Lacmoid-Induced Conformational Changes Inhibit Fibrillation of Human Islet Amyloid Polypeptide

Abstract

Type 2 diabetes is a devastating metabolic disorder affecting millions of people worldwide. Deposition of amyloid formed by human islet amyloid polypeptide (IAPP) around pancreatic β-cells is one of the possible causes of the disease. IAPP is a 37-residue peptide expressed by the pancreatic β-cells and cosecreted with insulin, and its misfolding and aggregation into toxic amyloid fibrils are closely linked to β-cell dysfunction. Herein, it is demonstrated that lacmoid effectively inhibits IAPP fibrillation and disaggregates preformed fibrils. Thioflavin T fluorescence in combination with morphological analysis by atomic force microscopy and transmission electron microscopy confirms complete inhibition and disaggregation of IAPP fibrillation at equimolar concentrations of lacmoid. Additionally, circular dichroism and Fourier transform infrared spectroscopy reveal significant changes in the secondary structure of IAPP during fibrillation in the presence of lacmoid. Cytotoxicity assay in U2OS cells show that lacmoid reduces IAPP fibril-induced toxicity. Molecular docking studies further reveal that the Asn14 residue of IAPP plays a critical role in its interaction with lacmoid. The findings collectively highlight the importance of lacmoid as an inhibitor of IAPP fibrillation which may have potential to develop as a drug candidate for the treatment of type 2 diabetes.