A new GLP-1 analogue with prolonged glucose-lowering activity in vivo via backbone-based modification at the N-terminus. Issue 6 (15th March 2016)

• Record Type: Journal Article
• Authors: Bai, Xiaohui; Niu, Youhong; Zhu, Jingjing; Yang, An-Qi; Wu, Yan-Fen; Ye, Xin-Shan
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 6(2016)
• Page Start: 1163
• Page End: 1170
• Publication Date: 2016-03-15
• Subjects: 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-ethanedithiol -- DIPEA N, N-diisopropylethylamine -- HATU 2-(7-aza-1H-benzotriazole-1-yl)-1, 1, 3, 3-tetramethyluronium hexafluorophosphate; GLP-1 analogues -- N-terminus modifications of GLP-1 -- Amide N-methylation -- β-Peptide -- Drug design; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.01.036
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: GLP-1 analogue10 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, which will benefit the development of GLP-1-based anti-diabetic drugs. 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 analogues2 –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 analogues7 –13 were synthesized. By two rounds of screening, analogue10 was identified. Analogue10 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.