Effect and mechanism of oritavancin on hIAPP amyloid formation†

Abstract

Amyloidosis of the human islet amyloid polypeptide (hIAPP) is closely related to the pathogenesis of type 2 diabetes (T2D) and serves as both a diagnostic hallmark and a key therapeutic target for T2D. In this study, we discovered that oritavancin (Ori), a glycopeptide antibiotic primarily prescribed for Gram-positive bacterial infections, can dose-dependently inhibit recombinant hIAPP (rhIAPP) amyloid formation. Ori specifically inhibited rhIAPP amyloid formation at the initial nucleation stage but didn’t affect mature rhIAPP fibrils. As a result, Ori reduced amyloidosis of rhIAPP induced pancreatic NIT-1 cell apoptosis and reactive oxygen species (ROS) release. Based on the results from studies involving antibiotic homologues of Ori and its acid hydrolysates, we demonstrated that both the N-(4-chlorobiphenyl) methyl group (CBP) and glycopeptide backbone were necessary for inhibiting rhIAPP amyloid formation. The mechanism behind Ori on rhIAPP amyloid formation lies in the direct interaction of the two molecules identified by ESI-MS and molecular docking assays. Consequently, this research not only lays the groundwork for developing novel therapeutic approaches for T2D but also presents the opportunity to repurpose Ori as a treatment option.