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Glucagon‐Like Peptide‐1 (GLP‐1)‐Based Therapeutics: Current Status and Future Opportunities beyond Type 2 Diabetes
ChemMedChem ( IF 3.4 ) Pub Date : 2018-02-28 , DOI: 10.1002/cmdc.201700781
Jia Ying Cheang 1 , Peter M. Moyle 1
Affiliation  

Glucagon‐like peptide‐1 (GLP‐1) is secreted by intestinal L‐cells following food intake, and plays an important role in glucose homeostasis due to its stimulation of glucose‐dependent insulin secretion. Further, GLP‐1 is also associated with protective effects on pancreatic β‐cells and the cardiovascular system, decreased appetite, and weight loss, making GLP‐1 derivatives an exciting treatment for type 2 diabetes and obesity. Despite these benefits, wild‐type GLP‐1 exhibits a short circulation time due to its poor metabolic stability and rapid renal clearance, and must be administered by injection, making it a poor therapeutic agent. Many strategies have been used to improve the circulation time of GLP‐1 (e.g., mutations, unnatural amino acids, depot formulations, use of exendin‐4 sequences, and fusions with high‐molecular‐weight proteins or polymers), with its therapeutic utility further improved by adding agonist activity for gastric inhibitory peptide and glucagon receptors. This minireview focuses on strategies that have been used to improve the pharmacokinetics of GLP‐1 and provides an overview of GLP‐1‐based therapeutics in the pipeline.

中文翻译:

基于胰高血糖素样肽-1(GLP-1)的疗法:2型糖尿病以外的现状和未来机遇

摄入食物后,肠L细胞分泌胰高血糖素样肽-1(GLP-1),由于其刺激葡萄糖依赖性胰岛素分泌,因此在葡萄糖稳态中起重要作用。此外,GLP-1还具有对胰腺β细胞和心血管系统的保护作用,食欲下降和体重减轻,使GLP-1衍生物成为2型糖尿病和肥胖症的激动人心的治疗方法。尽管有这些好处,但由于野生型GLP-1的代谢稳定性差和肾脏清除率很快,因此循环时间短,必须通过注射给药,使其成为不良的治疗剂。已经采用了许多策略来改善GLP-1的循环时间(例如,突变,非天然氨基酸,长效制剂,使用exendin-4序列,以及与高分子量蛋白质或聚合物的融合),通过增加针对胃抑制肽和胰高血糖素受体的激动剂活性,进一步提高了其治疗效用。这份小型回顾重点介绍了已用于改善GLP-1药代动力学的策略,并概述了即将推出的基于GLP-1的疗法。
更新日期:2018-02-28
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