Inhibitory Activity of Red Panda Islet Amyloid Polypeptide on Human IAPP Aggregation

Human islet amyloid polypeptide (hIAPP), a 37-residue hormone co-secreted with insulin from pancreatic β-cells, undergoes self-assembly into cytotoxic amyloid fibrils in the pathogenesis of type 2 diabetes (T2D). The resulting islet amyloid deposits are implicated in progressive β-cell dysfunction and loss, making hIAPP aggregation an attractive therapeutic target. Nonhuman islet amyloid polypeptide (IAPP) orthologs have recently emerged as a valuable source of mechanistic insight, with several variants-including raccoon and chicken IAPPs-demonstrating the capacity to inhibit hIAPP fibril formation. Here, the biophysical characterization of red panda (Ailurus fulgens) IAPP (rpIAPP) and its effects on hIAPP aggregation are reported. Using thioflavin T fluorescence assays, circular dichroism spectroscopy, and atomic force microscopy, red panda IAPP is found to inhibit hIAPP fibrillation at substoichiometric concentrations, with significant inhibitory activity observed at molar ratios as low as 1:0.5 (hIAPP:rpIAPP). These results position red panda IAPP as one of the more potent nonhuman IAPP inhibitors characterized to date and support its further evaluation as a scaffold for the rational design of peptide-based therapeutics targeting T2D-associated amyloidogenesis.