Disaggregation of islet amyloid polypeptide fibrils as a potential anti-fibrillation mechanism of tetrapeptide TNGQ

Abstract

Islet amyloid polypeptide (IAPP) fibrillation has been commonly associated with the exacerbation of type 2 diabetes prognosis. Consequently, inhibition of IAPP fibrillation to minimize β-cell cytotoxicity is an important approach towards β-cell preservation and type 2 diabetes management. In this study, three tetrapeptides, TNGQ, MANT, and YMSV, were identified as potential IAPP fibrillation inhibitors. The potential anti-fibrillation mechanisms of these tetrapeptides were monitored using thioflavin T (ThT) fluorescence assay, circular dichroism (CD) spectroscopy, dynamic light scattering (DLS) and molecular docking. ThT fluorescence kinetics and microscopy, as well as transmission electron microscopy, showed that TNGQ was the most effective inhibitor based on the absence of normal IAPP fibrillar morphology and alluded to its IAPP fibrillar disaggregatory potential. CD spectroscopy showed that TNGQ maintained the α-helical conformation of monomeric IAPP, while DLS confirmed the presence of varying fibrillation species. Molecular docking showed that interactions between TNGQ and MANT and monomeric IAPP favoured hydrogen bonding and electrostatic interactions. Furthermore, TNGQ bound at the IAPP surface, unlike YMSV, which had the highest docking score but interact mainly through hydrophobic interactions in the IAPP core. These findings indicate the potential of TNGQ in the development of peptide-based anti-fibrillation and antidiabetic nutraceuticals.