The molecular mechanisms of the anti-amyloid effects of phenols.
Previous investigations demonstrated that various aromatic compounds, many of which are known antioxidants, inhibit amyloid fibril formation. Yet, the mechanism of action of these compounds is not fully understood and contribution of their antioxidative potency has not been addressed. In recent publications, Ono et al. (2003, 2004) studied the anti-amyloid effects of 11 phenols on each of three consecutive processes: (1) seeding (formation) of nascent fibrils, (2) elongation (extension) of the fibrils, and (3) depolymerization (destabilization) of the formed assemblies. The aim of the present study was to evaluate the molecular mechanisms that mediate the effects of the studied inhibitors on each of these processes. Hierarchical clustering analyses indicated that the studied inhibitors can be categorized into three groups: 'slightly active' inhibitors, 'highly active' inhibitors and 'selective inhibitors' that differ markedly in their effects on these three stages. Analyses of the correlations between the effects of the studied compounds on the various stages of amyloid fibril formation, and their known physicochemical properties provided novel insights on the specific role of hydrophobic and aromatic interactions as well as the antioxidative potency on the process of amyloid fibril formation and dissociation. Specifically, the hydrophobic and/or aromatic character of the compounds makes the major contribution to the anti-formation and anti-extension effects, whereas the antioxidative potency relates mostly to the promotion of destabilization.
Shoval
Hila
H
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Israel.
Lichtenberg
Dov
D
Gazit
Ehud
E
D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D003300:Copper / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008055:Lipids / Q000097:blood; D010084:Oxidation-Reduction / Q000187:drug effects; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000682:Amyloid; D000975:Antioxidants; D008055:Lipids; D010636:Phenols; D003300:Copper