Formation of cyclic structure at amino-terminus of glucagon-like peptide-1 exhibited a prolonged half-life in vivo

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• 作者：Zhenghong Cao^a ; ¹ ; Ying Li^c ; ¹ ; Lida Tang^d ; Weiren Xu^d ; Changxiao Liu^d ; Jianning Zhang^c ; ; Min Gong^b ; ^d ; ^{gongm@tjipr.com}
• 关键词：GLP-1 analogs ; Cyclic conformation ; Long-acting GLP-1 ; Insulin stimulation ; HbA1c
• 刊名：Diabetes Research and Clinical Practice
• 出版年：2012
• 期刊代码：78_01688227
• 类别：med
• 出版时间：June, 2012
• 卷：96
• 期：3
• 页码：362-370
• 文件大小：346 K

摘要

The multiple physiological characterizations of glucagon-like peptide-1 (GLP-1) make it a promising drug candidate for the therapy of type 2 diabetes. However, the biological half-life of GLP-1 is short in vivo due to degradation by dipeptidyl peptidase-IV (DPP-IV) and renal clearance. The stabilization of GLP-1 is critical for its utility in drug development. In this study, several GLP-1 mutants containing an N-terminal cyclic conformation were prepared in that the existence of cyclic conformation is predicted to increase the stabilization of GLP-1 in vivo. In this study, the binding capacities of the mutants were determined, the stabilities of the mutants were investigated and the physiological functions of the mutants were compared with those of wild-type GLP-1 in animals. The results indicated that the mutant (GLP1N8) remarkably raised the half-life in vivo; it also showed better glucose tolerance and higher HbA_1c reduction than GLP-1 and exendin-4 in rodents. These results suggest that the GLP-1 analog (GLP1N8) which contains an N-terminal cyclic structure might be utilized as possible potent anti-diabetic drugs in the treatment of type 2 diabetes mellitus.