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

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Endocrinology

Background:

• Peptide therapeutics face limitations due to rapid proteolysis and short half-lives.
• Azapeptides, modified peptides with nitrogen substitutions, offer improved stability while retaining function.
• Clinical potential of azapeptides, particularly for metabolic diseases, remains largely unexplored.

Purpose of the Study:

• To design, synthesize, and evaluate azapeptide-based glucagon-like peptide-1 receptor agonists (GLP-1RAs).
• To assess the stability, potency, and in vivo efficacy of azapeptide GLP-1RAs in preclinical models of metabolic dysfunction.

Main Methods:

• Solid-phase synthesis was employed to generate GLP-1 analogues with aza-substitutions.
• In vitro assays assessed dipeptidyl peptidase-4 (DPP-4) resistance and GLP-1 receptor (GLP-1R) signaling potency.
• In vivo studies in lean and diet-induced obese mice evaluated pharmacokinetic profiles, glucose tolerance, body weight, and metabolic parameters.

Main Results:

• The lead azapeptide analogue, AzaA8, demonstrated resistance to DPP-4 degradation (>24 hours) and maintained picomolar potency at the GLP-1R.
• AzaA8 exhibited an extended plasma half-life in mice compared to unmodified GLP-1.
• In vivo, AzaA8 improved glucose tolerance in lean mice and reduced body weight, decreased leptin and insulin levels, and enhanced glucose handling in obese mice without adverse inflammatory effects.

Conclusions:

• Targeted aza-substitution effectively yields protease-stable and biologically active GLP-1RAs.
• Azapeptide-based GLP-1RAs show significant metabolic benefits, including weight reduction and improved glucose control.
• Azapeptides represent a promising scaffold for developing next-generation incretin-based therapies for diabetes and obesity.