Dataset Information

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

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.

SUBMITTER: Fremaux J

PROVIDER: S-EPMC6389962 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Fremaux Juliette J Venin Claire C Mauran Laura L Zimmer Robert H RH Guichard Gilles G Goudreau Sébastien R SR

Nature communications 20190225 1

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 pept ...[more]

PMID: 30804332

Similar Datasets

Project description:BackgroundExtracellular matrix proliferation is an issue which leads to lung tissue damage in diabetes mellitus. Glucagon-like peptide-1 (GLP-1) analogues can improve the proliferation of extracellular matrix in diabetic pulmonary disease. In this study, we investigated the effect of GLP-1 on pulmonary fibrosis through the AMPK/microRNA-27a (miR-27a) pathway.MethodsHuman embryonic lung fibroblast (MRC-5) cells were cultured with a high-glucose medium, and were treated with miR-27a inhibitor, GLP-1 analogues, and AMPK inhibitor. Cell Counting Kit-8 (CCK-8) detected the proliferation of MRC-5 cells. The fibrosis-related genes were analyzed, including Col-IV, fibronectin, NF-κB p65, α-SMA, and TGF-β1. Bioinformatics and dual-luciferase reporter assays were used to identify the targets for miR-27a.ResultsCompared with the control group, the expression of miR-27a in the hyperglycemic group was significantly up-regulated (P<0.01) and the expression of peroxisome proliferator-activated receptor γ (PPARγ) significantly down-regulated (P<0.01). The expression of Col-IV, fibronectin, NF-κB p65, α-SMA and TGF-β1 increased significantly (P<0.01). The expression level of apoptosis factor caspase-3 decreased significantly (P<0.01). MiR-27a inhibitor could reverse the expression of these proteins. The effect of GLP-1 on miR-27a was time- and concentration-dependent. After pretreating MRC-5 cells via GLP-1, with or without compound C (AMPK inhibitor), the expression of miR-27a in the GLP-1 treated group was significantly lower than that in Vehicle group. The expression of miR-27a was increased after inhibition of the AMPK pathway. A predictive TargetScan algorithm showed that the PPARγ gene was a potential target of miR-27a. MiR-27a was also shown to target 3'-UTR of PPARγ.ConclusionsMiR-27a plays an important regulatory role in diabetic pulmonary fibrosis. GLP-1 could down-regulate the expression level of miR-27a by activating AMPK. Furthermore, the target gene PPARγ was up-regulated, consequently improving extracellular matrix proliferation in MRC-5 cells.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets