bioRxiv : the preprint server for biologyNov 24, 2025

Stable GLP-1-like Peptide Improves Metabolism in Diet-Induced Obesity

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

A protease-resistant azapeptide GLP-1 analogue preserved GLP-1 receptor activity and improved metabolic measures in obese mice.

Evidence

This peptide design, in vitro, and mouse preclinical study synthesized aza-substituted GLP-1 analogues, with AzaA8 resisting DPP-4 degradation for more than 24 hours and improving glucose tolerance, body weight, leptin, and insulin outcomes in lean and diet-induced obese mice.

Caveat

The metabolic benefits were shown in mice and early platform assays, not in human diabetes or obesity trials.

Simplified

Peptide therapeutics are limited by rapid proteolysis and short half-lives. Azapeptides, created by replacing one or more α-carbon(s) on the peptide backbone with nitrogen atom(s), offer a strategy to improve peptide stability while preserving functional efficiency, yet their clinical potential has remained underexplored. Herein, we report the design, synthesis,andevaluations of azapeptide-based glucagon-like peptide-1 receptor agonists (GLP-1RAs). Using a solid-phase synthesis platform, we generated GLP-1 analogues with aza-substitutions at protease-sensitive residues. The lead analogue, AzaA/R-GLP-1(AzaA8), resisted dipeptidyl peptidase-4 degradation (>24 h), maintained picomolar potency at the GLP-1 receptor (GLP-1R) signaling, and exhibited an extended plasma half-life in mice relative to unmodified controls. In lean mice, AzaA8 improved oral glucose tolerance, and in high-fat diet-induced obese mice, chronic administration reduced body weight, decreased leptin and insulin levels, and enhanced glucose handling without detectable inflammatory adverse effects. These findings demonstrate that a targeted aza-substitution yields a protease-stable, biologically active GLP-1RA with metabolic benefits, establishing azapeptides as a promising scaffold for next-generation incretin-based therapies in diabetes and obesity. in vitro in vivo8 34

Funding

Competing interests

No competing interests reported.

PubMed

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Stable GLP-1-like Peptide Improves Metabolism in Diet-Induced Obesity

Abstract

Funding

Competing interests

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Abstract

Funding

Competing interests

Related papers

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