CN111712264A - 特异于epha2的双环肽配体 - Google Patents
特异于epha2的双环肽配体 Download PDFInfo
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- CN111712264A CN111712264A CN201880089159.1A CN201880089159A CN111712264A CN 111712264 A CN111712264 A CN 111712264A CN 201880089159 A CN201880089159 A CN 201880089159A CN 111712264 A CN111712264 A CN 111712264A
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Abstract
本发明涉及与芳族分子支架共价结合的多肽,使得两个或更多个肽环在与支架的连接点之间相对。具体而言,本发明描述了作为Eph受体酪氨酸激酶A2(EphA2)的高亲和力结合物的肽。本发明还包括药物缀合物,其包含缀合至一个或多个效应物和/或官能团的所述肽的、涉及包含所述肽配体和药物缀合物的药物组合物、以及涉及所述肽配体和药物缀合物在预防、抑制或治疗特征在于患病组织(例如肿瘤)中EphA2过度表达的疾病或病症中的用途。
Description
技术领域
本发明涉及与芳族分子支架共价结合的多肽,使得两个或更多个肽环在与支架的连接点之间相对(subtended)。具体而言,本发明描述了作为Eph受体酪氨酸激酶A2(EphA2)的高亲和力结合物的肽。本发明还包括药物缀合物,其包含缀合至一个或多个效应物和/或官能团的所述肽、包含所述肽配体和药物缀合物的药物组合物、以及所述肽配体和药物缀合物在预防、抑制或治疗特征在于患病组织(例如肿瘤)中EphA2过度表达的疾病或病症的用途。
背景技术
环肽能够以高亲和力和靶向特异性结合于蛋白质靶标,因此是对于治疗学发展有吸引力的一类分子。事实上,临床上已经成功使用了几种环肽,例如抗菌肽万古霉素、免疫抑制剂药物环孢菌素或抗癌药奥曲肽(Driggers等人(2008),Nat Rev Drug Discov 7(7),608-24)。良好的结合性质来源于肽和靶标之间形成的相对大的相互作用表面以及环状结构的降低的构象柔性。典型地,大环结合于数百平方埃的表面,例如环肽CXCR4拮抗剂CVX15(Wu等人(2007),Science330,1066-71),结合整合蛋白αVb3的具有Arg-Gly-Asp基序的环肽(Xiong等人(2002),Science 296(5565),151-5),或与尿激酶型纤溶酶原激活物结合的环肽抑制剂upain-1(Zhao等人(2007),J Struct Biol 160(1),1-10)。
由于其环状构型,肽大环较线性肽柔性小,导致其与靶标结合时熵的损失较小并产生更高的结合亲和力。降低的柔性还导致锁定靶标特异性构象,与线性肽相比增加结合特异性。这种作用已经通过一种有效的、选择性基质金属蛋白酶8(MMP-8)抑制剂来例证,当其环被打开时该抑制剂丧失对其他MMP的选择性(Cherney等人(1998),J Med Chem 41(11),1749-51)。通过大环化获得的有利的结合性质在具有多于一个的肽环的多环肽中更为显著,例如在万古霉素、乳链菌肽和放线菌素中。
不同的研究团队以前已经将具有半胱氨酸残基的多肽连接到合成分子结构上(Kemp和McNamara(1985),J.Org.Chem;Timmerman等人(2005),ChemBioChem)。Meloen及其同事已经使用三(溴甲基)苯和相关分子将多个肽环快速和定量地环化到合成支架上,用于蛋白质表面的结构模拟(Timmerman等人(2005),ChemBioChem)。WO 2004/077062和WO2006/078161中公开了产生候选药物化合物的方法,其中所述化合物通过将含半胱氨酸的多肽与分子支架例如三(溴甲基)苯连接产生。
已经开发了基于噬菌体展示的组合方法以产生并筛选出针对目标靶标的双环肽的大型文库(Heinis等人(2009),Nat Chem Biol 5(7),502-7和WO2009/098450)。简言之,在噬菌体上展示含有三个半胱氨酸残基和六个随机氨基酸的两个区域(Cys-(Xaa)6-Cys-(Xaa)6-Cys)的线性肽的组合文库,并通过将半胱氨酸侧链共价连接至一个小分子(三(溴甲基)苯)而环化。
发明内容
根据本发明的第一方面,提供了特异于EphA2的肽配体,其包含多肽和芳族分子支架,所述多肽包含被至少两个环序列隔开的至少三个半胱氨酸残基,所述芳族分子支架与所述多肽的半胱氨酸残基形成共价键,使得在分子支架上形成至少两个多肽环。
根据本发明的另一方面,提供了一种药物缀合物,其包含缀合至一个或多个效应物和/或官能团的本文所定义的肽配体。
根据本发明的另一方面,提供了一种药物组合物,其包含本文所定义的肽配体或药物缀合物与一种或多种药学上可接受的赋形剂。
根据本发明的另一方面,提供了本文所定义的肽配体或药物缀合物,其用于预防、抑制或治疗特征在于患病组织(例如肿瘤)中EphA2过度表达的疾病或病症。
具体实施方式
在一个实施方案中,所述环序列包含4、5、6或7个氨基酸。
在另一个实施方案中,所述环序列包含由两个环序列隔开的三个半胱氨酸残基,所述两个环序列均由5个氨基酸组成(例如表3、表4和表9中所列的那些)。
在另一个实施方案中,所述环序列包含由两个环序列隔开的三个半胱氨酸残基,所述两个环序列均由6个氨基酸组成(例如表3至表10中所列的那些)。
在另一个实施方案中,所述环序列包含由两个环序列隔开的三个半胱氨酸残基,其中一个环序列由6个氨基酸组成,另一个环序列由5个氨基酸组成(例如表4中列出的那些)。
在另一个实施方案中,所述环序列包含由两个环序列隔开的三个半胱氨酸残基,其中一个环序列由6个氨基酸组成,另一个环序列由4个氨基酸组成(例如表4中列出的那些)。
在另一个实施方案中,所述环序列包含由两个环序列隔开的三个半胱氨酸残基,其中一个环序列由6个氨基酸组成,另一个环序列由7个氨基酸组成(例如表8中列出的那些)。
在一个实施方案中,肽配体包含选自以下的氨基酸序列:
Ci-X1-Cii-X2-Ciii
其中X1和X2代表表3至表10中列出的半胱氨酸残基之间氨基酸残基,Ci、Cii和Ciii分别代表第一、第二和第三半胱氨酸残基,或其药学上可接受的盐。
在另一个实施方案中,肽配体包含选自表3至表10中的一个或多个列出的一个或多个肽配体的氨基酸序列。
在一个实施方案中,分子支架选自(1,3,5-三(溴甲基)苯)(TBMB),并且肽配体选自表3至10中列出的任何一种肽配体。
在一个实施方案中,肽配体选自化合物1-308中的任一种,或其药学上可接受的盐。
在另一个实施方案中,肽配体选自化合物1-286、289、292-293和296-297中的任一种,或其药学上可接受的盐。
除非另有定义,否则本文使用的所有技术和科学术语具有与本领域普通技术人员通常理解的相同的含义,例如肽化学、细胞培养和噬菌体展示、核酸化学和生物化学领域。对于分子生物学、遗传和生物化学方法使用标准技术(参见Sambrook等人,MolecularCloning:A Laboratory Manual,第三版,2001,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY;Ausubel等人,Short Protocols in Molecular Biology(1999)第四版,John Wiley&Sons,Inc.),其通过引用并入本文。
命名法
编号
当提及本发明的肽内的氨基酸残基位置时,由于半胱氨酸残基是不变的,因而从编号中省略了半胱氨酸残基(Ci、Cii和Ciii),因此,本发明的肽内的氨基酸残基的编号参考如下:
-Ci-M1-N2-D3-W4-L5-Cii-S6-L7-G8-W9-T10-Ciii-(SEQ ID NO:1)。
为了该描述的目的,假设所有双环肽都被TBMB(1,3,5-三(溴甲基)苯)环化,产生三取代的1,3,5-三甲基苯结构。与TBMB的环化发生在Ci、Cii和Ciii上。
分子形式
将双环核心序列的N-或C-末端延伸添加到序列的左侧或右侧,并用连字符隔开。例如,N末端(β-Ala)-Sar10-Ala尾将表示为:
(β-Ala)-Sar10-A-(SEQ ID NO:X)。
反向肽序列
根据Nair等人(2003)J Immunol 170(3),1362-1373中公开的,设想本文公开的肽序列也将以其逆反形式使用。例如,顺序是反向的(即N-末端变成C-末端,反之亦然),它们的立体化学也被颠倒(即D-氨基酸变成L-氨基酸,反之亦然)。
肽配体
本文所指的肽配体是指共价结合至分子支架的肽、缩氨酸或拟肽。通常,此类肽、缩氨酸或拟肽包括具有天然或非天然氨基酸的肽、能够与支架形成共价键的两个或更多个反应性基团(即半胱氨酸残基)、以及所述反应性基团之间相对的序列,其被称为环序列是因为当肽、缩氨酸或拟肽与支架结合时,其形成环。在本申请的情况下,肽、缩氨酸或拟肽包含至少三个半胱氨酸残基(本文称为Ci、Cii和Ciii),其在支架上形成至少两个环。
肽配体的优势
本发明的某些双环肽具有许多有利的性质,使它们被认为是适合注射、吸入、鼻、眼、口或局部施用的类药物分子。这些有利的性质包括:
-物种交叉反应性。这是临床前药效学和药代动力学评估的典型要求。
-蛋白酶稳定性。双环肽配体在大多数情况下应表现出对血浆蛋白酶、上皮(“膜锚定”)蛋白酶、胃和肠蛋白酶、肺表面蛋白酶、细胞内蛋白酶等的稳定性。应当在不同物种之间保持蛋白酶的稳定性,以便可以在动物模型中开发双环肽前导候选物,并可以可靠地对人进行施用;
-理想的溶解度曲线。这是带电荷的亲水残基相对于疏水性残基以及分子内/分子间H键的比例的函数,这对于制剂和吸收目的很重要;
-循环中最佳的血浆半衰期。取决于临床适应症和治疗方案,可能需要开发具有短或延长的体内暴露时间的双环肽,以管理慢性或急性疾病状态。最佳暴露时间取决于持续暴露的要求(以实现最大的治疗效率)与短时间暴露的要求(以最大程度地减少由于持续暴露于试剂而产生的毒理学影响);和
-选择性。本发明的某些肽配体对其他Eph受体酪氨酸激酶如EphA1、EphA3、EphA4、EphA6、EphA7和EphB1和因子XIIA、碳酸酐酶9和CD38表现出良好的选择性(对本发明所选肽配体的选择性数据可参见表12)。还应注意,本发明的所选肽配体表现出与其他物种(例如小鼠)的交叉反应性,以允许在动物模型中进行测试(表3、表5、表7、表8和表11)。
药学上可接受的盐
将理解盐形式在本发明的范围内,并且提及肽配体则包括所述配体的盐形式。
本发明的盐可以通过常规的化学方法,例如Pharmaceutical Salts:Properties,Selection,and Use,P.Heinrich Stahl(编辑),Camille G.Wermuth(编辑),ISBN:3-90639-026-8,Hardcover,388页,2002年8月中描述的方法,由含有碱或酸部分的母体化合物合成。通常,可以通过将这些化合物的游离酸或碱形式与适当的碱或酸在水中或在有机溶剂中或在两者的混合物中反应,制备这些盐。
酸式加成盐(单盐或二盐)可以用各种酸(无机和有机酸)形成。酸式加成盐的示例包括与选自以下的酸形成的单盐或二盐:乙酸、2,2-二氯乙酸、己二酸、海藻酸、抗坏血酸(例如L-抗坏血酸)、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、丁酸、(+)樟脑酸、樟脑磺酸、(+)-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环己氨磺酸、十二烷基磺酸、乙烷-1,2-二磺酸、乙磺酸、2-羟基乙磺酸、甲酸、富马酸、半乳糖酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、葡萄糖醛酸(如D-葡萄糖醛酸)、谷氨酸(如L-谷氨酸)、α-氧代戊二酸、乙醇酸、马尿酸、氢卤酸(如氢溴酸、盐酸、氢碘酸)、羟乙磺酸、乳酸(如(+)-L-乳酸、(±)-DL-乳酸)、乳糖酸、马来酸、苹果酸、(-)-L-苹果酸、丙二酸、(±)-DL-扁桃酸、甲磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘甲酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、磷酸、丙酸、丙酮酸、L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、丹宁酸、(+)-L-酒石酸、硫氰酸、对甲苯磺酸、十一碳烯酸和戊酸,以及酰化氨基酸和阳离子交换树脂。
一组具体的盐包括由以下形成的盐:乙酸、盐酸、氢碘酸、磷酸、硝酸、硫酸、柠檬酸、乳酸、琥珀酸、马来酸、苹果酸、羟乙磺酸、富马酸、苯磺酸、甲苯磺酸、硫酸、甲磺酸(甲磺酸盐)、乙磺酸、萘磺酸、戊酸、丙酸、丁酸、丙二酸、葡萄糖醛酸和乳糖醛酸。一种具体的盐是盐酸盐。另一种具体的盐是乙酸盐。
如果化合物是阴离子的或具有可以是阴离子的官能团(例如,-COOH可以是-COO-),则可以用产生适当的阳离子的有机或无机碱形成盐。合适的无机阳离子的示例包括但不限于碱金属离子如Li+、Na+和K+,碱土金属阳离子如Ca2+和Mg2+,以及其他阳离子如Al3+或Zn+。合适的有机阳离子的示例包括但不限于铵离子(即NH4+)和取代的铵离子(例如,NH3R+、NH2R2 +、NHR3 +、NR4 +)。一些合适的取代铵离子的示例为衍生自以下的那些:甲胺、乙胺、二乙胺、丙胺、二环己胺、三乙胺、丁胺、乙二胺、乙醇胺、二乙醇胺、哌嗪、苄胺、苯基苄胺、胆碱、葡甲胺和氨丁三醇,以及氨基酸,如赖氨酸和精氨酸。常见的季铵离子的示例是N(CH3)4 +。
当本发明的肽含有胺官能团时,例如根据本领域技术人员熟知的方法通过与烷基化剂反应,它们可以形成季铵盐。这样的季铵化合物在本发明肽的范围内。
修饰的衍生物
应当理解,如本文定义的肽配体的修饰的衍生物在本发明的范围内。这种合适的修饰的衍生物的示例包含一个或多个选自以下的修饰:N-末端和/或C-末端修饰;用一个或多个非天然氨基酸残基替换一个或多个氨基酸残基(例如用一个或多个等排或等电子氨基酸替换一个或多个极性氨基酸残基;用其他非天然的等排或等电子氨基酸替换一个或多个非极性氨基酸残基);加入间隔子基团;用一个或多个氧化耐受性氨基酸残基替换一个或多个氧化敏感性氨基酸残基;用一个或多个替换氨基酸(例如,丙氨酸)替换一个或多个氨基酸残基,用一个或多个D-氨基酸残基替换一个或多个L-氨基酸残基;双环肽配体中一个或多个酰胺键的N-烷基化;用替代键(surrogate bond)替换一个或多个肽键;肽骨架(peptide backbone)长度修饰;用另一个化学基团取代一个或多个氨基酸残基的α-碳上的氢,用合适的胺、硫醇、羧酸和酚反应性试剂修饰氨基酸如半胱氨酸、赖氨酸、谷氨酸/天冬氨酸和酪氨酸,以功能化所述氨基酸,和引入或替换氨基酸,以引入适合于官能化的正交反应性,例如携带叠氮化物或炔烃基团的氨基酸分别允许用携带炔烃或叠氮化物的部分进行官能化。
在一个实施方案中,修饰的衍生物包含N-末端和/或C-末端修饰。在一个进一步实施方案中,其中所述修饰的衍生物包含使用合适的氨基反应性化学的N-末端修饰,和/或使用合适的羧基反应性化学的C-末端修饰。在一个进一步实施方案中,所述N-末端或C-末端修饰包含加入效应物基团,包括但不限于细胞毒性剂、放射螯合剂(radiochelator)或发色团。
在一个进一步实施方案中,修饰的衍生物包含N-末端修饰。在一个进一步实施方案中,N-末端修饰包含N-末端乙酰基。在该实施方案中,在肽合成期间,N-末端残基被乙酸酐或其他合适的试剂封端,产生N-末端乙酰化的分子。该实施方案提供了除去氨基肽酶的潜在识别位点并避免双环肽降解可能性的优点。
在一个替代实施方案中,N-末端修饰包含加入有助于效应物基团缀合和保持双环肽对其靶标的效力的分子间隔子基团。
在一个进一步实施方案中,修饰的衍生物包含C-末端修饰。在一个进一步实施方案中,C-末端修饰包含酰胺基。在该实施方案中,C-末端残基在肽合成期间被合成为酰胺,产生C末端酰胺化的分子。该实施方案提供了除去羧肽酶的潜在识别位点并降低双环肽的蛋白水解降解可能性的优点。
在一个实施方案中,修饰的衍生物包含用一个或多个非天然氨基酸残基替换一个或多个氨基酸残基。在该实施方案中,可以选择非天然氨基酸,其具有不被降解性蛋白酶识别,也不对靶标效力产生任何副作用的等排/等电子侧链。
可替代地,可以使用具有约束的氨基酸侧链的非天然氨基酸,使得在构象和空间上阻碍邻近肽键的蛋白水解。具体而言,这些涉及脯氨酸类似物、大体积侧链、Cα-二取代衍生物(例如,氨基异丁酸,Aib)、和环氨基酸、为氨基-环丙基羧酸的简单衍生物。
在一个实施方案中,修饰的衍生物包含加入间隔子基团。在一个进一步实施方案中,修饰的衍生物包含向N-末端半胱氨酸(Ci)和/或C-末端半胱氨酸(Ciii)加入间隔子基团。
在一个实施方案中,修饰的衍生物包含用一个或多个氧化耐受性氨基酸残基替换一个或多个氧化敏感性氨基酸残基。在一个进一步实施方案中,修饰的衍生物包含用萘基丙氨酸或丙氨酸残基替换色氨酸残基。该实施方案提供改善所得到的双环肽配体的药物稳定性谱的优点。
在一个实施方案中,修饰的衍生物包含用一个或多个疏水性氨基酸残基替换一个或多个带电荷的氨基酸残基。在替代实施方案中,修饰的衍生物包含用一个或多个带电荷的氨基酸残基替换一个或多个疏水性氨基酸残基。带电荷的氨基酸残基与疏水性氨基酸残基的正确平衡是双环肽配体的重要特征。例如,疏水性氨基酸残基影响血浆蛋白结合的程度,因此影响血浆中可利用的游离级分的浓度,而带电荷的氨基酸残基(特别是精氨酸)可以影响肽与细胞表面上的磷脂膜的相互作用。两者组合可以影响肽药物的半衰期、分布容积和暴露,并可以根据临床终点进行调整。另外,带电荷的氨基酸残基与疏水性氨基酸残基的正确组合和数量可以减少注射部位的刺激(如果肽药物已经被皮下施用)。
在一个实施方案中,修饰的衍生物包含用一个或多个D-氨基酸残基替换一个或多个L-氨基酸残基。据信该实施方案通过空间位阻增加蛋白水解稳定性并通过D-氨基酸的倾向来稳定β-转角的构象(Tugyi等人(2005)PNAS,102(2),413–418)。
在一个实施方案中,修饰的衍生物包括除去任何氨基酸残基并用丙氨酸例如D-丙氨酸取代。该实施方案提供了鉴定关键结合残基并去除潜在的蛋白水解攻击位点的优点。这类丙氨酸的结果,例如D-丙氨酸取代(也称为丙氨酸扫描)可见于表9。
应当注意,上述提及的每种修饰用于有意地改善肽的效力或稳定性。基于修饰的进一步的效力改善可以通过以下机制来实现:
-并入展现疏水效应并导致降低的解离速率的疏水部分,从而实现更高的亲和力;
-并入展现大范围离子相互作用的带电荷基团,导致结合速率更快和更高的亲和力(参见例如Schreiber等人,Rapid,electrostatically assisted association ofproteins(1996),Nature Struct.Biol.3,427-31);和
-在肽中合并入另外的约束,例如通过正确地约束氨基酸的侧链,从而使靶标结合后的熵损失最小化;约束骨架的扭转角,从而使靶标结合后的熵损失最小化;和出于相同的原因而在分子中引入另外的环化。
(综述参见Gentilucci等人,Curr.Pharmaceutical Design,(2010),16,3185-203,和Nestor等人,Curr.Medicinal Chem(2009),16,4399-418)。
同位素变异
本发明包括本发明的所有药学上可接受的(放射性)同位素标记的肽配体,其中一个或多个原子被具有相同原子数的原子代替,但原子质量或质量数不同于通常在自然界中发现的原子质量或质量数,和本发明的肽配体中连接能够容纳相关的(放射性)同位素的金属螯合基团(称为“效应物”),和本发明的肽配体中的某些官能团被共价替换为相关的(放射性)同位素或同位素标记的官能团。
适合于包含在本发明肽配体中的同位素的示例包括氢的同位素,如2H(D)和3H(T),碳的同位素,如11C、13C和14C,氯的同位素,如36Cl,氟的同位素,如18F,碘的同位素,如123I、125I和131I,氮的同位素,如13N和15N,氧的同位素,如15O、17O和18O,磷的同位素,如32P,硫的同位素,如35S,铜的同位素,如64Cu,镓的同位素,如67Ga或68Ga,钇的同位素,如90Y,和镥的同位素,如177Lu,以及铋的同位素,如213Bi。
某些同位素标记的本发明的肽配体,例如并入放射性同位素的那些肽配体,可用于药物和/或底物组织分布研究,并临床评估患病组织的EphA2靶标的存在和/或不存在。本发明的肽配体可以进一步具有有价值的诊断性质,因为它们可用于检测或鉴定标记化合物与其他分子、肽、蛋白质、酶或受体之间复合物的形成。检测或鉴定方法可以使用用标记试剂所标记的化合物,标记试剂如放射性同位素、酶、荧光物质、发光物质(例如鲁米诺、鲁米诺衍生物、荧光素、发光蛋白和荧光素酶)等。放射性同位素氚,即3H(T)和碳-14,即14C,鉴于其容易并入和方便的检测手段,而特别用于该目的。
用较重的同位素如氘(即2H(D))进行取代可以提供由更大的代谢稳定性产生的某些治疗优势,例如增加的体内半衰期或降低的剂量需求,因此在一些情况下可能是优选的。
用正电子发射同位素(如11C、18F、15O和13N)取代可用于正电子发射断层扫描(PET)研究以检查靶标占有率。
通常可以通过本领域技术人员已知的常规技术或通过与所附实施例中描述的那些类似的方法来制备本发明的肽配体的同位素标记的化合物,使用适当的同位素标记的试剂代替之前使用的非标记的试剂。
芳族分子支架
本文提及的术语“芳族分子支架”是指本文定义的任何分子支架,其包含芳族(即不饱和)碳环或杂环环体系。
应理解的是,芳族分子支架可包含芳族部分。芳族支架内合适的芳族部分的示例包括联苯撑(biphenylene)、三联苯(terphenylene)、萘或蒽。
还应理解,芳族分子支架可包含杂芳族部分。芳族支架内的合适的杂芳族部分的示例包括吡啶、嘧啶、吡咯、呋喃和噻吩。
还应理解,芳族分子支架可包含卤代甲基芳烃部分,例如双(溴甲基)苯、三(溴甲基)苯、四(溴甲基)苯或其衍生物。芳族分子支架的非限制性示例包括:双、三、或四(卤甲基)苯;双、三或四(卤甲基)吡啶;双、三或四(卤甲基)哒嗪;双、三或四(卤甲基)嘧啶;双、三或四(卤甲基)吡嗪;双、三或四(卤甲基)-1,2,3-三嗪;双、三或四(卤甲基)-1,2,4-三嗪;双、三或四(卤甲基)吡咯、呋喃、噻吩;双、三或四(卤甲基)咪唑、恶唑、噻唑;双、三或四(卤甲基)-3H-吡唑、-异恶唑、-异噻唑;双、三或四(卤甲基)联苯撑;双、三或四(卤甲基)三联苯;1,8-双(卤甲基)萘;双、三或四(卤甲基)蒽;和双、三或四(2-卤甲基苯基)甲烷。
芳族分子支架的更具体的示例包括:1,2-双(卤甲基)苯;3,4-双(卤甲基)吡啶;3,4-双(卤甲基)哒嗪;4,5-双(卤甲基)嘧啶;4,5-双(卤甲基)吡嗪;4,5-双(卤甲基)-1,2,3-三嗪;5,6-双(卤甲基)-1,2,4-三嗪;3,4-双(卤甲基)吡咯、呋喃、噻吩和其他位置异构体;4,5-双(卤甲基)咪唑、恶唑、噻唑;4,5-双(卤甲基)-3H-吡唑、-异恶唑、-异噻唑;2,2'-双(卤甲基)联苯撑;2,2″-双(卤甲基)三联苯;1,8-双(卤甲基)萘;1,10-双(卤甲基)蒽;双(2-卤甲基苯基)甲烷;1,2,3-三(卤甲基)苯;2,3,4-三(卤甲基)吡啶;2,3,4-三(卤甲基)哒嗪;3,4,5-三(卤甲基)嘧啶;4,5,6-三(卤甲基)-1,2,3-三嗪;2,3,4-三(卤甲基)吡咯、呋喃、噻吩;2,4,5-双(卤甲基)咪唑、恶唑、噻唑;3,4,5-双(卤甲基)-1H-吡唑、-异恶唑、-异噻唑;2,4,2'-三(卤甲基)联苯撑;2,3',2”-三(卤甲基)三联苯;1,3,8-三(卤甲基)萘;1,3,10-三(卤甲基)蒽;双(2-卤甲基苯基)甲烷;1,2,4,5-四(卤甲基)苯;1,2,4,5-四(卤甲基)吡啶;2,4,5,6-四(卤甲基)嘧啶;2,3,4,5-四(卤甲基)吡咯、呋喃、噻吩;2,2',6,6'-四(卤甲基)联苯撑;2,2″,6,6″-四(卤甲基)三联苯;2,3,5,6-四(卤甲基)萘和2,3,7,8-四(卤甲基)蒽;和双(2,4-双(卤甲基)苯基)甲烷。
如之前的文件中所述,分子支架可以是小分子,例如有机小分子。
在一个实施方案中,分子支架可以是大分子。在一个实施方案中,分子支架是由氨基酸、核苷酸或碳水化合物组成的大分子。
在一个实施方案中,分子支架包含能够与多肽的官能团反应形成共价键的反应性基团。
分子支架可以包括与肽形成连接的化学基团,例如胺、硫醇、醇、酮、醛、腈、羧酸、酯、烯烃、炔烃、叠氮化物、酸酐、琥珀酰亚胺、马来酰亚胺、烷基卤化物和酰基卤化物。
在一个实施方案中,分子支架可以包含三(溴甲基)苯,特别是1,3,5-三(溴甲基)苯(‘TBMB’)或其衍生物,或可以由其组成。
在一个实施方案中,分子支架是2,4,6-三(溴甲基)均三甲苯。该分子类似于1,3,5-三(溴甲基)苯,但含有三个另外与苯环连接的甲基。这具有以下优点:另外的甲基可以与多肽形成进一步的接触,并因此增加另外的结构约束。
本发明的分子支架含有允许本发明编码文库的多肽的官能团与分子支架形成共价键的化学基团。所述化学基团选自多种官能团,包括胺、硫醇、醇、酮、醛、腈、羧酸、酯、烯烃、炔烃、酸酐、琥珀酰亚胺、马来酰亚胺、叠氮化物、烷基卤化物和酰基卤化物。
可用于在分子支架上与半胱氨酸的巯基反应的支架反应性基团是烷基卤化物(或也称为卤代烃或卤代烷)。
示例包括溴甲基苯(以TBMB为例的支架反应性基团)或碘乙酰胺。用于选择性地将化合物与蛋白质中的半胱氨酸偶联的其他支架反应性基团是马来酰亚胺、含有αβ不饱和羰基的化合物和含有α卤甲基羰基的化合物。可用作本发明分子支架的马来酰亚胺的示例包括:三-(2-马来酰亚氨基乙基)胺、三-(2-马来酰亚氨基乙基)苯、三-(马来酰亚氨基)苯。含有α卤甲基羰基的化合物的示例是N,N',N”-(苯-1,3,5-三基)三(2-溴乙酰胺)。硒代半胱氨酸也是与半胱氨酸具有相似反应性的天然氨基酸,并可用于相同的反应。因此,无论何时提及半胱氨酸,除非上下文另有说明,否则通常可以接受用硒代半胱氨酸取代。
效应物和官能团
根据本发明的一个进一步方面,本发明提供一种药物缀合物,其包含缀合至一个或多个效应物和/或官能团的如本文定义的肽配体。
效应物和/或官能团可以连接于例如多肽的N和/或C末端、多肽内的氨基酸、或分子支架。
合适的效应物基团包括抗体及其部分或片段。例如,效应物基团可以包括抗体轻链恒定区(CL)、抗体CH1重链结构域、抗体CH2重链结构域、抗体CH3重链结构域、或其任何组合,以及一个或多个恒定结构域。效应物基团还可以包含抗体的铰链区(通常在IgG分子的CH1和CH2结构域之间发现这种区域)。
在本发明该方面的一个进一步实施方案中,根据本发明的效应物基团是IgG分子的Fc区。有利地,根据本发明的肽配体-效应物基团包含具有一天或更长、两天或更长、3天或更长、4天或更长、5天或更长、6天或更长、或7天或更长的tβ半衰期的肽配体Fc融合物,或由其组成。最有利地,根据本发明的肽配体包含具有一天或更长的tβ半衰期的肽配体Fc融合物,或由其组成。
官能团通常包括结合基团、药物、用于连接其他实体的反应性基团、有助于将大环肽摄取入细胞中的官能团等。
肽穿透细胞的能力将允许肽有效地针对细胞内的靶标。可以被具有穿透细胞能力的肽接近的靶标包括转录因子、细胞内信号传导分子如酪氨酸激酶和参与细胞凋亡途径的分子。能够穿透细胞的官能团包括已经添加到肽或分子支架的肽或化学基团。肽,如衍生自如VP22、HIV-Tat、果蝇(触角足(Antennapedia))的同源盒蛋白的那些,例如,如Chen和Harrison,Biochemical Society Transactions(2007)第35卷,第4部分,第821页;Gupta等人,Advanced Drug Discovery Reviews(2004)第57卷9637中所描述。已经显示在通过质膜的易位中有效的短肽的示例包括来自果蝇触角足蛋白的16个氨基酸的穿透肽(Derossi等人(1994)J Biol.Chem.第269卷,第10444页)、18个氨基酸的“模型两亲肽”(Oehlke等人(1998)Biochim Biophys Acts第1414卷,第127页)和HIV TAT蛋白的富含精氨酸的区域。非缩氨酸方法包括使用可以容易地连接到生物分子上的小分子模拟物或SMOC(Okuyama等人(2007)Nature Methods第4卷,第153页)。将胍基添加到分子中的其他化学策略也增强细胞穿透(Elson-Scwab等人(2007)J Biol Chem第282卷,第13585页)。可以将小分子量分子如类固醇添加到分子支架中以增强细胞摄取。
可以与肽配体连接的一类官能团包括抗体及其结合片段,如Fab、Fv或单结构域片段。具体而言,可以使用与能够增加体内肽配体半衰期的蛋白质结合的抗体。
在一个实施方案中,根据本发明的肽配体-效应物基团具有选自12小时或更长、24小时或更长、2天或更长、3天或更长、4天或更长、5天或更长、6天或更长、7天或更长、8天或更长、9天或更长、10天或更长、11天或更长、12天或更长、13天或更长、14天或更长、15天或更长、或20天或更长的tβ半衰期。有利地,根据本发明的肽配体-效应物基团或组合物将具有12至60小时范围内的tβ半衰期。在一个进一步实施方案中,其将具有一天或更长的tβ半衰期。在一个更进一步实施方案中,将在12至26小时的范围内。
在本发明的一个具体的实施方案中,所述官能团选自金属螯合剂,其适合于络合具有药用相关性的金属放射性同位素。
可能的效应物基团还包括酶,例如用于酶/前药治疗的羧肽酶G2,其中肽配体替换ADEPT中的抗体。
在本发明的一个具体的实施方案中,所述官能团选自药物,例如用于癌症治疗的细胞毒性剂。合适的示例包括:烷化剂如顺铂和卡铂,以及奥沙利铂、氮芥、环磷酰胺、苯丁酸氮芥、异环磷酰胺;抗代谢物,包括嘌呤类似物硫唑嘌呤和巯嘌呤或嘧啶类似物;植物生物碱和萜类化合物,包括长春花生物碱类,如长春新碱、长春花碱、长春瑞滨和长春地辛;鬼臼毒素及其衍生物依托泊苷和替尼泊苷;紫杉烷,包括紫杉醇(paclitaxel),最初称为紫杉醇(Taxol);拓扑异构酶抑制剂包括喜树碱:伊立替康和拓扑替康,以及II型抑制剂,包括安丫啶、依托泊苷,磷酸依托泊苷和替尼泊苷。其他试剂可以包括抗肿瘤抗生素,其包括免疫抑制剂放线菌素D(用于肾移植)、多柔比星、表柔比星、博来霉素、刺胞霉素等。
在本发明的一个进一步具体的实施方案中,细胞毒性剂选自美登木素生物碱(如DM1)或单甲基奥瑞他汀(例如MMAE)。
DM1是一种细胞毒性剂,其是美登素的含巯基衍生物,并具有以下结构:
单甲基奥瑞他汀E(MMAE)是合成的抗肿瘤剂,并具有以下结构:
在本发明的又一具体实施方案中,细胞毒性剂选自美登木素生物碱类(例如DM1)。数据显示在本文的表11中,该数据证明了缀合至含有DM1的毒素的肽配体的作用。
在一个实施方案中,细胞毒性剂通过可裂解的键(例如二硫键或蛋白酶敏感的键)与双环肽连接。在一个进一步实施方案中,与二硫键相邻的基团被修饰以控制二硫键的阻碍,并且由此控制裂解的速率和伴随的细胞毒性剂的释放。
已发表的工作确定了通过在二硫键的任一侧引入空间位阻来改变二硫键对还原的敏感性的潜力(Kellogg等人(2011)Bioconjugate Chemistry,22,717)。更大程度的空间位阻降低细胞内谷胱甘肽和细胞外(全身的)还原剂的还原速率,从而降低了细胞内外释放毒素的容易程度。因此,可以通过仔细选择二硫键的任一侧的阻碍程度,来实现循环中二硫化物稳定性(其使毒素的不良副作用最小化)与细胞内环境中的有效释放(其最大化治疗效果)的最佳选择。
通过在分子构建体的靶向实体(这里是双环肽)或毒素侧上引入一个或多个甲基来调节二硫键的任一侧的阻碍。
在一个实施方案中,细胞毒性剂和接头选自WO 2016/067035中描述的那些细胞毒性剂和接头的任何组合(其细胞毒性剂和接头通过引用并入本文)。
在一个实施方案中,细胞毒性剂是DM1,并且药物缀合物包含式(A)的化合物:
其中所述双环选自本文定义的化合物72中的任何一种。
在一个可选的实施方案中,细胞毒性剂是DM1,并且药物缀合物包含式(B)的化合物:
其中所述双环选自本文定义的化合物72、226、227和303中的任何一种。
在一个实施方案中,细胞毒性剂是DM1,并且药物缀合物包含式(A)的化合物,其中所述双环选自本文所定义的化合物72。该BDC在本文中称为BDC-1。本文提供的数据证明了BDC-1在EphA2竞争结合测定法中出色的竞争结合,如表11所示。
在一个替代实施方案中,细胞毒性剂是DM1,并且药物缀合物包含式(B)的化合物,其中所述双环选自如本文所定义的化合物72。该BDC在本文中称为BDC-2。本文提供的数据证明了BDC-2在EphA2竞争结合测定法中出色的竞争结合,如表11所示。
在一个可选的实施方案中,细胞毒性剂是DM1,并且药物缀合物包含式(B)的化合物,其中所述双环选自本文所定义的化合物226。该BDC在本文中称为BDC-3。本文提供的数据证明了BDC-3在EphA2竞争结合测定法中出色的竞争结合,如表11所示。
在一个可选的实施方案中,细胞毒性剂是DM1,并且药物缀合物包含式(B)的化合物,其中所述双环选自本文所定义的化合物227。该BDC在本文中称为BDC-4。本文提供的数据证明了BDC-4在EphA2竞争结合测定法中出色的竞争结合,如表11所示。
在一个可选的实施方案中,细胞毒性剂是DM1,并且药物缀合物包含式(B)的化合物,其中所述双环选自本文所定义的化合物303。该BDC在本文中称为BDC-5。本文提供的数据证明了BDC-5在EphA2竞争结合测定法中出色的竞争结合,如表11所示。
在一个实施方案中,药物缀合物选自BDC-1至BDC-5。在另一个实施方案中,药物缀合物选自BDC-1至BDC-4。
合成
本发明的肽可以通过标准技术合成制备,然后在体外与分子支架反应。当进行此操作时,可以使用标准化学方法。这使得能够快速大规模制备可溶性材料用于进一步的下游实验或验证。这样的方法可以使用例如Timmerman等人(同上)中公开的常规化学方法来实现。
因此,本发明还涉及如本文所述选择的多肽或缀合物的制备,其中制备包括如下说明的任选的进一步步骤。在一个实施方案中,这些步骤在通过化学合成制得的最终产物多肽/缀合物上进行。
当制备缀合物或复合物时,目标多肽中的氨基酸残基任选可以被取代。
肽也可以被延伸,以并入例如另一个环,因此引入多特异性。
为了延伸肽,可以使用标准固相或溶液相化学法,使用正交保护的赖氨酸(和类似物),简单地在其N-末端或C-末端或在环内化学延伸。可以使用标准(生物)缀合技术来引入活化的或可活化的N-或C-末端。可替代地,可以通过片段缩合或天然化学连接进行添加(例如,如(Dawson等人1994.Synthesis of Proteins by Native ChemicalLigation.Science 266:776-779)中所述),或通过酶,例如使用如(Chang等人Proc NatlAcad Sci U S A.1994Dec 20;91(26):12544-8或Hikari等人Bioorganic&MedicinalChemistry Letters Volume 18,Issue 22,15 November 2008,6000-6003页)中描述的subtiligase进行添加。
可替代地,可以通过二硫键进一步缀合来延伸或修饰肽。这具有允许第一和第二肽一旦处于细胞还原环境中时彼此分离的另外的优点。在这种情况下,可以在第一肽的化学合成期间加入分子支架(例如TBMB),以使得与三个半胱氨酸基团反应;然后可以将另外的半胱氨酸或硫醇附加到第一肽的N或C末端,使得该半胱氨酸或硫醇仅与第二肽的游离半胱氨酸或硫醇反应,形成二硫键连接的双环肽-肽缀合物。
类似的技术同样适用于两种双环和双特异性大环化合物的合成/偶联,潜在地产生四特异性分子。
此外,可以以相同的方式,使用适当的化学方法,在N-或C-末端或通过侧链的偶联来完成其他官能团或效应物基团的加入。在一个实施方案中,以不阻断任一实体活性的方式进行偶联。
药物组合物
根据本发明的一个进一步方面,本发明提供一种药物组合物,其包含本文定义的肽配体或药物缀合物和一种或多种药学上可接受的赋形剂。
一般地,本发明的肽配体将与药理学上适当的赋形剂或载体一起以纯化的形式使用。典型地,这些赋形剂或载体包括水性或醇/水溶液、乳剂或混悬液,包括生理盐水和/或缓冲介质。肠胃外载剂包括氯化钠溶液、林格氏右旋糖、右旋糖和氯化钠和乳酸林格氏试剂。如果有必要将多肽复合物保持在混悬液中,合适的生理学上可接受的佐剂可以选自增稠剂如羧甲基纤维素、聚乙烯吡咯烷酮、明胶和海藻酸盐。
静脉内载剂包括液体和营养补充剂和电解质补充剂,如基于林格氏右旋糖的那些。还可以存在防腐剂和其他添加剂,例如抗微生物剂、氧化耐受性剂、螯合剂和惰性气体(Mack(1982)Remington's Pharmaceutical Sciences,第16版)。
本发明的肽配体可以用作单独施用的组合物,或者与其他试剂联合施用。这些可以包括抗体、抗体片段和各种免疫治疗药物,例如环孢霉素、甲氨蝶呤、阿霉素或顺铂和免疫毒素。药物组合物可以包括与本发明的蛋白配体联合的各种细胞毒素或其他试剂的“鸡尾酒混合物”,或甚至包括具有不同特异性的根据本发明选择的多肽的组合,例如使用不同靶配体选择的多肽,无论是否在施用之前进行合并。
根据本发明的药物组合物的施用途径可以是本领域普通技术人员通常已知的那些。对于治疗方法,本发明的肽配体可以根据标准技术施用于任何患者。施用可以通过任何适当的模式,包括肠胃外、静脉内、肌肉内、腹腔内、经皮、经肺途径、或者适当地通过直接导管输注。优选地,通过吸入施用根据本发明的药物组合物。施用的剂量和频率取决于患者的年龄、性别和状况,其他药物的同时施用,禁忌症和临床医生要考虑的其他参数。
本发明的肽配体可以被冻干储存并在使用前重构在合适的载体中。已经证明这种技术是有效的,并且可以采用本领域已知的冻干和重构技术。本领域技术人员将理解,冻干和重构可导致不同程度的活性损失,并且可能必须向上调整水平以进行补偿。
可以施用含有本发明肽配体或其鸡尾酒混合物的组合物用于预防性和/或治疗性治疗。在某些治疗应用中,将实现所选细胞群体的至少部分抑制、阻遏、调节、杀死或某些其他可测量参数的足够量定义为“治疗有效剂量”。实现该剂量所需的量将取决于疾病的严重程度和患者自身免疫系统的一般状态,但通常每千克体重0.005至5.0mg所选择的肽配体,更常用0.05至2.0mg/kg/剂量的剂量。对于预防性应用,含有本发明肽配体或其鸡尾酒混合物的组合物也可以以相似或稍低的剂量施用。
包含根据本发明的肽配体的组合物可以用于在预防和治疗环境中帮助改变、灭活、杀死或除去哺乳动物中的选择性靶细胞群体。此外,本文所述的肽配体可以选择性地用于在体外(extracorporeally)或体外(in vitro)从细胞的异质集合物中杀死、消耗或以其他方式有效去除靶细胞群体。来自哺乳动物的血液可以与选择的肽配体体外组合,由此从血液中将不期望的细胞杀死或以其他方式除去,并根据标准技术返回哺乳动物。
治疗用途
本发明的双环肽作为EphA2结合剂具有特定的用途。Eph受体酪氨酸激酶(Eph)属于一大群受体酪氨酸激酶(RTK),这些激酶可在酪氨酸残基上将蛋白质磷酸化。Eph及其膜结合的ephrin配体(ephrin)控制细胞的定位和组织(tissue)的组织化(organization)(Poliakov等人(2004)Dev Cell 7,465-80)。在较高的配体低聚状态下发生功能性生化Eph反应(Stein等人(1998)Genes Dev 12,667-678)。
在其他模式功能中,表明各种Eph和ephrin在血管发育中起作用。EphB4和ephrin-B2的敲除导致缺乏将毛细血管床重塑成血管的能力(Poliakov等人,同上),并导致胚胎致死。在新形成的成体微血管中也观察到了一些Eph受体和ephrin的持续表达(Brantley-Sieders等人(2004)Curr Pharm Des 10,3431-42;Adams(2003)J Anat 202,105-12)。
还观察到成人中一些ephrin及其受体的不受调控的再生会促进肿瘤的侵袭、转移和新血管生成(Nakamoto等人(2002)Microsc Res Tech 59,58-67;Brantley-Sieders等人,同上)。此外,已经发现一些Eph家族成员在来自多种人类肿瘤的肿瘤细胞上过度表达(Brantley-Sieders等人,同上);Marme(2002)Ann Hematol 81 Suppl 2,S66;Booth等人(2002)Nat Med 8,1360-1)。
EPH受体A2(A型ephrin受体2)是一种在人类中由EPHA2基因编码的蛋白质。
EphA2在人的多种癌症中上调,通常与疾病进展、转移和不良预后相关,例如:乳腺癌(Zelinski等人(2001)Cancer Res.61,2301–2306;Zhuang等人(2010)Cancer Res.70,299–308;Brantley-Sieders等人(2011)PLoS One 6,e24426)、肺癌(Brannan等人(2009)Cancer Prev Res(Phila)2,1039–1049;Kinch等人(2003)Clin Cancer Res.9,613-618;Guo等人(2013)J Thorac Oncol.8,301-308)、胃癌(Nakamura等人(2005)Cancer Sci.96,42-47;Yuan等人(2009)Dig Dis Sci 54,2410-2417)、胰腺癌(Mudali等人(2006)Clin ExpMetastasis 23,357-365)、前列腺癌(Walker-Daniels等人(1999)Prostate 41,275–280)、肝癌(Yang等人(2009)Hepatol Res.39,1169–1177)和胶质母细胞瘤(Wykosky等人(2005)Mol Cancer Res.3,541–551;Li等人(2010)Tumour Biol.31,477–488)。
EphA2在癌症进展中的全部作用仍未确定,尽管有证据表明在癌症进展的许多阶段都有相互作用,包括肿瘤细胞生长、存活、侵袭和血管生成。EphA2表达的下调抑制了肿瘤癌细胞的增殖(Binda等人(2012)Cancer Cell 22,765-780),而EphA2的阻断抑制了VEGF诱导的细胞迁移(Hess等人(2001)Cancer Res.61,3250–3255)、萌发和血管生成(Cheng等人(2002)Mol Cancer Res.1,2–11;Lin等人(2007)Cancer 109,332-40)和转移性进展(Brantley-Sieders等人(2005)FASEB J.19,1884–1886)。
已显示针对EphA2的抗体药物缀合物可在大鼠和小鼠异种移植模型中显著降低肿瘤生长(Jackson等人(2008)Cancer Research 68,9367-9374),并且已经在人中尝试了类似的方法,尽管由于治疗相关的不良事件,治疗已被迫终止(Annunziata等人(2013)InvestNew drugs 31,77-84)。
根据本发明的方法选择的多肽配体可用于体内治疗和预防应用、体外和体内诊断应用、体外测定和试剂应用等。具有选择的特异性水平的配体在其中需要交叉反应性的涉及在非人动物中进行测试的应用中是有用的,或在需要仔细控制与同系物或旁系同源物的交叉反应性的诊断应用中是有用的。在一些应用中,例如疫苗应用,可以利用引发对预定范围的抗原的免疫应答的能力来定制针对具体疾病和病原体的疫苗。
对于哺乳动物施用,优选至少90至95%同质性的基本上纯的肽配体,并且对于药物用途,特别是当哺乳动物是人时,最优选98至99%或更高的同质性。一旦按需要被纯化(部分纯化或纯化至同质),所选择的多肽可以在诊断或治疗(包括体外)或开发和进行测定程序、免疫荧光染色等中使用(Lefkovite和Pernis,(1979和1981)ImmunologicalMethods,卷I和II,Academic Press,NY)。
根据本发明的另一方面,提供了如本文所定义的肽配体或药物缀合物,其用于预防、抑制或治疗特征在于患病组织(例如肿瘤)中EphA2过度表达的疾病或病症。
根据本发明的另一方面,提供了一种预防、抑制或治疗特征在于患病组织(例如肿瘤)中EphA2过度表达的疾病或病症的方法,其包括向需要其的患者施用如本文定义的肽配体的效应物基团和药物缀合物。
在一个实施方案中,EphA2是哺乳动物EphA2。在另一个实施方案中,哺乳动物EphA2是人EphA2。
在一个实施方案中,特征在于患病组织中EphA2过度表达的疾病或病症选自癌症。
可以被治疗(或被抑制)的癌症(及其良性对应物)的示例包括但不限于上皮起源的肿瘤(腺瘤和各种类型的癌,包括腺癌、鳞癌、移行细胞癌和其他癌),例如膀胱和泌尿道癌、乳腺癌、胃肠道癌(包括食道癌、胃(胃)癌、小肠癌、结肠癌、直肠癌和肛门癌)、肝癌(肝细胞癌)、胆囊和胆道系统癌、外分泌胰腺癌、肾癌、肺癌(例如腺癌、小细胞肺癌、非小细胞肺癌、支气管肺泡癌和间皮瘤)、头颈癌(例如舌癌、颊腔癌、喉癌、咽癌、鼻咽癌、扁桃体癌、唾液腺癌、鼻腔癌和鼻旁窦癌)、卵巢癌、输卵管癌、腹膜癌、阴道癌、外阴癌、阴茎癌、子宫颈癌、子宫肌癌、子宫内膜癌、甲状腺癌(例如甲状腺滤泡癌)、肾癌、前列腺癌、皮肤和附属物癌(例如黑色素瘤、基底细胞癌、鳞状细胞癌、角化棘皮瘤、异常增生痣);血液系统恶性肿瘤(即白血病、淋巴瘤)和恶化前的血液系统病症以及边缘恶性病症,包括血液系统恶性肿瘤和淋巴谱系的相关病症(例如急性淋巴细胞性白血病[ALL]、慢性淋巴细胞性白血病[CLL]、B细胞淋巴瘤如弥漫性大B细胞淋巴瘤[DLBCL]、滤泡性淋巴瘤、伯基特氏淋巴瘤、套细胞淋巴瘤、T细胞淋巴瘤和白血病、自然杀伤[NK]细胞淋巴瘤、霍奇金淋巴瘤、毛细胞白血病、意义不确定的单克隆丙种球蛋白病、浆细胞瘤、多发性骨髓瘤和移植后淋巴增生性病症)、和血液系统恶性肿瘤和髓系的相关病症(例如急性髓性白血病[AML]、慢性髓性白血病[CML]、慢性骨髓单核细胞白血病[CMML]、嗜酸性粒细胞增多综合征、骨髓增生性病症,例如真性红细胞增多症、原发性血小板增多症和原发性骨髓纤维化、骨髓增生综合征、骨髓增生异常综合症和早幼粒细胞性白血病);间充质起源的肿瘤,例如软组织肉瘤、骨或软骨肉瘤,例如骨肉瘤、纤维肉瘤、软骨肉瘤、横纹肌肉瘤、平滑肌肉瘤、脂肪肉瘤、血管肉瘤、卡波西肉瘤、尤因肉瘤、滑膜肉瘤、上皮样肉瘤、胃肠道间质瘤、良性和恶性组织肉瘤以及隆突性皮纤维肉瘤;中枢或周围神经系统的肿瘤(例如星形细胞瘤、神经胶质瘤和胶质母细胞瘤、脑膜瘤、室管膜瘤、松果体瘤和神经鞘瘤);内分泌肿瘤(例如垂体瘤、肾上腺肿瘤、胰岛细胞瘤、甲状旁腺肿瘤、类癌和甲状腺髓样癌);眼和附件肿瘤(例如视网膜母细胞瘤);生殖细胞和滋养细胞肿瘤(例如畸胎瘤、精原细胞瘤、无性细胞瘤(dysgerminoma)、葡萄胎和绒毛膜癌);小儿和胚胎肿瘤(例如,髓母细胞瘤、神经母细胞瘤、威尔姆斯肿瘤和原始神经外胚层肿瘤);或先天性或其他形式的综合症,使患者容易患恶性肿瘤(例如着色性干皮病)。
在进一步的实施方案中,所述癌症选自:乳腺癌、肺癌、胃癌、胰腺癌、前列腺癌、肝癌、胶质母细胞瘤和血管生成。
在另一个实施方案中,所述癌症选自肺癌,例如非小细胞肺癌。本文提供的数据证明,从第32天起,本发明的BDC(BDC-8)彻底根除了非小细胞肺癌,在暂停给药后第28天,未发生肿瘤再生长。该数据清楚地证明了本发明的BDC在癌症例如肺癌,特别是非小细胞肺癌中的临床应用。
本文提到的术语“预防”涉及在疾病诱导之前施用保护性的组合物。“抑制”是指在诱导事件之后但在疾病的临床表现之前施用组合物。“治疗”涉及在疾病症状变得明显之后施用保护性的组合物。
可获得用于筛选肽配体在预防或治疗疾病中的有效性的动物模型系统。本发明允许开发可以与人和动物靶标交叉反应的多肽配体,从而允许使用动物模型,这促进了动物模型系统的使用。
下面参考以下实施例进一步描述本发明。
实施例
材料和方法
肽合成
基于Fmoc化学,使用Peptide Instruments制造的Symphony和SymphonyX肽合成仪和MultiSynTech的Syro II合成仪进行肽合成。使用标准的Fmoc-氨基酸(Sigma,Merck),其带有适当的侧链保护基:在每种情况下均使用适用的标准偶联条件,然后使用标准方法进行脱保护。通过HPLC纯化肽,分离后用1,3,5-三(溴甲基)苯修饰(TBMB,Sigma)。为此,将线性肽用H2O稀释至~35mL,加入~500μl的100mM TBMB的乙腈溶液,并用~5mL的1M NH4HCO3的H2O溶液引发反应。反应在RT下进行~30至60分钟,一旦反应完成(通过MALDI判断),用~500ul的1M半胱氨酸盐酸盐(Sigma)淬灭。冻干后,将修饰的肽在Gemini C18柱(Phenomenex)中纯化,使用水/乙腈和0.1%三氟乙酸作为流动相。合并含有正确环化物质的纯级分,冻干并在-20℃下保存。
除非另有说明,所有氨基酸均以L-构型使用。
双环肽药物缀合物BDC-1至BDC-5的制备
使用WO 2016/067035中公开的方案进行表11中列出的双环肽药物缀合物BDC-1至BDC-5的合成。
具有式(C)和(D)的活化的双环肽:
通过将双环前体的游离氨基分别与DMSO中的SPP(N-琥珀酰亚胺基4-(2-吡啶基二硫基)戊酸酯,Annova Chem)和SPDB(N-琥珀酰亚胺基3-(2-吡啶基二硫基)丙酸酯,AnnovaChem)进行反应,合成上述双环肽。在室温下,浓度为10mM或更高的双环前体、与1.3倍过量的SPP或SPDB、和20倍过量的二异丙基乙胺反应。根据LCMS判断,在1小时后判断反应完成。如上所述通过反相进行纯化。将适当的级分冻干。
在半水性条件下(50%二甲基乙酰胺和50%100mM乙酸钠pH 5.0,补充有2mMEDTA),将具有式(C)和(D)的活化双环肽用1.15当量的DM1(作为游离巯基)进行二硫化物交换,在氮气保护下、在室温下放置21小时。在反应中具有结构C和D的活化双环肽的浓度为10mM或更高。
然后使用C18柱进行标准反相纯化。分离纯度大于95%的级分并冻干。该物质不含可测量量的游离毒素。
生物数据
1.荧光偏振测量
(a)直接结合测定法
将带有荧光标签的肽(荧光素,SIGMA或Alexa Fluor488TM,Fisher Scientific)在含0.01%吐温20的PBS或含100mM NaCl和0.01%吐温的50mM HEPES,pH 7.4(两者均称为测定缓冲液)中稀释至2.5nM。在与该肽相同的测定缓冲液中将其与滴定蛋白质组合,在黑色壁和底部的低结合低体积384孔板中得到25μL总体积的1nM肽,通常为5μL测定缓冲液、10μL蛋白质(表1)、然后是10μL荧光肽。使用二分之一系列稀释,给出12个不同的浓度,最高浓度从已知高亲和力结合物的500nM,到低亲和力结合物的10μM,进行选择性测定。在配备有“FP485 520 520”光学模块的BMG PHERAstar FS上进行测量,该光学模块在485nm处激发,并在520nm处检测平行和垂直发射。将PHERAstar FS设置在25℃,每孔闪烁200次,定位延迟为0.1秒,以5至10分钟的间隔测量每孔,持续60分钟。在60分钟结束时孔中没有蛋白质,针对每个示踪剂测定用于分析的增益。使用Systat Sigmaplot 12.0版分析数据。将mP值拟合至用户定义的二次方程式以生成Kd值:f=ymin+(ymax-ymin)/Lig*((x+Lig+Kd)/2-sqrt((((x+Lig+Kd)/2)^2)-(Lig*x)))。“Lig”是所用示踪剂浓度的定义值。
(b)竞争结合测定法
测试不含荧光标签的肽与具有荧光标签和已知Kd的肽的竞争(表2)。如直接结合测定法所述,将肽在测定缓冲液中稀释至适当浓度,所述测定缓冲液具有最大浓度为5%的DMSO,然后以1比2进行系列稀释。将5μL的稀释肽添加到板中,然后以固定浓度(取决于所使用的荧光肽(表2))添加10μL的人或小鼠EphA2(表1),然后添加10μL荧光肽。按照直接结合测定法进行测量,但是在第一次测量之前测定增益。数据分析采用Systat Sigmaplot 12.0版进行,其中mP值拟合至用户定义的三次方程式,以生成Ki值:
f=ymin+(ymax-ymin)/Lig*((Lig*((2*((Klig+Kcomp+Lig+Comp-Prot*c)^2-3*(Kcomp*(Lig-Prot*c)+Klig*(Comp-Prot*c)+Klig*Kcomp))^0.5*COS(ARCCOS((-2*(Klig+Kcomp+Lig+Comp-Prot*c)^3+9*(Klig+Kcomp+Lig+Comp-Prot*c)*(Kcomp*(Lig-Prot*c)+Klig*(Comp-Prot*c)+Klig*Kcomp)-27*(-1*Klig*Kcomp*Prot*c))/(2*((((Klig+Kcomp+Lig+Comp-Prot*c)^2-3*(Kcomp*(Lig-Prot*c)+Klig*(Comp-Prot*c)+Klig*Kcomp))^3)^0.5)))/3))-(Klig+Kcomp+Lig+Comp-Prot*c)))/((3*Klig)+((2*((Klig+Kcomp+Lig+Comp-Prot*c)^2-3*(Kcomp*(Lig-Prot*c)+Klig*(Comp-Prot*c)+Klig*Kcomp))^0.5*COS(ARCCOS((-2*(Klig+Kcomp+Lig+Comp-Prot*c)^3+9*(Klig+Kcomp+Lig+Comp-Prot*c)*(Kcomp*(Lig-Prot*c)+Klig*(Comp-Prot*c)+Klig*Kcomp)-27*(-1*Klig*Kcomp*Prot*c))/(2*((((Klig+Kcomp+Lig+Comp-Prot*c)^2-3*(Kcomp*(Lig-Prot*c)+Klig*(Comp-Prot*c)+Klig*Kcomp))^3)^0.5)))/3))-(Klig+Kcomp+Lig+Comp-Prot*c))))。
“Lig”、“KLig”和“Prot”都是定义的值,分别涉及:荧光肽浓度、荧光肽的Kd和EphA2浓度。
表1:Ephrin受体和来源
表2:用于竞争结合测定法的荧光肽和EphA2的最终浓度
在上述测定中对本发明的肽配体进行了测试,结果列于表3-表12:
序列表
<110> 拜斯科阿迪有限公司
<120> 特异于EPHA2的双环肽配体
<130> BIC-C-P2289PCT
<150> GB1721265.5
<151> 2017-12-19
<160> 262
<170> PatentIn version 3.5
<210> 1
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 1
Ala Cys Met Asn Asp Trp Leu Cys Ser Leu Gly Trp Thr Cys Ala
1 5 10 15
<210> 2
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 2
Ala Cys Met Asn Asp Trp Leu Cys Ser Leu Gly Trp Thr Cys
1 5 10
<210> 3
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 3
Ala Cys Met Asn Asp Trp Leu Cys Glu Leu Gly Trp Thr Cys Ala
1 5 10 15
<210> 4
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 4
Ala Cys Thr Arg Gln Gly Ile Trp Cys Ala Leu Gly Phe Glu Pro Cys
1 5 10 15
Ala
<210> 5
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 5
Ala Cys Met Asn Asp Trp Leu Cys Thr Leu Gly Trp Ser Cys Ala
1 5 10 15
<210> 6
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 6
Ala Cys Met Asn Asp Trp Leu Cys Gln Leu Gly Trp Thr Cys Ala
1 5 10 15
<210> 7
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 7
Ala Cys Met Asn Asp Trp Leu Cys Thr Leu Gly Trp Thr Cys Ala
1 5 10 15
<210> 8
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 8
Ala Cys Met Asn Asp Trp Leu Cys Asp Leu Gly Trp Arg Cys Ala
1 5 10 15
<210> 9
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 9
Ala Cys Met Asn Asp Trp Leu Cys Glu Leu Gly Trp Ser Cys Ala
1 5 10 15
<210> 10
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 10
Ala Cys Arg Val Ser Pro Glu Tyr Cys Pro Phe Gly Pro Val Trp Cys
1 5 10 15
Ala Gly Ala Ala Ala
20
<210> 11
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 11
Ala Cys Pro Trp Gly Pro Ala Trp Cys Pro Val His Gly Lys Thr Cys
1 5 10 15
Ala
<210> 12
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 12
Ala Cys Pro Trp Gly Pro Ala Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
Ala
<210> 13
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 13
Ala Cys Pro Trp Gly Pro Ala Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
Ala Gly Ala Ala Ala
20
<210> 14
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 14
Ala Cys Pro Trp Gly Pro Met Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
Ala
<210> 15
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 15
Ala Cys Pro Trp Gly Pro Asn Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
Ala
<210> 16
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 16
Ala Gly Glu Met Ala Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys Ala
20
<210> 17
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 17
Ala Asp Val Thr Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys Ala
20
<210> 18
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 18
Ala Asp Val Arg Thr Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys Ala
20
<210> 19
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 19
Ala Asn Asp Val Thr Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys Ala
20
<210> 20
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 20
Ala Cys Val Pro Gln Gly Ile Trp Cys Ala Leu Gln Phe Glu Pro Cys
1 5 10 15
Ala
<210> 21
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 21
Ala Cys Gln Lys Gln Gly Leu Trp Cys Ala Leu Gly Phe Glu Pro Cys
1 5 10 15
Ala
<210> 22
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 22
Ala Cys Leu Val Asn Asp Asp Cys Phe Tyr Met Gly Leu Cys Ala
1 5 10 15
<210> 23
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 23
Cys Ala Asn Asp Trp Leu Cys Ser Leu Gly Trp Thr Cys
1 5 10
<210> 24
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 24
Cys Met Asn Asp Trp Leu Cys Ala Leu Gly Trp Thr Cys
1 5 10
<210> 25
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 25
Cys Met Asn Asp Trp Leu Cys Ser Ala Gly Trp Thr Cys
1 5 10
<210> 26
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 26
Ala Cys Met Asn Asp Trp Leu Cys Gln Leu Gly Trp Lys Cys Ala
1 5 10 15
<210> 27
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 27
Ala Cys Thr Gln Asn Asp Trp Leu Cys Ser Leu Gly Trp Thr Cys Ala
1 5 10 15
<210> 28
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 28
Ala Cys Arg Asn Ile Pro Thr Met Cys Pro Phe Gly Pro Val Trp Cys
1 5 10 15
Ala
<210> 29
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 29
Ala Cys Arg Val Ser Pro Glu Tyr Cys Pro Phe Gly Pro Val Trp Cys
1 5 10 15
Ala
<210> 30
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 30
Ala Cys Arg Val Ser Pro Glu Tyr Cys Pro Phe Gly Pro Thr Trp Cys
1 5 10 15
Ala
<210> 31
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 31
Ala Cys Arg Val Ser Pro Glu Tyr Cys Pro Phe Gly Pro Ser Trp Cys
1 5 10 15
Ala
<210> 32
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 32
Ala Cys Arg Val Ser Pro Glu Tyr Cys Pro Phe Gly Pro Glu Trp Cys
1 5 10 15
Ala
<210> 33
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 33
Ala Cys Arg Val Ser Pro Glu Tyr Cys Pro Phe Gly Pro Tyr Trp Cys
1 5 10 15
Ala
<210> 34
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 34
Ala Cys Arg Val Ser Pro Glu Tyr Cys Pro Phe Gly Pro Leu Trp Cys
1 5 10 15
Ala
<210> 35
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 35
Ala Cys Arg Val Ser Pro Glu Tyr Cys Pro Phe Gly Pro Asp Trp Cys
1 5 10 15
Ala
<210> 36
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 36
Ala Cys Pro Trp Gly Pro Ala Trp Cys Pro Val Arg Asp Thr Asn Cys
1 5 10 15
Ala
<210> 37
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 37
Ala Cys Pro Trp Gly Pro Ala Trp Cys Pro Val Asn Gly Ala Arg Cys
1 5 10 15
Ala
<210> 38
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 38
Ala Cys Pro Trp Gly Pro Ala Trp Cys Pro Val Arg Asn Pro Cys Ala
1 5 10 15
<210> 39
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 39
Ala Cys Pro Trp Gly Pro Ala Trp Cys Pro Val Ser Arg Val Cys Ala
1 5 10 15
<210> 40
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 40
Ala Cys Pro Trp Gly Pro Ala Trp Cys Pro Val Arg Ser Cys Ala
1 5 10 15
<210> 41
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 41
Ala Cys Pro Trp Gly Pro Ala Trp Cys Pro Val Lys Pro Thr Cys Ala
1 5 10 15
<210> 42
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 42
Ala Cys Pro Trp Gly Pro Ala Trp Cys Pro Val Asn Arg Asn Gly Cys
1 5 10 15
Ala
<210> 43
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 43
Ala Val His Ile Pro Cys Pro Trp Gly Pro Ser Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys Ala
20
<210> 44
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 44
Ala Glu Gly Leu Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys Ala
20
<210> 45
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 45
Ala Asp His Ala Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys Ala
20
<210> 46
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 46
Ala Asp Val His Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys Ala
20
<210> 47
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 47
Ala His Asp Val Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys Ala
20
<210> 48
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 48
Ala Arg Asp Asp Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys Ala
20
<210> 49
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 49
Ala Cys Thr Thr Gly Ser Ile Trp Cys Ala Leu Gln Phe Glu Pro Cys
1 5 10 15
Ala
<210> 50
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 50
Ala Cys Val Pro Gln Gly Ile Trp Cys Ala Leu Arg Tyr Glu Pro Cys
1 5 10 15
Ala
<210> 51
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 51
Ala Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
Ala
<210> 52
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 52
Ala Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 53
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是HyP
<400> 53
Ala Cys Xaa Trp Gly Pro Phe Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 54
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是Aib
<400> 54
Ala Cys Xaa Trp Gly Pro Phe Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 55
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是4FlPro
<400> 55
Ala Cys Xaa Trp Gly Pro Phe Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 56
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是1Nal
<400> 56
Ala Cys Pro Xaa Gly Pro Phe Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 57
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是2Nal
<400> 57
Ala Cys Pro Xaa Gly Pro Phe Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 58
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Aze
<400> 58
Ala Cys Pro Trp Gly Xaa Phe Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 59
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是HyP
<400> 59
Ala Cys Pro Trp Gly Xaa Phe Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 60
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Aib
<400> 60
Ala Cys Pro Trp Gly Xaa Phe Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 61
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是4FlPro
<400> 61
Ala Cys Pro Trp Gly Xaa Phe Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 62
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Pip
<400> 62
Ala Cys Pro Trp Gly Xaa Phe Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 63
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 63
Ala Cys Pro Trp Gly Pro Ala Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 64
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是4Pal
<400> 64
Ala Cys Pro Trp Gly Pro Xaa Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 65
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是4BrPhe
<400> 65
Ala Cys Pro Trp Gly Pro Xaa Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 66
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是4MeOPhe
<400> 66
Ala Cys Pro Trp Gly Pro Xaa Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 67
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是HPhe
<400> 67
Ala Cys Pro Trp Gly Pro Xaa Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 68
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是4,4-BPA
<400> 68
Ala Cys Pro Trp Gly Pro Xaa Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 69
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是NO2Phe5
<400> 69
Ala Cys Pro Trp Gly Pro Xaa Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 70
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是3,4-DCPhe
<400> 70
Ala Cys Pro Trp Gly Pro Xaa Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 71
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 71
Ala Cys Pro Trp Gly Pro Tyr Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 72
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是3PaI
<400> 72
Ala Cys Pro Trp Gly Pro Xaa Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 73
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是Phg
<400> 73
Ala Cys Pro Trp Gly Pro Xaa Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 74
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<400> 74
Ala Cys Pro Trp Gly Pro Xaa Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 75
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是2Nal
<400> 75
Ala Cys Pro Trp Gly Pro Xaa Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 76
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (8)..(8)
<223> Xaa是1Nal
<400> 76
Ala Cys Pro Trp Gly Pro Phe Xaa Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 77
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (10)..(10)
<223> Xaa是Aze
<400> 77
Ala Cys Pro Trp Gly Pro Phe Trp Cys Xaa Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 78
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (10)..(10)
<223> Xaa是HyP
<400> 78
Ala Cys Pro Trp Gly Pro Phe Trp Cys Xaa Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 79
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (10)..(10)
<223> Xaa是4FlPro
<400> 79
Ala Cys Pro Trp Gly Pro Phe Trp Cys Xaa Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 80
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是tBuGly
<400> 80
Ala Cys Pro Trp Gly Pro Phe Trp Cys Pro Xaa Asn Arg Pro Gly Cys
1 5 10 15
<210> 81
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 81
Ala Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Ala Arg Pro Gly Cys
1 5 10 15
<210> 82
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (12)..(12)
<223> Xaa是D-Ala
<400> 82
Ala Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Xaa Arg Pro Gly Cys
1 5 10 15
<210> 83
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (13)..(13)
<223> Xaa是HArg
<400> 83
Ala Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Xaa Pro Gly Cys
1 5 10 15
<210> 84
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 84
Ala Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg Ala Gly Cys
1 5 10 15
<210> 85
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是D-Ala
<400> 85
Ala Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg Xaa Gly Cys
1 5 10 15
<210> 86
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是Aze
<400> 86
Ala Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg Xaa Gly Cys
1 5 10 15
<210> 87
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是HyP
<400> 87
Ala Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg Xaa Gly Cys
1 5 10 15
<210> 88
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是Pip
<400> 88
Ala Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg Xaa Gly Cys
1 5 10 15
<210> 89
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是4FlPro
<400> 89
Ala Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg Xaa Gly Cys
1 5 10 15
<210> 90
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是Aib
<400> 90
Ala Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg Xaa Gly Cys
1 5 10 15
<210> 91
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 91
Ala Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg Pro Ala Cys
1 5 10 15
<210> 92
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是D-Ala
<400> 92
Ala Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg Pro Xaa Cys
1 5 10 15
<210> 93
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是1Nal2
<400> 93
Ala Cys Xaa Xaa Gly Pro Phe Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 94
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (8)..(8)
<223> Xaa是1Nal
<400> 94
Ala Cys Xaa Trp Gly Pro Phe Xaa Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 95
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (12)..(12)
<223> Xaa是D-Ala
<400> 95
Ala Cys Pro Xaa Gly Pro Phe Trp Cys Pro Val Xaa Arg Pro Gly Cys
1 5 10 15
<210> 96
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是D-Ala
<400> 96
Ala Cys Pro Xaa Gly Pro Phe Trp Cys Pro Val Asn Arg Pro Xaa Cys
1 5 10 15
<210> 97
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (8)..(8)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (12)..(12)
<223> Xaa是D-Ala
<400> 97
Ala Cys Pro Trp Gly Pro Phe Xaa Cys Pro Val Xaa Arg Pro Gly Cys
1 5 10 15
<210> 98
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (8)..(8)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是D-Ala
<400> 98
Ala Cys Pro Trp Gly Pro Phe Xaa Cys Pro Val Asn Arg Pro Xaa Cys
1 5 10 15
<210> 99
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Aib
<400> 99
Ala Cys Pro Xaa Gly Xaa Phe Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 100
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (8)..(8)
<223> Xaa是1Nal
<400> 100
Ala Cys Pro Xaa Gly Pro Phe Xaa Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 101
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是tBuGly
<400> 101
Ala Cys Pro Xaa Gly Pro Phe Trp Cys Pro Xaa Asn Arg Pro Gly Cys
1 5 10 15
<210> 102
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (13)..(13)
<223> Xaa是HArg
<400> 102
Ala Cys Pro Xaa Gly Pro Phe Trp Cys Pro Val Asn Xaa Pro Gly Cys
1 5 10 15
<210> 103
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (8)..(8)
<223> Xaa是1Nal
<400> 103
Ala Cys Pro Trp Gly Xaa Phe Xaa Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 104
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (12)..(12)
<223> Xaa是D-Ala
<400> 104
Ala Cys Xaa Xaa Gly Pro Phe Trp Cys Pro Val Xaa Arg Pro Gly Cys
1 5 10 15
<210> 105
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是D-Ala
<400> 105
Ala Cys Xaa Xaa Gly Pro Phe Trp Cys Pro Val Asn Arg Pro Xaa Cys
1 5 10 15
<210> 106
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是tBuGly
<400> 106
Ala Cys Pro Xaa Gly Xaa Phe Trp Cys Pro Xaa Asn Arg Pro Gly Cys
1 5 10 15
<210> 107
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (12)..(12)
<223> Xaa是D-Ala
<400> 107
Ala Cys Pro Xaa Gly Xaa Phe Trp Cys Pro Val Xaa Arg Pro Gly Cys
1 5 10 15
<210> 108
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是D-Ala
<400> 108
Ala Cys Pro Xaa Gly Xaa Phe Trp Cys Pro Val Asn Arg Pro Xaa Cys
1 5 10 15
<210> 109
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (12)..(12)
<223> Xaa是D-Ala
<400> 109
Ala Cys Pro Xaa Gly Pro Phe Trp Cys Pro Xaa Xaa Arg Pro Gly Cys
1 5 10 15
<210> 110
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (13)..(13)
<223> Xaa是HArg
<400> 110
Ala Cys Pro Xaa Gly Pro Phe Trp Cys Pro Xaa Asn Xaa Pro Gly Cys
1 5 10 15
<210> 111
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是Aib
<400> 111
Ala Cys Pro Xaa Gly Pro Phe Trp Cys Pro Xaa Asn Arg Xaa Gly Cys
1 5 10 15
<210> 112
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是D-Ala
<400> 112
Ala Cys Pro Xaa Gly Pro Phe Trp Cys Pro Xaa Asn Arg Pro Xaa Cys
1 5 10 15
<210> 113
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (12)..(12)
<223> Xaa是D-Ala
<220>
<221> Xaa
<222> (13)..(13)
<223> Xaa是HArg
<400> 113
Ala Cys Pro Xaa Gly Pro Phe Trp Cys Pro Val Xaa Xaa Pro Gly Cys
1 5 10 15
<210> 114
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (13)..(13)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是D-Ala
<400> 114
Ala Cys Pro Xaa Gly Pro Phe Trp Cys Pro Val Asn Xaa Pro Xaa Cys
1 5 10 15
<210> 115
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是Aib
<400> 115
Ala Cys Xaa Xaa Gly Xaa Phe Trp Cys Pro Val Asn Arg Xaa Gly Cys
1 5 10 15
<210> 116
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (13)..(13)
<223> Xaa是HArg
<400> 116
Ala Cys Pro Xaa Gly Xaa Phe Trp Cys Pro Xaa Asn Xaa Pro Gly Cys
1 5 10 15
<210> 117
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是Aib
<400> 117
Ala Cys Pro Xaa Gly Xaa Phe Trp Cys Pro Xaa Asn Arg Xaa Gly Cys
1 5 10 15
<210> 118
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (13)..(13)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是Aib
<400> 118
Ala Cys Pro Xaa Gly Pro Phe Trp Cys Pro Xaa Asn Xaa Xaa Gly Cys
1 5 10 15
<210> 119
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<400> 119
His Xaa Val Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys Ala
20
<210> 120
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<400> 120
His Xaa Val Pro Cys Xaa Xaa Gly Xaa Phe Xaa Cys Pro Xaa Asn Xaa
1 5 10 15
Pro Xaa Cys
<210> 121
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<400> 121
His Xaa Val Pro Cys Xaa Xaa Gly Xaa Phe Xaa Cys Pro Xaa Asn Arg
1 5 10 15
Xaa Xaa Cys
<210> 122
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> misc_feature
<222> (5)..(5)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> misc_feature
<222> (8)..(8)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> misc_feature
<222> (10)..(10)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> misc_feature
<222> (12)..(12)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> misc_feature
<222> (15)..(15)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是HArg
<220>
<221> misc_feature
<222> (17)..(17)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<220>
<221> misc_feature
<222> (19)..(19)
<223> Xaa可以是任何天然存在的氨基酸
<400> 122
His Xaa Val Pro Xaa Cys Pro Xaa Gly Xaa Phe Xaa Cys Pro Xaa Asn
1 5 10 15
Xaa Pro Xaa Cys
20
<210> 123
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是Aib
<400> 123
His Xaa Val Pro Cys Pro Xaa Gly Xaa Phe Xaa Cys Pro Xaa Asn Arg
1 5 10 15
Xaa Gly Cys
<210> 124
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<400> 124
His Xaa Val Pro Cys Pro Xaa Gly Xaa Phe Xaa Cys Pro Xaa Asn Arg
1 5 10 15
Xaa Xaa Cys
<210> 125
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是C5g
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<400> 125
His Xaa Xaa Pro Cys Xaa Xaa Gly Xaa Phe Xaa Cys Pro Xaa Asn Arg
1 5 10 15
Xaa Xaa Cys
<210> 126
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是C5g
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<400> 126
His Xaa Xaa Pro Cys Pro Xaa Gly Xaa Phe Xaa Cys Pro Xaa Asn Xaa
1 5 10 15
Pro Xaa Cys
<210> 127
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 127
Ala Asp Val His Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys
<210> 128
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是3,3-DPA
<400> 128
Ala Asp Val His Cys Pro Xaa Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys Ala
20
<210> 129
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<400> 129
Ala Asp Val His Cys Pro Xaa Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys Ala
20
<210> 130
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 130
Ala Asp Val His Cys Pro Trp Ala Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys Ala
20
<210> 131
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 131
Ala Asp Val His Cys Pro Trp Gly Ala Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys Ala
20
<210> 132
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<400> 132
Ala Asp Val His Cys Pro Trp Gly Xaa Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys Ala
20
<210> 133
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 133
Ala Asp Val His Cys Pro Trp Gly Pro Phe Trp Cys Ala Pro Val Asn
1 5 10 15
Arg Pro Gly Cys Ala
20
<210> 134
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是D-Ala
<400> 134
Ala Asp Val His Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Xaa Arg
1 5 10 15
Pro Gly Cys Ala
20
<210> 135
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是D-Ala
<400> 135
Ala Asp Val His Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Xaa
1 5 10 15
Pro Gly Cys Ala
20
<210> 136
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 136
Ala Asp Val Thr Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys
<210> 137
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<400> 137
Ala Xaa Val Thr Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys
<210> 138
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是D-Asp
<400> 138
Ala Xaa Xaa Thr Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys
<210> 139
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是Cba
<400> 139
Ala Xaa Xaa Thr Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys
<210> 140
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是Cpa
<400> 140
Ala Xaa Xaa Thr Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys
<210> 141
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是Cpg
<400> 141
Ala Xaa Xaa Thr Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys
<210> 142
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是C5g
<400> 142
Ala Xaa Xaa Val Thr Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 143
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是tBuGly
<400> 143
Ala Asp Xaa Thr Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys
<210> 144
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是AC3C
<400> 144
Ala Xaa Val Thr Cys Xaa Trp Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys
<210> 145
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是AC4C
<400> 145
Ala Xaa Val Thr Cys Xaa Trp Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys
<210> 146
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是AC5C
<400> 146
Ala Xaa Val Thr Cys Xaa Trp Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys
<210> 147
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是4BenzylPro
<400> 147
Ala Xaa Val Thr Cys Xaa Trp Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys
<210> 148
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是4PhenylPro
<400> 148
Ala Xaa Val Thr Cys Xaa Trp Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys
<210> 149
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<400> 149
Ala Xaa Val Thr Cys Pro Xaa Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys
<210> 150
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (10)..(10)
<223> Xaa是HArg
<400> 150
Ala Xaa Val Thr Cys Pro Trp Gly Pro Xaa Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys
<210> 151
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<400> 151
Ala Xaa Val Thr Cys Pro Trp Gly Pro Asn Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys
<210> 152
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<400> 152
Ala Xaa Val Thr Cys Pro Trp Gly Pro Ala Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys
<210> 153
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<400> 153
Ala Xaa Val Thr Cys Pro Trp Gly Pro Phe Trp Cys Pro Leu Asn Arg
1 5 10 15
Pro Gly Cys
<210> 154
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<400> 154
Ala Xaa Val Thr Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Xaa Cys
<210> 155
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<400> 155
Ala Xaa Val Thr Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Xaa
1 5 10 15
Pro Xaa Cys
<210> 156
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是Aib
<220>
<221> misc_feature
<222> (17)..(17)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<400> 156
Ala Xaa Val Thr Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Xaa Xaa Cys
<210> 157
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是Aib
<400> 157
Ala Xaa Val Thr Cys Pro Xaa Gly Xaa Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Xaa Gly Cys
<210> 158
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是Aib
<400> 158
Ala Xaa Val Thr Cys Pro Trp Gly Xaa Phe Xaa Cys Pro Val Asn Arg
1 5 10 15
Xaa Gly Cys
<210> 159
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是Aib
<400> 159
Ala Xaa Val Thr Cys Pro Trp Gly Xaa Phe Trp Cys Pro Xaa Asn Arg
1 5 10 15
Xaa Gly Cys
<210> 160
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是Aib
<400> 160
Ala Xaa Val Thr Cys Pro Xaa Gly Xaa Phe Xaa Cys Pro Val Asn Arg
1 5 10 15
Xaa Gly Cys
<210> 161
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是HArg
<400> 161
Ala Xaa Val Thr Cys Pro Xaa Gly Xaa Phe Xaa Cys Pro Xaa Asn Xaa
1 5 10 15
Pro Gly Cys
<210> 162
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是Aib
<400> 162
Ala Xaa Val Thr Cys Pro Xaa Gly Xaa Phe Xaa Cys Pro Xaa Asn Arg
1 5 10 15
Xaa Gly Cys
<210> 163
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<400> 163
Ala Xaa Val Thr Cys Pro Xaa Gly Xaa Phe Xaa Cys Pro Xaa Asn Xaa
1 5 10 15
Pro Xaa Cys
<210> 164
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (1)..(1)
<223> Xaa是D-Asp
<400> 164
Xaa Val Thr Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg Pro
1 5 10 15
Gly Cys
<210> 165
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (1)..(1)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (8)..(8)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (10)..(10)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (13)..(13)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是Aib
<400> 165
Xaa Val Thr Cys Pro Xaa Gly Xaa Phe Xaa Cys Pro Xaa Asn Arg Xaa
1 5 10 15
Gly Cys
<210> 166
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (8)..(8)
<223> Xaa是1Nal
<400> 166
Ala His Asp Val Pro Cys Pro Xaa Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys Ala
20
<210> 167
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (8)..(8)
<223> Xaa是1Nal
<400> 167
Ala His Asp Val Pro Cys Pro Xaa Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 168
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (12)..(12)
<223> Xaa是1Nal
<400> 168
Ala His Asp Val Pro Cys Pro Trp Gly Pro Phe Xaa Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 169
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (8)..(8)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是tBuGly
<400> 169
Ala His Asp Val Pro Cys Pro Xaa Gly Pro Phe Trp Cys Pro Xaa Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 170
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (8)..(8)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (10)..(10)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 170
Ala His Asp Val Pro Cys Pro Xaa Gly Xaa Phe Trp Cys Pro Xaa Asn
1 5 10 15
Xaa Pro Gly Cys
20
<210> 171
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (8)..(8)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (10)..(10)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是Aib
<400> 171
Ala His Asp Val Pro Cys Pro Xaa Gly Xaa Phe Trp Cys Pro Xaa Asn
1 5 10 15
Arg Xaa Gly Cys
20
<210> 172
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 172
Ala His Asp Val Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 173
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (1)..(1)
<223> Xaa是D-Ala
<400> 173
Xaa His Asp Val Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 174
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 174
Ala Ala Asp Val Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 175
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-His
<400> 175
Ala Xaa Asp Val Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 176
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-His
<400> 176
Ala Xaa Asp Val Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys
<210> 177
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Ala
<400> 177
Ala Xaa Asp Val Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 178
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<400> 178
Ala Xaa Asp Val Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 179
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是Thi
<400> 179
Ala Xaa Asp Val Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 180
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是ThiAz
<400> 180
Ala Xaa Asp Val Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 181
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是2FuAla
<400> 181
Ala Xaa Asp Val Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 182
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-His
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是tBuGly
<400> 182
Ala Xaa Asp Xaa Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 183
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 183
Ala His Ala Val Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 184
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是D-Ala
<400> 184
Ala His Xaa Val Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 185
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 185
Ala His Glu Val Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 186
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是D-Glu
<400> 186
Ala His Xaa Val Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 187
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是D-Asp
<400> 187
Ala His Xaa Val Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 188
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是tBuGly
<400> 188
Ala His Xaa Xaa Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 189
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是Sar
<400> 189
Ala His Xaa Val Xaa Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 190
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是Aib
<400> 190
Ala His Xaa Val Xaa Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 191
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 191
Ala His Asp Ala Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 192
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是D-Ala
<400> 192
Ala His Asp Xaa Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 193
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是Aib
<400> 193
Ala His Asp Xaa Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 194
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是tBuGly
<400> 194
Ala His Asp Xaa Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 195
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 195
Ala His Asp Val Ala Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 196
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是D-Ala
<400> 196
Ala His Asp Val Xaa Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 197
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是Aib
<400> 197
Ala His Asp Val Xaa Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 198
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是Aze
<400> 198
Ala His Asp Val Xaa Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 199
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是Pip
<400> 199
Ala His Asp Val Xaa Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 200
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 200
His Asp Val Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys
<210> 201
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (1)..(1)
<223> Xaa是D-His
<400> 201
Xaa Asp Val Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys
<210> 202
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<400> 202
His Xaa Val Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys
<210> 203
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (8)..(8)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 203
Ala His Xaa Val Pro Cys Pro Xaa Gly Pro Phe Trp Cys Pro Xaa Asn
1 5 10 15
Xaa Pro Gly Cys
20
<210> 204
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-His
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是Psi-Ala
<400> 204
Ala Xaa Asp Val Pro Cys Pro Trp Gly Pro Xaa Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 205
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-His
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是HArg
<400> 205
Ala Xaa Asp Val Pro Cys Pro Trp Gly Pro Phe Trp Cys Pro Xaa Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 206
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-His
<220>
<221> Xaa
<222> (8)..(8)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 206
Ala Xaa Asp Val Pro Cys Pro Xaa Gly Pro Phe Trp Cys Pro Xaa Asn
1 5 10 15
Xaa Pro Gly Cys
20
<210> 207
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-His
<220>
<221> Xaa
<222> (8)..(8)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (10)..(10)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (12)..(12)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 207
Ala Xaa Asp Val Pro Cys Pro Xaa Gly Xaa Phe Xaa Cys Pro Xaa Asn
1 5 10 15
Xaa Pro Gly Cys
20
<210> 208
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-His
<220>
<221> Xaa
<222> (8)..(8)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (10)..(10)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (12)..(12)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是Aib
<400> 208
Ala Xaa Asp Val Pro Cys Pro Xaa Gly Xaa Phe Xaa Cys Pro Xaa Asn
1 5 10 15
Arg Xaa Gly Cys
20
<210> 209
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-His
<220>
<221> Xaa
<222> (10)..(10)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是Aib
<400> 209
Ala Xaa Asp Val Pro Cys Pro Trp Gly Xaa Phe Trp Cys Pro Xaa Asn
1 5 10 15
Arg Xaa Gly Cys
20
<210> 210
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<400> 210
His Xaa Val Pro Cys Xaa Xaa Gly Xaa Phe Xaa Cys Pro Xaa Asn Arg
1 5 10 15
Pro Gly Cys
<210> 211
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是HArg
<400> 211
His Xaa Val Pro Cys Xaa Xaa Gly Xaa Phe Xaa Cys Pro Xaa Asn Xaa
1 5 10 15
Pro Gly Cys
<210> 212
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<400> 212
His Xaa Val Pro Cys Xaa Xaa Gly Xaa Phe Xaa Cys Pro Xaa Asn Xaa
1 5 10 15
Xaa Xaa Cys
<210> 213
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是Aib
<400> 213
His Xaa Val Pro Cys Xaa Xaa Gly Xaa Phe Xaa Cys Pro Xaa Asn Arg
1 5 10 15
Xaa Gly Cys
<210> 214
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<400> 214
His Xaa Val Pro Cys Xaa Xaa Gly Xaa Phe Trp Cys Pro Xaa Asn Xaa
1 5 10 15
Pro Xaa Cys
<210> 215
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (10)..(10)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是Aib
<400> 215
His Xaa Val Pro Cys Xaa Xaa Gly Pro Xaa Xaa Cys Pro Xaa Asn Arg
1 5 10 15
Xaa Gly Cys
<210> 216
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (10)..(10)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<400> 216
His Xaa Val Pro Cys Xaa Xaa Gly Pro Xaa Xaa Cys Pro Xaa Asn Xaa
1 5 10 15
Pro Xaa Cys
<210> 217
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (10)..(10)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<400> 217
His Xaa Val Pro Cys Xaa Trp Gly Pro Xaa Xaa Cys Pro Xaa Asn Xaa
1 5 10 15
Pro Xaa Cys
<210> 218
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (10)..(10)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<400> 218
His Xaa Val Pro Cys Xaa Trp Gly Pro Xaa Trp Cys Pro Xaa Asn Xaa
1 5 10 15
Pro Xaa Cys
<210> 219
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是D-Ala
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<400> 219
His Xaa Val Pro Cys Xaa Xaa Gly Xaa Phe Xaa Cys Pro Xaa Asn Xaa
1 5 10 15
Pro Xaa Cys
<210> 220
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (10)..(10)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是Aib
<400> 220
His Xaa Val Pro Cys Pro Xaa Gly Xaa Xaa Xaa Cys Pro Xaa Asn Arg
1 5 10 15
Xaa Gly Cys
<210> 221
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (10)..(10)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<400> 221
His Xaa Val Pro Cys Pro Xaa Gly Xaa Xaa Xaa Cys Pro Xaa Asn Arg
1 5 10 15
Xaa Xaa Cys
<210> 222
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (10)..(10)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<400> 222
His Xaa Val Pro Cys Pro Xaa Gly Xaa Xaa Xaa Cys Pro Xaa Asn Xaa
1 5 10 15
Pro Xaa Cys
<210> 223
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<400> 223
His Xaa Val Pro Cys Pro Xaa Gly Xaa Phe Xaa Cys Pro Xaa Asn Arg
1 5 10 15
Pro Gly Cys
<210> 224
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是HArg
<400> 224
His Xaa Val Pro Cys Pro Xaa Gly Xaa Phe Xaa Cys Pro Xaa Asn Xaa
1 5 10 15
Pro Gly Cys
<210> 225
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<400> 225
His Xaa Val Pro Cys Pro Xaa Gly Xaa Phe Xaa Cys Pro Xaa Asn Xaa
1 5 10 15
Xaa Xaa Cys
<210> 226
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是Aib
<400> 226
His Xaa Val Pro Cys Pro Xaa Gly Xaa Phe Xaa Cys Pro Val Asn Arg
1 5 10 15
Xaa Gly Cys
<210> 227
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<400> 227
His Xaa Val Pro Cys Pro Xaa Gly Xaa Phe Trp Cys Pro Xaa Asn Xaa
1 5 10 15
Pro Xaa Cys
<210> 228
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是Aib
<400> 228
His Xaa Val Pro Cys Pro Xaa Gly Xaa Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Xaa Gly Cys
<210> 229
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (8)..(8)
<223> Xaa是Aza-Gly
<400> 229
His Xaa Val Pro Cys Pro Trp Xaa Pro Phe Trp Cys Pro Val Asn Arg
1 5 10 15
Pro Gly Cys
<210> 230
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是Aib
<400> 230
His Xaa Val Pro Cys Pro Trp Gly Xaa Phe Xaa Cys Pro Val Asn Arg
1 5 10 15
Xaa Gly Cys
<210> 231
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<400> 231
His Xaa Val Pro Cys Pro Trp Gly Xaa Phe Xaa Cys Pro Xaa Asn Xaa
1 5 10 15
Pro Xaa Cys
<210> 232
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是Aib
<400> 232
His Xaa Val Pro Cys Pro Trp Gly Xaa Phe Trp Cys Pro Xaa Asn Arg
1 5 10 15
Xaa Gly Cys
<210> 233
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<400> 233
His Xaa Val Pro Cys Pro Trp Gly Xaa Phe Trp Cys Pro Xaa Asn Xaa
1 5 10 15
Pro Xaa Cys
<210> 234
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (10)..(10)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<400> 234
His Xaa Val Pro Cys Pro Trp Gly Pro Xaa Trp Cys Pro Xaa Asn Xaa
1 5 10 15
Pro Xaa Cys
<210> 235
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是C5g
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<400> 235
His Xaa Xaa Pro Cys Xaa Trp Gly Xaa Phe Trp Cys Pro Xaa Asn Arg
1 5 10 15
Xaa Xaa Cys
<210> 236
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是C5g
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是Aib
<400> 236
His Xaa Xaa Pro Cys Pro Xaa Gly Xaa Phe Xaa Cys Pro Xaa Asn Arg
1 5 10 15
Xaa Gly Cys
<210> 237
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是C5g
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是Aib
<400> 237
His Xaa Xaa Thr Cys Pro Xaa Gly Xaa Phe Xaa Cys Pro Xaa Asn Arg
1 5 10 15
Xaa Gly Cys
<210> 238
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是C5g
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (16)..(16)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<400> 238
His Xaa Xaa Thr Cys Pro Xaa Gly Xaa Phe Xaa Cys Pro Xaa Asn Xaa
1 5 10 15
Pro Xaa Cys
<210> 239
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<400> 239
Ala Xaa Asp Val Thr Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 240
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (8)..(8)
<223> Xaa是1Nal
<400> 240
Ala Xaa Asp Val Thr Cys Pro Xaa Gly Pro Phe Trp Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 241
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (8)..(8)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (12)..(12)
<223> Xaa是1Nal
<400> 241
Ala Xaa Asp Val Thr Cys Pro Xaa Gly Pro Phe Xaa Cys Pro Val Asn
1 5 10 15
Arg Pro Gly Cys
20
<210> 242
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (8)..(8)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (10)..(10)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (15)..(15)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是HArg
<400> 242
Ala Xaa Asp Val Thr Cys Pro Xaa Gly Xaa Phe Trp Cys Pro Xaa Asn
1 5 10 15
Xaa Pro Gly Cys
20
<210> 243
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是Aib
<400> 243
His Xaa Val Thr Cys Pro Xaa Gly Xaa Phe Xaa Cys Pro Xaa Asn Arg
1 5 10 15
Xaa Gly Cys
<210> 244
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 244
Ala Cys Ala Trp Gly Pro Phe Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 245
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 245
Ala Cys Pro Ala Gly Pro Phe Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 246
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 246
Ala Cys Pro Trp Ala Pro Phe Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 247
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 247
Ala Cys Pro Trp Gly Ala Phe Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 248
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 248
Ala Cys Pro Trp Gly Pro Phe Ala Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 249
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 249
Ala Cys Pro Trp Gly Pro Phe Trp Cys Ala Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 250
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 250
Ala Cys Pro Trp Gly Pro Phe Trp Cys Pro Ala Asn Arg Pro Gly Cys
1 5 10 15
<210> 251
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 251
Ala Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Ala Pro Gly Cys
1 5 10 15
<210> 252
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (3)..(3)
<223> Xaa是D-Ala
<400> 252
Ala Cys Xaa Trp Gly Pro Phe Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 253
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (4)..(4)
<223> Xaa是D-Ala
<400> 253
Ala Cys Pro Xaa Gly Pro Phe Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 254
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (5)..(5)
<223> Xaa是D-Ala
<400> 254
Ala Cys Pro Trp Xaa Pro Phe Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 255
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (6)..(6)
<223> Xaa是D-Ala
<400> 255
Ala Cys Pro Trp Gly Xaa Phe Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 256
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是D-Ala
<400> 256
Ala Cys Pro Trp Gly Pro Xaa Trp Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 257
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (8)..(8)
<223> Xaa是D-Ala
<400> 257
Ala Cys Pro Trp Gly Pro Phe Xaa Cys Pro Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 258
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (10)..(10)
<223> Xaa是D-Ala
<400> 258
Ala Cys Pro Trp Gly Pro Phe Trp Cys Xaa Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 259
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是D-Ala
<400> 259
Ala Cys Pro Trp Gly Pro Phe Trp Cys Pro Xaa Asn Arg Pro Gly Cys
1 5 10 15
<210> 260
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (13)..(13)
<223> Xaa是D-Ala
<400> 260
Ala Cys Pro Trp Gly Pro Phe Trp Cys Pro Val Asn Xaa Pro Gly Cys
1 5 10 15
<210> 261
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 261
Ala Cys Pro Trp Ala Pro Phe Trp Cys Ala Val Asn Arg Pro Gly Cys
1 5 10 15
<210> 262
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<220>
<221> Xaa
<222> (2)..(2)
<223> Xaa是D-Asp
<220>
<221> Xaa
<222> (7)..(7)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (9)..(9)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是1Nal
<220>
<221> Xaa
<222> (14)..(14)
<223> Xaa是tBuGly
<220>
<221> Xaa
<222> (17)..(17)
<223> Xaa是Aib
<220>
<221> Xaa
<222> (18)..(18)
<223> Xaa是D-Asp
<400> 262
His Xaa Val Pro Cys Pro Xaa Ala Xaa Phe Xaa Cys Ala Xaa Asn Arg
1 5 10 15
Xaa Xaa Cys
Claims (21)
1.一种特异于EphA2的肽配体,其包含多肽和芳族分子支架,所述多肽包含由至少两个环序列隔开的至少三个半胱氨酸残基,所述芳族分子支架与所述多肽的半胱氨酸残基形成共价键从而在所述分子支架上形成至少两个多肽环。
2.根据权利要求1所述的肽配体,其中所述环序列包含4、5、6或7个氨基酸。
3.根据权利要求1或2所述的肽配体,其中所述环序列包含由两个环序列隔开的三个半胱氨酸残基,所述两个环序列均由5个氨基酸组成(例如表3、表4和表94中列出的那些)。
4.根据权利要求1或2所述的肽配体,其中所述环序列包含由两个环序列隔开的三个半胱氨酸残基,所述两个环序列均由6个氨基酸组成(例如表3至表10中列出的那些)。
5.根据权利要求1或2所述的肽配体,其中所述环序列包含由两个环序列隔开的三个半胱氨酸残基,所述两个环序列之一由6个氨基酸组成,而另一个由5个氨基酸组成(例如表4中所列的那些)。
6.根据权利要求1或2所述的肽配体,其中所述环序列包含由两个环序列隔开的三个半胱氨酸残基,所述两个环序列之一由6个氨基酸组成,而另一个由4个氨基酸组成(例如表4中所列的那些)。
7.根据权利要求1或2所述的肽配体,其中所述环序列包含由两个环序列隔开的三个半胱氨酸残基,所述两个环序列之一由6个氨基酸组成,而另一个由7个氨基酸组成(例如表8中所列的那些)。
8.根据权利要求1至7中任一项所述的肽配体,其中所述肽配体包含选自以下的氨基酸序列:
Ci-X1-Cii-X2-Cii,
其中X1和X2代表表3至表10中列出的半胱氨酸残基之间氨基酸残基,Ci、Cii和Ciii分别代表第一、第二和第三半胱氨酸残基,或其药学上可接受的盐。
9.根据权利要求1至8中任一项所述的肽配体,其中所述肽配体包含选自表3至表10中的一个或多个所列出的一个或多个肽配体的氨基酸序列。
10.根据权利要求1至9中任一项所述的肽配体,其中所述分子支架选自(1,3,5-三(溴甲基)苯)(TBMB),所述肽配体选自表3至表10所列出的任何一种肽配体。
11.根据权利要求1至10中任一项所述的肽配体,其选自化合物1-286、289、292-293和296-297中的任一种或其药学上可接受的盐。
12.根据权利要求1至11中任一项所述的肽配体,其中所述药学上可接受的盐选自游离酸或钠、钾、钙、铵盐。
13.根据权利要求1至12中任一项所述的肽配体,其中所述EphA2为人EphA2。
14.一种药物缀合物,其包含缀合至一个或多个效应物和/或官能团的权利要求1至13中任一项所述的肽配体。
15.根据权利要求14所述的药物缀合物,其中所述细胞毒性剂选自DM1。
16.根据权利要求14或15所述的药物缀合物,其选自BDC-1至BDC-5中的任何一种,例如选自BDC-1至BDC-4中的任何一种。
17.一种药物组合物,其包含权利要求1至13中任一项所述的肽配体或权利要求14至16中任一项所述的药物缀合物,以及一种或多种药学上可接受的赋形剂。
18.根据权利要求14至16中任一项所述的药物缀合物,其用于预防、抑制或治疗特征在于患病组织中EphA2过度表达的疾病或病症的用途。
19.根据权利要求14至16中任一项所述的药物缀合物,其用于预防、抑制或治疗癌症。
20.根据权利要求14至16中任一项所述的药物缀合物,其用于预防、抑制或治疗肺癌。
21.根据权利要求14至16中任一项所述的药物缀合物,其用于预防、抑制或治疗非小细胞肺癌。
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GBGB1721265.5A GB201721265D0 (en) | 2017-12-19 | 2017-12-19 | Bicyclic peptide ligands specific for EphA2 |
PCT/GB2018/053676 WO2019122861A1 (en) | 2017-12-19 | 2018-12-19 | Bicyclic peptide ligands specific for epha2 |
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EP (1) | EP3727462A1 (zh) |
JP (2) | JP7460523B2 (zh) |
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