摘要
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 insulinotropic hormone with excellent blood glucose-lowering activity, however, it is rapidly inactivated in the plasma mainly by dipeptidyl peptidase IV(DPP-IV). To overcome this problem, various N-terminal modifications of GLP-1 have been performed to prolong the in vivo biological activity, by improving the DPP-IV resistance while retaining receptor affinity and receptor activation. These studies have included modifications of His7, Ala8 or Glu9 at the N-terminus of GLP-1 and some other modifications. Among them, Ala8 substitutions with glycine(Gly8) and α-aminoisobutyric acid(Aib8) have been clinically applied in the development of diabetic therapy, such as Exenatide, Semaglutide, Albiglutide and Taspoglutide. In this review, we introduce N-terminal modifications of GLP-1 that have been reported, and discuss their potential and challenges for the treatment of type 2 diabetes.
基金
Beijing Natural Science Foundation(Grant No.715 2085)