Peptide-oligourea hybrids analogue of GLP-1 with improved action in vivo

Nature Communications
Juliette FremauxSébastien R Goudreau

Abstract

Peptides have gained so much attention in the last decade that they are now part of the main strategies, with small molecules and biologics, for developing new medicines. Despite substantial progress, the successful development of peptides as drugs still requires a number of limitations to be addressed, including short in vivo half-lives and poor membrane permeability. Here, we describe the use of oligourea foldamers as tool to improve the pharmaceutical properties of GLP-1, a 31 amino acid peptide hormone involved in metabolism and glycemic control. Our strategy consists in replacing four consecutive amino acids of GLP-1 by three consecutive ureido residues by capitalizing on the structural resemblance of oligourea and α-peptide helices. The efficacy of the approach is demonstrated with three GLP-1-oligourea hybrids showing prolonged activity in vivo. Our findings should enable the use of oligoureas in other peptides to improve their pharmaceutical properties and may provide new therapeutic applications.

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Citations

Jun 7, 2019·Chembiochem : a European Journal of Chemical Biology·Brian P CarySamuel H Gellman
May 23, 2020·Science Advances·Peng SangJianfeng Cai
Sep 11, 2020·Chemistry : a European Journal·Márton ZwillingerIvan Huc
Aug 26, 2019·Journal of Molecular Biology·Alejandra TomasColin Leech
Nov 8, 2019·Acta Biomaterialia·Hannah R ReeseStefano Menegatti
Dec 31, 2020·International Journal of Molecular Sciences·Anna K PuszkoAleksandra Misicka
Mar 21, 2021·Science Advances·Johanne MbiandaFrançoise Ochsenbein
Sep 18, 2020·Accounts of Chemical Research·Peng SangJianfeng Cai
Apr 4, 2020·Molecular Pharmaceutics·Wencheng SuPeijian Zou
Aug 28, 2021·International Journal of Pharmaceutics·Huanbo TanPeijian Zou

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Methods Mentioned

BETA
three hybrids

Software Mentioned

GraphPad Prism

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