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

Bioorganic & Medicinal Chemistry
Xiaohui BaiXin-Shan Ye

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.

References

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May 15, 2007·Gastroenterology·Laurie L Baggio, Daniel J Drucker
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Oct 30, 2014·Expert Opinion on Drug Safety·Anthony H Barnett

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Citations

Nov 5, 2016·Journal of the American Chemical Society·Marlies V HagerSamuel H Gellman
Jun 7, 2019·Chembiochem : a European Journal of Chemical Biology·Brian P CarySamuel H Gellman
Mar 18, 2020·Chembiochem : a European Journal of Chemical Biology·Amila TuralićTamás A Martinek
May 24, 2019·The Journal of Organic Chemistry·Carlos J SaavedraAlicia Boto

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