α/Sulfono-γ-AApeptide Hybrid Analogues of Glucagon with Enhanced Stability and Prolonged In Vivo Activity

Peptide
drugs have the advantages of target specificity and good
drugability and have become one of the most increasingly important
hotspots in new drug research in biomedical sciences. However, peptide
drugs generally have low bioavailability and metabolic stability,
and therefore, the modification of existing peptide drugs for the
purpose of improving stability and retaining activity is of viable
importance. It is known that glucagon is an effective therapy for
treating severe hypoglycemia, but its short half-life prevents its
wide therapeutic use. Herein, we report that combined unnatural residues
and long fatty acid conjugation afford potent α/sulfono-γ-AApeptide
hybrid analogues of Glucagon with enhanced stability and prolonged
in vivo activity. This strategy could be adopted to develop stabilized
analogues of other short-acting bioactive peptides.