Open AccessIdentifying Phlorofucofuroeckol-A as a Dual Inhibitor of Amyloid-β25-35 Self-Aggregation and Insulin Glycation: Elucidation of the Molecular Mechanism of Action
Author(s) -
Su Hui Seong,
Pradeep Paudel,
Hyun Ah Jung,
Jae Sue Choi
Publication year - 2019
Publication title -
marine drugs
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.848
H-Index - 110
ISSN - 1660-3397
DOI - 10.3390/md17110600
Subject(s) - glycation , insulin , chemistry , biochemistry , insulin receptor , insulin degrading enzyme , thioflavin , amyloid (mycology) , docking (animal) , pharmacology , alzheimer's disease , insulin resistance , medicine , enzyme , receptor , biology , disease , inorganic chemistry , nursing
Both amyloid-β (Aβ) and insulin are amyloidogenic peptides, and they play a critical role in Alzheimer's disease (AD) and type-2 diabetes (T2D). Misfolded or aggregated Aβ and glycated insulin are commonly found in AD and T2D patients, respectively, and exhibit neurotoxicity and oxidative stress. The present study examined the anti-Aβ 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 Aβ 25-35 self-assembly. Molecular docking and dynamic simulation analyses confirmed that these phlorotannins have a strong potential to interact with Aβ 25-35 peptides and interrupt their self-assembly and conformational transformation, thereby inhibiting Aβ 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 β-sheet rich structures in Aβ 25-35 and advanced glycation end-products (AGEs) in insulin.