Flavonoids with Vicinal Hydroxyl Groups Inhibit Human Calcitonin Amyloid Formation.

Human calcitonin (hCT) is a 32-residue peptide hormone that can aggregate into amyloid fibrils and cause cellular toxicity. In this study, we investigated the inhibition effects of a group of polyphenolic molecules on hCT amyloid formation. Our results suggest that the gallate moiety in epigallocatechin-3-gallate (EGCG), a well-recognized amyloid inhibitor, is not critical for its inhibition activity of the hCT amyloid formation. Our results demonstrate that the flavonoid compounds such as myricetin, quercetin, and baicalein that contain vicinal hydroxyl groups on the phenyl ring effectively prevent hCT fibrillization. This structural feature can also be applied to non-flavonoid polyphenolic inhibitors. Moreover, our results indicate a plausible mechanistic role of these vicinal hydroxyl groups which might include the oxidation to form a quinone and the subsequent Schiff base formation with the lysine or histidine residues of hCT. This may further disrupt the crucial electrostatic and aromatic interactions involved in the process of hCT amyloid fibril formation. The inhibition activity of the polyphenolic compounds against hCT fibril formation may likely be attributed to a combination of factors such as Schiff base formation, aromatic stacking, and hydrogen bonding interactions.