Identifying Phlorofucofuroeckol-A as a Dual Inhibitor of Amyloid-?25-35 Self-Aggregation and Insulin Glycation: Elucidation of the Molecular Mechanism of Action.

ABSTRACT: Both amyloid-? (A?) and insulin are amyloidogenic peptides, and they play a critical role in Alzheimer's disease (AD) and type-2 diabetes (T2D). Misfolded or aggregated A? and glycated insulin are commonly found in AD and T2D patients, respectively, and exhibit neurotoxicity and oxidative stress. The present study examined the anti-A?25-35 aggregation and anti-insulin glycation activities of five phlorotannins isolated from Ecklonia stolonifera. Thioflavin-T assay results suggest that eckol, dioxinodehydroeckol, dieckol, and phlorofucofuroeckol-A (PFFA) significantly inhibit A?25-35 self-assembly. Molecular docking and dynamic simulation analyses confirmed that these phlorotannins have a strong potential to interact with A?25-35 peptides and interrupt their self-assembly and conformational transformation, thereby inhibiting A?25-35 aggregation. In addition, PFFA dose-dependently inhibited d-ribose and d-glucose induced non-enzymatic insulin glycation. To understand the molecular mechanism for insulin glycation and its inhibition, we predicted the binding site of PFFA in insulin via computational analysis. Interestingly, PFFA strongly interacted with the Phe1 in insulin chain-B, and this interaction could block d-glucose access to the glycation site of insulin. Taken together, our novel findings suggest that phlorofucofuroeckol-A could be a new scaffold for AD treatment by inhibiting the formation of ?-sheet rich structures in A?25-35 and advanced glycation end-products (AGEs) in insulin.

SUBMITTER: Seong SH 

PROVIDER: S-EPMC6891666 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature