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引用本文:杨娜,张拥军,王为民.GLP-1的结构修饰策略与药物的研究进展[J].中国现代应用药学,2024,41(18):97-105.
Yang Na,Zhang Yongjun,Wang Weimin.Structural Modification Strategies and Drug Research Progress of GLP-1[J].Chin J Mod Appl Pharm(中国现代应用药学),2024,41(18):97-105.
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GLP-1的结构修饰策略与药物的研究进展
杨娜, 张拥军, 王为民
中国计量大学
摘要:
胰高血糖素样肽-1,是由小肠内L细胞所分泌的一种肽类激素,在临床上主要用于2型糖尿病及并发症的治疗,具有降血糖、降血脂、减重和保护心血管系统等作用。天然的GLP-1在体内由于易被酶降解、被肾清除而导致其血浆半衰期仅1~2 min,限制了其在临床上的应用。通过对GLP-1进行一系列的结构修饰,可以延长GLP-1类药物血浆半衰期而发挥治疗效果。自2005年FDA批准全球首个治疗糖尿病的GLP-1受体激动剂药物艾塞那肽后,目前已有多种GLP-1受体激动剂相关药物上市,GLP-1类药物从最初的单靶点发展到目前的双靶点甚至三靶点制剂,有利于协同降糖和调节脂肪代谢,极大的拓宽了该类药物的治疗领域。本文主要综述了GLP-1类药物的不同结构修饰策略对临床效果的影响,以及已被批准GLP-1类药物的作用特点,以期为未来新药研发提供参考。
关键词:  GLP-1  2型糖尿病  长效受体激动剂  构效关系  研究进展
DOI:
分类号:R97
基金项目:
Structural Modification Strategies and Drug Research Progress of GLP-1
Yang Na, Zhang Yongjun, Wang Weimin
China JiLiang University
Abstract:
Glucagon-like peptide-1 is a peptide hormone secreted by L cells in the small intestine. Clinically, it is primarily used for the treatment of type 2 diabetes mellitus and its complications. It exhibits effects such as lowering blood glucose levels, reducing blood lipids, improving weight loss, and protecting the cardiovascular system. Due to the rapid degradation of GLP-1 by DPP-4 and clearance by the kidneys, exogenously administered GLP-1 has half-life of 1-2 min, which limits its clinical application. Through a series of structural modifications to GLP-1, the plasma half-life of GLP-1 analogs can be prolonged to exert therapeutic effects. The first GLP-1 receptor agonist (GLP-1 RA) was Exenatide, which was approved by the FDA in 2005 for the treatment of T2DM, and since that time, several GLP-1 RAs have been added to the drug class. GLP-1 analogs have developed from the initial single target to the current double target or even triple target preparations, which is conducive to coordinated blood sugar reduction and regulation of fat metabolism, and greatly broadens the therapeutic field of such drugs. This article mainly discusses the impact of different structural modification strategies of GLP-1 drugs on clinical efficacy, as well as the characteristics of approved GLP-1 drugs and future research and development trends, in order to provide reference for future new drug development.
Key words:  GLP-1  type 2 diabetes  long-acting receptor agonists  structure activity relationship  research progress
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