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胰高血糖素样肽-1(GLP-1)是一种人体内源性的肠促胰素,具有极强的体内降血糖活性,但在血浆中易被二肽基肽酶IV(DPP-IV)迅速降解失活,由于DPP-IV的酶切位点靠近GLP-1的N端,因此对N端进行结构修饰,可以延长GLP-1的体内降血糖活性。过去有关GLP-1的N端修饰研究中,主要包括对His7、Ala8和Glu9的结构修饰以及一些其他的结构改造(包括GLP-1的缩短肽类似物、小分子受体激动剂等),以期望在增强对DPP-IV酶降解耐受能力的同时,保持较好的受体结合力与激动活性。至今为止,用甘氨酸(Gly)或者α-氨基异丁酸(Aib)取代GLP-1的N端Ala8修饰策略已被用于II型糖尿病药物(Exenatide、Semaglutide、Albiglutide、Taspoglutide等)的临床研究中。本文具体描述已经报道的各类GLP-1的N端修饰研究工作进展,并讨论其在II型糖尿病治疗药物研发中的应用前景。
Glucagon-like peptide-1 (GLP-1) is an endogenous human pancreaticin that has a very high in vivo hypoglycemic activity but is predisposed to dipeptidyl peptidase IV (DPP- IV) rapid degradation inactivation, due to DPP-IV cleavage site near the N-terminus of GLP-1, structural modification of the N-terminus can prolong the hypoglycemic activity of GLP-1 in vivo. In the past, N-terminal modification studies on GLP-1 mainly included structural modifications of His7, Ala8 and Glu9 and some other structural modifications (including shortened peptide analogues of GLP-1, small molecule receptor agonists, etc.) It is expected to maintain good receptor binding and agonistic activity while enhancing the tolerance to DPP-IV degradation. To date, the N-terminal Ala8 modification strategy of replacing GLP-1 with glycine (Gly) or α-aminoisobutyric acid (Aib) has been used in clinical studies with type II diabetes drugs (Exenatide, Semaglutide, Albiglutide, Taspoglutide, etc.) . This article describes the progress of N-terminal modification of GLP-1, which has been reported in detail, and discusses its potential application in the development of therapeutic agents for type II diabetes.