Protease-Resistant Azapeptide GLP-1 Analogue Improves Metabolic Control in Diet-Induced Obesity.

ABSTRACT: 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, in vitro and in vivo evaluations 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, AzaA⁸/R³⁴-GLP-1(AzaA8), resisted dipeptidyl peptidase-4 degradation (>24 h), maintained picomolar potency at the GLP-1 receptor (GLP-1R) signaling, a

SUBMITTER: He M 

PROVIDER: S-EPMC12632547 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature