Molecular Mechanisms Underlying The Flavonoid-induced Inhibition of α-synuclein Fibrillation

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Flavonoids, Inhibition, Monomers, Oxidation, Peptides, Proteins

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The molecular mechanism underlying the flavonoid-induced inhibition of α-synuclein fibrillation was thoroughly examined by various biochemical and biophysical approaches. The noncovalent binding of the inhibitory flavonoids to α-synuclein and the covalent modification by the flavonoid quinone led to the restriction of the conformational changes in this natively unfolded protein and to the stabilization of soluble flavonoid-modified species of α-synuclein (monomers and oligomers). All of these factors rather than a single one contribute to the inhibition of WT α-synuclein fibrillation induced by the flavonoid. The structural requirements that appear necessary to provide a flavonoid the ability to inhibit α-synuclein fibrillation were determined to be vicinal dihydroxyphenyl moieties, irrespective of the ring position where they are located. Flavonoids with three vicinal hydroxyl groups exhibited enhanced inhibitory effects on α-synuclein fibrillation. The antioxidant activities of flavonoids were generally correlated with their in vitro inhibitory effects on α-synuclein fibrillation. The flavonoids inhibiting α-synuclein fibrillation and stabilizing the protein monomeric conformation can serve as a model for the development of therapeutic drugs in combating Parkinson’s disease.

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Biochemistry, v. 48, issue 34, p. 8206-8224