2. Academic Validation
  3. Protease-Resistant Azapeptide GLP-1 Analogue Improves Metabolic Control in Diet-Induced Obesity

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

  • bioRxiv. 2025 Nov 18:2025.05.09.653092. doi: 10.1101/2025.05.09.653092.
Mingzhu He 1,  Kai Fan Cheng 1,  Sonya VanPatten 1,  Marcelo D T Torres 2 3 4 5,  Bayan Al Jabari 1,  Ibrahim T Mughrabi 6,  Borja Ballarín-González 7,  Myoungsun Son 8,  Cesar de la Fuente-Nunez 2 3 4 5,  Yousef Al-Abed 1 6 9
Affiliations

Affiliations

  • 1 The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA.
  • 2 Machine Biology Group, Departments of Psychiatry and Microbiology, Institute for Biomedical Informatics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 3 Departments of Bioengineering and Chemical and Biomolecular Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA.
  • 4 Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA.
  • 5 Penn Institute for Computational Science, University of Pennsylvania, Philadelphia, PA, USA.
  • 6 Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY USA.
  • 7 Novo Nordisk A/S, Måløv, Denmark.
  • 8 Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA.
  • 9 Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Northwell Health, Hempstead, NY, USA.
PMID: 41278761 DOI: 10.1101/2025.05.09.653092
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, 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.

Keywords

GLP-1 receptor agonist (GLP-1RA); azapeptide; high-fat diet-induced obesity (HF-DIO).

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