Peptidomimetics, synthetically modified peptides which have been engineered to eliminate certain undesirable features of native therapeutic peptides including short half-lives, immunogenicity, and delivery challenges, are a growing class of peptide-based therapeutics. Azapeptides (C to N substitution(s)), a type of peptidomimetic with several examples in clinical use, are known to exhibit increased resistance to endogenous proteases, extending plasma half-life, while potentially retaining or enhancing biological activities and therefore therapeutic efficacy. Previously, we have developed a unique synthesis platform that enables rapid and efficient solid-phase synthesis of custom azapeptides using standard peptide synthesizer technology. To test the capabilities of our azapeptide synthesis platform for a therapeutically relevant peptide of longer length, we designed and synthesized several 31 amino-acid long analogs with aza-amino acid substitutions at critical sites of semaglutide, a popular type 2 diabetes and weight loss, glucagon-like peptide-1 (GLP-1) receptor agonist. The leading receptor agonist analogue (AzaA8/R34-GLP-1) was identified based on its protease resistance, ex vivo whole blood stability, in vitro receptor potency (cAMP signaling), and efficacy in a high fat diet-induced obesity murine model. This AzaGLP-1 analogue displays significant biological activity and therapeutic efficacy on glucose metabolism which demonstrates its potential for further development as a therapeutic agent.
