Q23E、Q23T、Q23S和Q23N。
13.根据实施方案1-12中任一项所述的人GLP-1多肽变体，其中所述K26处包含氨基酸取代，所述氨基酸取代为K26R。
14.根据实施方案1-13中任一项所述的人GLP-1多肽变体，其包含SEQ ID NO:153所示的氨基酸序列。
15.根据实施方案1-14中任一项所述的人GLP-1多肽变体，其包含SEQ ID NO:29、31-53和61-71中任一项所示的氨基酸序列。
16.融合蛋白或免疫缀合物，其包含实施方案1-15中任一项所述的人GLP-1多肽变体。
17.根据实施方案16所述的融合蛋白或免疫缀合物，其还包含免疫球蛋白Fc区。
18.根据实施方案17所述的融合蛋白或免疫缀合物，其中所述免疫球蛋白Fc区为源自IgG的Fc区。
19.根据实施方案16或17所述的融合蛋白或免疫缀合物，其中所述免疫球蛋白Fc区为源自IgG4的Fc区。
20.根据实施方案16-19中任一项所述的融合蛋白或免疫缀合物，其中所述免疫球蛋白Fc区包含SEQ ID NO:139-143中任一项所示的氨基酸序列。
21.根据实施方案16-22中任一项所述的融合蛋白或免疫缀合物，其中所述人GLP-1多肽变体与所述免疫球蛋白Fc区框内融合。
22.根据实施方案16-21中任一项所述的融合蛋白或免疫缀合物，其包含连接肽。
23.根据实施方案22所述的融合蛋白或免疫缀合物，其中所述人GLP-1多肽变体与所述免疫球蛋白Fc区通过所述连接肽连接。
24.根据实施方案22或23所述的融合蛋白或免疫缀合物，其中所述连接肽包含SEQID NO:
144-149中任一项所示的氨基酸序列。
25.根据实施方案16-24中任一项所述的融合蛋白或免疫缀合物，其包含SEQ IDNO:96、98-120和128-138中任一项所示的氨基酸序列。
26.分离的核酸分子，其编码实施方案1-15中任一项所述的人GLP-1多肽变体或实施方案16-25中任一项所述的融合蛋白或免疫缀合物。
27.载体，其包含实施方案26所述的分离的核酸分子。
28.细胞，其包含或表达实施方案1-15中任一项所述的人GLP-1多肽变体、实施方案16-25中任一项所述的融合蛋白或免疫缀合物、实施方案26所述的分离的核酸分子或实施方案27所述的载体。
29.药物组合物，其包含实施方案1-15中任一项所述的人GLP-1多肽变体、实施方案16-25中任一项所述的融合蛋白或免疫缀合物、实施方案26所述的分离的核酸分子、实施方案27所述的载体或实施方案28所述的细胞，以及任选地药学上可接受的佐剂。
30.实施方案1-15中任一项所述的人GLP-1多肽变体或实施方案16-25中任一项所述的融合蛋白或免疫缀合物用于制备药物的用途，所述药物用于预防和/或治疗代谢性疾病或病症。
31.根据实施方案30所述的用途，其中所述代谢性疾病或病症包括GLP-1相关代谢性病症。
32.根据实施方案30-31中任一项所述的用途，其中所述代谢性疾病或病症包括糖尿病。
33.增加或促进有需要的受试者中胰岛素表达的方法，所述方法包括向所述受试者施用有效量的实施方案1-15中任一项所述的人GLP-1多肽变体或实施方案16-25中任一项所述的融合蛋白或免疫缀合物。
不欲被任何理论所限，下文中的实施例仅仅是为了阐释本申请的融合蛋白、制备方法和用途等，而不用于限制本申请发明的范围。
实施例
本申请的实施例中使用的阳性对照度拉糖肽(Dulaglutide)为Eli Lilly&Co的糖尿病药物，代号LY-2189265，度拉糖肽的氨基酸序列如SEQ ID NO：4所示，在本申请中称为GLP-1-Fc或KN042。
实施例1融合蛋白的制备
制备GLP-1多肽变体GLP-1-XX和Fc的融合蛋白，从N端至C端依次包含GLP-1多肽变体(氨基酸序列如SEQ ID NO:5-71中任一项所示)、连接肽(G4S)3和源自IgG4的Fc区。
将包含编码融合蛋白的核酸序列的载体转入细胞，表达纯化得融合蛋白GM-XX。氨基酸序列如SEQ ID NO:72-138中任一项所示。本申请的融合蛋白和对应的人GLP-1多肽变体的氨基酸突变及序列如表1所示。
表1实施例中使用的融合蛋白、人GLP-1多肽变体的氨基酸突变和序列
实施例2本申请融合蛋白与GLP-1受体的结合亲和力
使用ELISA检测实施例1中的融合蛋白与GLP-1受体的结合亲和力。表达GLP-1受体和小鼠Fc的融合蛋白，称为GLP1R-muFc(SEQ ID NO：3)，将GLP1R-muFc稀释至5μg/ml，包被96孔板，室温固定30min。PBS清洗1次后用1％BSA37℃封闭30min，0.05％PBST20清洗3次。每孔加入50μl，10μg/ml，4倍浓度梯度稀释的待测样品，KN042为阳性对照。37℃孵育1小时，PBST清洗5次。每孔加入50μl用含有1％BSA的0.05％PBST20稀释2000倍的小鼠单克隆HP6023抗人IgG4Fc-HRP(abcam,ab99817)，37℃孵育1小时，PBST清洗5次。每孔加入50μlTMB显色3min，加入50μl/孔1M H2SO4终止反应，用酶标仪(Molecular Devices,SpectraMaxM3)进行检测OD值。KN042作为阳性对照。
结果如图1-13和16-20所示。
图1显示氨基酸突变W31Y后的融合蛋白与GLP-1受体的结合活性好于F28Y的突变。
图2显示氨基酸突变W31Y后的融合蛋白与阳性对照KN042相近。
图3显示W31处的氨基酸突变后的融合蛋白与GLP-1受体的结合活性好于F28处的氨基酸突变后的融合蛋白的结合活性。
图4和图5显示Q23处的多种氨基酸突变后，和Y19处的多种氨基酸突变后的融合蛋白均保持与GLP-1受体的结合活性。
图6和图7显示F28处的氨基酸突变后的融合蛋白与GLP-1受体的结合活性显著降低。
从图1至图7可以看出，W31、Q23、Y19处的氨基酸突变后的融合蛋白仍保持与GLP-1受体的结合活性，而F28处的氨基酸突变使与GLP-1受体的结合活性显著降低。
图8显示K26R-W31Y双突变的融合蛋白与GLP-1受体的结合活性好于K26R-F28Y双突变。
图9显示K26R-W31Y、K26R-Q23T、K26R-Q23S、K26R-Q23N、K26R-Y19L、K26R-Y19T和K26R-Y19F双突变的融合蛋白与GLP-1受体的结合活性良好，与阳性对照KN042接近。
图10显示K26R-W31Y、K26R-Q23E、K26R-Y19I、K26R-Y19V、K26R-Y19A和K26R-Y19S双突变的融合蛋白与GLP-1受体的结合活性良好，与阳性对照KN042接近。
图11显示K26R-W31Y、K26R-Q23N、K26R-Q23S和K26R-Q23T双突变的融合蛋白与GLP-1受体的结合活性良好。
图12显示W31Y和Y19处氨基酸突变的双突变的融合蛋白与GLP-1受体的结合活性良好。
图13显示W31Y-Y19A和W31Y-Q23E的氨基酸双突变的融合蛋白与GLP-1受体的结合活性良好。
从图8至图13可以看出，包含K26、W31、Y19和Q23中2个位置处的氨基酸突变的融合蛋白与GLP-1受体的结合活性良好。
图16显示GM-WY和GM-WYFL与GLP-1受体都能结合。
图17显示GM-WIFL、GM-WA、GM-WL和GM-WLFL与GLP-1受体都能结合。
图16和17显示，没有包含至少2个选自W31、Y19、Q23和K26氨基酸位置处的氨基酸突变的GLP-1多肽变体的融合蛋白的结合活性较弱。
图18显示W31Y-K26R-Q23处氨基酸突变的三突变的融合蛋白，或W31Y-K26R-Y19处氨基酸突变的三突变融合蛋白与GLP-1受体的结合活性良好。
图19显示W31Y-K26R-Q23处氨基酸突变的三突变的融合蛋白，或W31Y-K26R-Y19处氨基酸突变的三突变融合蛋白与GLP-1受体的结合活性良好。
图20显示W31Y-K26R-Q23N三突变的融合蛋白，或W31Y-K26R-Y19A三突变的融合蛋白与GLP-1受体的结合活性良好。
从图18至图20可以看出，包含K26、W31、Y19和Q23中3个位置处的氨基酸突变的融合蛋白与GLP-1受体的结合活性良好。
此外，本申请的结果还显示具有K26R-W31Y双突变的融合蛋白的体外生物活性(如，与GLP-1受体的结合活性、激活cAMP/PKA信号通路的活性)好于K26R-W31A以及K26A-W31Y双突变。
实施例3荧光素酶法检测本申请融合蛋白对cAMP/PKA信号通路的激活作用
利用GLP-1多肽变体的融合蛋白结合GLP-1受体，激活腺苷酸环化酶，促进细胞内环磷酸腺苷(cAMP)水平升高的原理，基于CREB(cAMP反应元件结合蛋白)报告基因检测本申请融合蛋白对cAMP/PKA信号通路的激活作用。利用人GLP-1R质粒和CREB驱使的荧光素酶报告质粒转染HER293细胞。转染后，消化收集HER293-GLP1R-CREB-D4细胞，计数，用含有10％FBS的DMEM培养基调整细胞数至4×105细胞/ml，接种至96孔板，每孔50μl。使用含有10％FBS的DMEM培养基将待测样品从1000ng/ml起被稀释为9个浓度；KN042作为阳性对照。上述96孔板每孔再加入50μl一系列浓度的待测样品，37℃孵育6小时或24小时。弃去上清，每孔加入荧光素酶底物。室温放置5min后，取出50μl，使用荧光素酶分析系统Bio-GloTMLuciferase Assay System(Promega,G7940)检测荧光素酶的活性，并且用酶标仪(Molecular Devices,SpectraMax M3)进行读数。荧光强度体现cAMP的水平，从而反应GLP-1受体激活的程度。
结果如图14-15和图21-26所示，本申请的融合蛋白均能激活GLP-1受体，从而激活cAMP/PKA信号通路。说明本申请的融合蛋白GM-WYYA、GM-WYQE、GM-KRWY、GM-KRWYQE、GM-KRWYYA、GM-KRWYYL、GM-KRWYYS、GM-KRWYYI、GM-KRWYYT、GM-KRWYQN、GM-KRWYQT、GM-KRWYQS体外稳定性好。
图14显示W31Y-Y19A双突变的GLP-1多肽变体与Fc区的融合蛋白能够激活GLP-1受体，从而升高cAMP水平，且孵育时间变长，由6小时(14A)增加为24小时(14B)，激活能力越强。激活能力较阳性对照相对提高，说明申请的融合蛋白GM-WYYA体现出更好的体外稳定性。
图15显示W31Y-Q23E双突变的GLP-1多肽变体与Fc区的融合蛋白能够激活GLP-1受体，从而升高cAMP水平，且孵育时间变长，由6小时(15A)增加为24小时(15B)，激活能力越强。激活能力较阳性对照相对提高，说明申请的融合蛋白GM-WYQE体现出更好的体外稳定性。
图21显示K26R-W31Y双突变和K26R-W31Y-Q23处氨基酸突变的三突变的融合蛋白均能够激活GLP-1受体。
图22和图23显示K26R-W31Y-Y19处氨基酸突变的三突变的融合蛋白均能够激活GLP-1受体。
图24和图26显示K26R-W31Y-Q23处氨基酸突变的三突变的融合蛋白和K26R-W31Y-Y19处氨基酸突变的三突变的融合蛋白均能够激活GLP-1受体。
图25显示K26R-W31Y-Q23处氨基酸突变的三突变的融合蛋白能够激活GLP-1受体。
实施例4药代动力学试验
考察GLP-1-Fc融合蛋白的体内药代动力学。实验在SPF动物房进行，动物房环境温度23±2℃，相对湿度40-70％，12小时明暗交替。实验动物自由饮食，实验前适应至少3天。体重为180-220g的SPF级SD大鼠随机分组。皮下注射各组大鼠相对应供试品，dulaglutide作为对照。于给药前、给药后6h、24h、48h、72h、96h和120h经颈静脉采血约100ul。将采集的血液加入离心管中，室温静置30-60min。之后4℃，两小时内4000rpm离心10分钟，迅速分离血清。-80℃保存。样本进行ELISA检测。使用DAS(3.2.8)软件计算药代动力学参数。
结果显示，与对照相比，本申请的融合蛋白具有良好的药代动力学性质。图27显示的是本申请的融合蛋白GM-KRWY的半衰期比度拉糖肽长，为16.199h，且药物暴露量高于度拉糖肽，且血药浓度相近。图28显示的是本申请的融合蛋白GM-KRWYYL、GM-KRWYYA和GM-KRWYYI的半衰期比度拉糖肽长，为约13h至16.5h，且药物暴露量和血药浓度高于度拉糖肽。图29显示的是本申请的融合蛋白GM-KRWYQN、GM-KRWYQE和GM-KRWYYA的半衰期比度拉糖肽长，为约22h至25h，且药物暴露量和血药浓度高于度拉糖肽。
实施例5口服糖耐量试验(OGTT)
考察GLP-1-Fc融合蛋白的体内降血糖活性。小鼠禁食过夜，实验前测量血糖和体重后随机分组。腹腔注射各组小鼠相对应供试品，度拉糖肽作为对照。给药后0.5h应用1.5g/kg的葡萄糖口服负荷各小鼠。小鼠于葡萄糖负荷前，负荷后10、20、30、60和120min，使用手持式罗氏血糖仪(Roche，Accu-chek)测量小鼠尾尖血糖值。切除小鼠尾尖约1mm，从尾根部向尾尖挤压静脉采血测量血糖值。
结果显示，与对照相比，本申请的融合蛋白GM-KRWY(图30A和30B)、GM-KRWYYA和GM-KRWYQE(图31A和31B)具有同等水平的体内降血糖活性。
序列表
<110> 苏州康宁杰瑞生物科技有限公司
<120> 一种人GLP-1多肽变体及其应用
<130> 0041-PA-010
<160> 153
<170> PatentIn version 3.5
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<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-FQ
<400> 13
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Gln Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 14
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-FE
<400> 14
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Glu Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 15
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-FV
<400> 15
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Val Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 16
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-FK
<400> 16
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Lys Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 17
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-FI
<400> 17
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Ile Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 18
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-QN
<400> 18
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Asn Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 19
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-QT
<400> 19
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Thr Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 20
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-QS
<400> 20
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Ser Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 21
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-QE
<400> 21
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 22
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-YL
<400> 22
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Leu Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 23
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-YT
<400> 23
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Thr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 24
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-YF
<400> 24
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Phe Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 25
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-YI
<400> 25
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ile Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 26
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-YV
<400> 26
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Val Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 27
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-YS
<400> 27
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ser Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 28
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-YA
<400> 28
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ala Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 29
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-KRWY
<400> 29
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 30
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-KRFY
<400> 30
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Tyr Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 31
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-KRWYFY
<400> 31
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Tyr Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 32
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-KRQN
<400> 32
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Asn Ala Ala Arg Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 33
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-KRQT
<400> 33
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Thr Ala Ala Arg Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 34
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-KRQS
<400> 34
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Ser Ala Ala Arg Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 35
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-KRQE
<400> 35
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Arg Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 36
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-KRYL
<400> 36
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Leu Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 37
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-KRYT
<400> 37
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Thr Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 38
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-KRYF
<400> 38
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Phe Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 39
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-KRYI
<400> 39
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ile Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 40
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-KRYV
<400> 40
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Val Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 41
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-KRYS
<400> 41
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ser Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 42
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-KRYA
<400> 42
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ala Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 43
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-WYQN
<400> 43
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Asn Ala Ala Lys Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 44
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-WYQS
<400> 44
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Ser Ala Ala Lys Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 45
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-WYQT
<400> 45
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Thr Ala Ala Lys Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 46
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-WYQE
<400> 46
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Lys Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 47
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-WYYL
<400> 47
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Leu Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 48
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-WYYT
<400> 48
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Thr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 49
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-WYYF
<400> 49
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Phe Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 50
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-WYYI
<400> 50
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ile Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 51
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-WYYV
<400> 51
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Val Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 52
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-WYYS
<400> 52
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ser Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 53
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-WYYA
<400> 53
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ala Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 54
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-WYFY
<400> 54
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Tyr Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 55
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-WYFL
<400> 55
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Leu Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 56
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-WA
<400> 56
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Ala Leu Val Lys Gly Gly Gly
20 25 30
<210> 57
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-WL
<400> 57
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Leu Leu Val Lys Gly Gly Gly
20 25 30
<210> 58
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-FL
<400> 58
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Leu Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 59
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-WIFL
<400> 59
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Leu Ile Ala Ile Leu Val Lys Gly Gly Gly
20 25 30
<210> 60
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-WLFL
<400> 60
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Leu Ile Ala Leu Leu Val Lys Gly Gly Gly
20 25 30
<210> 61
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-KRWYQN
<400> 61
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Asn Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 62
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-KRWYQT
<400> 62
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Thr Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 63
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-KRWYQS
<400> 63
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Ser Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 64
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-KRWYQE
<400> 64
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 65
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-KRWYYF
<400> 65
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Phe Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 66
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-KRWYYL
<400> 66
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Leu Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 67
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-KRWYYT
<400> 67
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Thr Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 68
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-KRWYYI
<400> 68
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ile Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 69
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-KRWYYV
<400> 69
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Val Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 70
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-KRWYYS
<400> 70
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ser Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 71
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1-KRWYYA
<400> 71
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ala Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 72
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-WY
<400> 72
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 73
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-WR
<400> 73
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Arg Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 74
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-WK
<400> 74
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Lys Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 75
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-FY
<400> 75
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Tyr Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 76
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-FH
<400> 76
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu His Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 77
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-FT
<400> 77
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Thr Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 78
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-FN
<400> 78
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Asn Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 79
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-FS
<400> 79
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Ser Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 80
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-FQ
<400> 80
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Gln Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 81
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-FE
<400> 81
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Glu Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 82
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-FV
<400> 82
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Val Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 83
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-FK
<400> 83
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Lys Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 84
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-FI
<400> 84
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Ile Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 85
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-QN
<400> 85
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Asn Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 86
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-QT
<400> 86
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Thr Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 87
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-QS
<400> 87
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Ser Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 88
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-QE
<400> 88
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 89
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-YL
<400> 89
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Leu Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 90
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-YT
<400> 90
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Thr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 91
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-YF
<400> 91
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Phe Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 92
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-YI
<400> 92
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ile Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 93
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-YV
<400> 93
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Val Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 94
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-YS
<400> 94
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ser Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 95
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-YA
<400> 95
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ala Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 96
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-KRWY
<400> 96
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 97
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-KRFY
<400> 97
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Tyr Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 98
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-KRWYFY
<400> 98
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Tyr Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 99
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-KRQN
<400> 99
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Asn Ala Ala Arg Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 100
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-KRQT
<400> 100
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Thr Ala Ala Arg Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 101
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-KRQS
<400> 101
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Ser Ala Ala Arg Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 102
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-KRQE
<400> 102
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Arg Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 103
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-KRYL
<400> 103
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Leu Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 104
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-KRYT
<400> 104
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Thr Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 105
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-KRYF
<400> 105
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Phe Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 106
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-KRYI
<400> 106
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ile Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 107
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-KRYV
<400> 107
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Val Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 108
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-KRYS
<400> 108
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ser Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 109
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-KRYA
<400> 109
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ala Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 110
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-WYQN
<400> 110
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Asn Ala Ala Lys Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 111
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-WYQS
<400> 111
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Ser Ala Ala Lys Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 112
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-WYQT
<400> 112
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Thr Ala Ala Lys Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 113
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-WYQE
<400> 113
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Lys Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 114
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-WYYL
<400> 114
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Leu Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 115
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-WYYT
<400> 115
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Thr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 116
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-WYYF
<400> 116
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Phe Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 117
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-WYYI
<400> 117
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ile Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 118
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-WYYV
<400> 118
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Val Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 119
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-WYYS
<400> 119
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ser Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 120
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-WYYA
<400> 120
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ala Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 121
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-WYFY
<400> 121
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Tyr Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 122
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-WYFL
<400> 122
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Leu Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 123
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-WA
<400> 123
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Ala Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 124
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-WL
<400> 124
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Leu Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 125
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-FL
<400> 125
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Leu Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 126
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-WIFL
<400> 126
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Leu Ile Ala Ile Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 127
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-WLFL
<400> 127
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Leu Ile Ala Leu Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 128
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-KRWYQN
<400> 128
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Asn Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 129
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-KRWYQT
<400> 129
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Thr Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 130
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-KRWYQS
<400> 130
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Ser Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 131
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-KRWYQE
<400> 131
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Glu Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 132
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-KRWYYF
<400> 132
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Phe Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 133
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-KRWYYL
<400> 133
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Leu Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 134
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-KRWYYT
<400> 134
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Thr Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 135
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-KRWYYI
<400> 135
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ile Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 136
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-KRWYYV
<400> 136
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Val Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 137
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-KRWYYS
<400> 137
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ser Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 138
<211> 275
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GM-KRWYYA
<400> 138
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ala Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Leu Gly
275
<210> 139
<211> 232
<212> PRT
<213> 人类（Homo sapiens）
<400> 139
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 140
<211> 228
<212> PRT
<213> 人类（Homo sapiens）
<400> 140
Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val
1 5 10 15
Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
20 25 30
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
35 40 45
His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
50 55 60
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
65 70 75 80
Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn
85 90 95
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro
100 105 110
Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln
115 120 125
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
130 135 140
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ser Val
145 150 155 160
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
165 170 175
Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
180 185 190
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
195 200 205
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
210 215 220
Ser Pro Gly Lys
225
<210> 141
<211> 232
<212> PRT
<213> 人类（Homo sapiens）
<400> 141
Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Lys Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Ser Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Asn Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Ile Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 142
<211> 229
<212> PRT
<213> 人类（Homo sapiens）
<400> 142
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe
1 5 10 15
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly Lys
225
<210> 143
<211> 229
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> dulaglutide的Fc
<400> 143
Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
1 5 10 15
Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
20 25 30
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
35 40 45
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
50 55 60
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
65 70 75 80
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
85 90 95
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
100 105 110
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
115 120 125
Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
130 135 140
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
145 150 155 160
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
165 170 175
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
180 185 190
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys
195 200 205
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
210 215 220
Ser Leu Ser Leu Gly
225
<210> 144
<211> 2
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GS连接肽
<400> 144
Gly Ser
1
<210> 145
<211> 3
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GAP连接肽
<400> 145
Gly Ala Pro
1
<210> 146
<211> 5
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> G4S连接肽
<400> 146
Gly Gly Gly Gly Ser
1 5
<210> 147
<211> 10
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> (G4S)2连接肽
<400> 147
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 148
<211> 15
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> (G4S)3连接肽
<400> 148
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 149
<211> 20
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> (G4S)4连接肽
<400> 149
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 150
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1变体通式2
<220>
<221> X19
<222> (13)..(13)
<223> X19可以为Y、A、L、T、F、I、V或S
<220>
<221> X23
<222> (17)..(17)
<223> X23可以为Q、E、T、S或N
<400> 150
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Xaa Leu Glu Glu
1 5 10 15
Xaa Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 151
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1变体通式3
<220>
<221> X23
<222> (17)..(17)
<223> X23可以为Q、E、T、S或N
<400> 151
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Xaa Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 152
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1变体通式4
<220>
<221> X19
<222> (13)..(13)
<223> X19可以为Y、A、L、T、F、I、V或S
<400> 152
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Xaa Leu Glu Glu
1 5 10 15
Gln Ala Ala Arg Glu Phe Ile Ala Tyr Leu Val Lys Gly Gly Gly
20 25 30
<210> 153
<211> 31
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> GLP-1变体通式1
<220>
<221> X19
<222> (13)..(13)
<223> X19可以为Y、A、L、T、F、I、V或S
<220>
<221> X23
<222> (17)..(17)
<223> X23可以为Q、E、T、S或N
<220>
<221> X26
<222> (20)..(20)
<223> X26可以为K或R
<220>
<221> X31
<222> (25)..(25)
<223> X31可以为W、Y、K、R或A
<400> 153
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Xaa Leu Glu Glu
1 5 10 15
Xaa Ala Ala Xaa Glu Phe Ile Ala Xaa Leu Val Lys Gly Gly Gly
20 25 30
Claims (10)
1.人GLP-1多肽变体，其中与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列包含至少2个氨基酸突变，所述至少2个氨基酸突变位于选自下组的氨基酸位置处：W31、K26、Q23和Y19。
2.根据权利要求1所述的人GLP-1多肽变体，其具有人GLP-1的至少部分活性。
3.根据权利要求1-2中任一项所述的人GLP-1多肽变体，其中与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列包含选自下组的氨基酸位置处的至少2个突变：W31、K26和Y19。
4.根据权利要求1-3中任一项所述的人GLP-1多肽变体，其中与SEQ ID NO:2所示的氨基酸序列相比，所述人GLP-1多肽变体的氨基酸序列包含选自下组的氨基酸位置处的至少2个突变：W31、K26和Q23。
5.融合蛋白或免疫缀合物，其包含权利要求1-4中任一项所述的人GLP-1多肽变体。
6.分离的核酸分子，其编码权利要求1-4中任一项所述的人GLP-1多肽变体或权利要求5所述的融合蛋白或免疫缀合物。
7.载体，其包含权利要求6所述的分离的核酸分子。
8.细胞，其包含或表达权利要求1-4中任一项所述的人GLP-1多肽变体、权利要求5所述的融合蛋白或免疫缀合物、权利要求6所述的分离的核酸分子或权利要求7所述的载体。
9.药物组合物，其包含权利要求1-4中任一项所述的人GLP-1多肽变体、权利要求5所述的融合蛋白或免疫缀合物、权利要求6所述的分离的核酸分子、权利要求7所述的载体或权利要求8所述的细胞，以及任选地药学上可接受的佐剂。
10.权利要求1-4中任一项所述的人GLP-1多肽变体或权利要求5所述的融合蛋白或免疫缀合物用于制备药物的用途，所述药物用于预防和/或治疗代谢性疾病或病症。
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| PCT/CN2021/141606 WO2022143515A1 (zh) | 2020-12-29 | 2021-12-27 | 一种人glp-1多肽变体及其应用 |
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| CN101208099A (zh) * | 2004-07-21 | 2008-06-25 | Ambrx公司 | 利用非天然编码氨基酸的生物合成多肽 |
| CN101987868B (zh) * | 2009-07-30 | 2013-09-04 | 江苏豪森医药集团有限公司 | Glp-1类似物的衍生物或其可药用盐和用途 |
| CN102093475B (zh) * | 2009-12-11 | 2014-02-26 | 吴晓琰 | 胰高血糖素样肽-1的类似物 |
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| EP3642238A1 (en) * | 2017-06-21 | 2020-04-29 | Amgen Inc. | Method of treating or ameliorating metabolic disorders using antagonistic binding proteins for gastric inhibitory peptide receptor (gipr)/glp-1 receptor agonist fusion proteins |
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