Disaggregation of Islet Amyloid Polypeptide Fibrils as a Potential Anti-Fibrillation Mechanism of Tetrapeptide TNGQ

International Journal of Molecular Sciences

Ogadimma D. Okagu¹  Raliat O. Abioye¹  Chibuike C. Udenigwe¹ 

[1] Department of Chemistry and Biomolecular Sciences, Faculty of Science, University of Ottawa, Ottawa, ON K1N 6N5, Canada;

关键词: islet amyloid polypeptide;    aggregation;    disaggregation;    fibril formation;    bioactive peptides;    biomolecular interaction;   

DOI  :  10.3390/ijms23041972

来源: DOAJ

【 摘 要 】

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, we identified three tetrapeptides, TNGQ, MANT, and YMSV, that inhibited IAPP fibrillation. Using thioflavin T (ThT) fluorescence assay, circular dichroism (CD) spectroscopy, dynamic light scattering (DLS), and molecular docking, we evaluated the potential anti-fibrillation mechanism of the tetrapeptides. 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. 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 TNGQ and MANT interact with monomeric IAPP mainly by hydrogen bonding and electrostatic interaction, with TNGQ binding at IAPP surface compared to YMSV, which had the highest docking score, but interact mainly through hydrophobic interaction in IAPP core. The highly polar TNGQ was the most active and appeared to inhibit IAPP fibrillation by disaggregation of preformed IAPP fibrils. These findings indicate the potential of TNGQ in the development of peptide-based anti-fibrillation and antidiabetic nutraceuticals.

【 授权许可】

Unknown