A new GLP-1 analogue with prolonged glucose-lowering activity in vivo via backbone-based modification at the N-terminus

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• 作者：Xiaohui Bai^&dagger ; ; Youhong Niu^&dagger ; ; Jingjing Zhu ; An-Qi Yang ; Yan-Fen Wu ; ^{wuyanfen@pku.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Xin-Shan Ye ; ^{xinshan@bjmu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：GLP-1 ; glucagon-like peptide-1 ; DPP-IV ; dipeptidyl peptidase IV ; NEP ; neutral endopeptidase ; His ; histidine ; Thr ; threonine ; Val ; valine ; GLP-1R ; GLP-1 receptor ; Ala ; alanine ; Aha ; 6-amino-hexanoic acid ; DCM ; dichloromethane ; DMF ; dimethylformamide ; EA ; ethyl acetate ; PE ; petroleum ether ; Me ; methyl ; Fmoc ; 9-fluorenylmethoxycarbonyl ; AA ; amino acid ; HoAt ; 1-hydroxy-7-azabenzotriazole ; NMM ; 4-methylmorpholine ; NMP ; N-methyl-2-pyrrolidone ; Trt ; triphenylmethyl ; TFA ; trifluoroacetic acid ; EDT ; 1 ; 2-
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 March 2016
• 年：2016
• 卷：24
• 期：6
• 页码：1163-1170
• 全文大小：1270 K

文摘

Glucagon-like peptide-1 (GLP-1) is an endogenous insulinotropic hormone with wonderful glucose-lowering activity. However, its clinical use in type II diabetes is limited due to its rapid degradation at the N-terminus by dipeptidyl peptidase IV (DPP-IV). Among the N-terminal modifications of GLP-1, backbone-based modification was rarely reported. Herein, we employed two backbone-based strategies to modify the N-terminus of tGLP-1. Firstly, the amide N-methylated analogues 2–6 were designed and synthesized to make a full screening of the N-terminal amide bonds, and the loss of GLP-1 receptor (GLP-1R) activation indicated the importance of amide H-bonds. Secondly, with retaining the N-terminal amide H-bonds, the β-peptide replacement strategy was used and analogues 7–13 were synthesized. By two rounds of screening, analogue 10 was identified. Analogue 10 greatly improved the DPP-IV resistance with maintaining good GLP-1R activation in vitro, and showed approximately a 4-fold prolonged blood glucose-lowering activity in vivo in comparison with tGLP-1. This modification strategy will benefit the development of GLP-1-based anti-diabetic drugs.