O-glycosylated peptides curtail the aggregation and toxicity of human islet amyloid polypeptide

A key pathogenetic pathway of type 2 diabetes (T2D) is pancreatic beta cell failure, losing their capability of producing insulin and regulating blood glucose. Accumulated evidence has demonstrated that the elevated aggregations of human islet amyloid polypeptide (hIAPP), consisting of soluble oligomers and insoluble fibrils, contribute to the beta cell dysfunction and loss. In this work, a focused library of O-glycosylated peptides was designed to target hIAPP monomers. An N-acetylglucosamine modified peptide, S^NS, was identified as the most effective inhibitor against hIAPP fibrillation in this library. S^NS treatment in beta cells and isolated mouse islets suppressed the hIAPP-induced oxidative stress, cytotoxicity and apoptosis, resulting in beta cell protection and preservation of islet function. Therefore, these results suggest that O-glycosylated strategy will pave a new way for the design of peptide-based antagonists, and shed light on the creation of novel therapeutics for amyloid-related disease.