title: A new GLP-1 analogue with prolonged glucose-lowering activity in vivo via backbone-based modification at the N-terminus.
abstract: 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.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd No. 38, Beijing 100191, PR China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Bai
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd No. 38, Beijing 100191, PR China.
authors.forename: Youhong
authors.initials: Y
authors.lastname: Niu
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd No. 38, Beijing 100191, PR China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd No. 38, Beijing 100191, PR China.
authors.forename: An-Qi
authors.initials: AQ
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd No. 38, Beijing 100191, PR China. Electronic address: wuyanfen@pku.edu.cn.
authors.forename: Yan-Fen
authors.initials: YF
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd No. 38, Beijing 100191, PR China. Electronic address: xinshan@bjmu.edu.cn.
authors.forename: Xin-Shan
authors.initials: XS
authors.lastname: Ye
mesh_terms: D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D052216:Glucagon-Like Peptide 1
keywords: Amide N-methylation; Drug design; GLP-1 analogues; N-terminus modifications of GLP-1; β-Peptide