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Quercetin and baicalein act as a potent anti-amyloidogenic and fibril destabilizing agents for SOD1 fibrils.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that has been associated with the deposition of aggregates of superoxide dismutase 1 (SOD1). Effective therapeutics against SOD1 fibrillation is still an area of active research. Herein, we demonstrate the potential of two naturally occurring flavonoids (quercetin and baicalein) to inhibit fibrillation of wild type SOD1 with the aid of series of biophysical techniques. Our seeding experiments reveal that both these flavonoids significantly affect the fibril elongation. Interestingly, our ThT binding assay, TEM and SDS PAGE experiments suggest that these flavonoids also disintegrate the fibrils into shorter fragments but does not completely depolymerize them into monomers. Binding parameters obtained from UV-Vis suggest that these flavonoids bind moderately to native SOD1 dimer and have different binding sites. Docking of these flavonoids with non- native monomer, non-native trimer and oligomer derived from 11 residues segment of SOD1 indicate that both quercetin and baicalein can bind to these species and thus, can arrest the elongation of fibrils by blocking the fibrillar core regions on the intermediate species formed during aggregation of SOD1. MTT assay data revealed that both the flavonoids reduced the cytotoxicity of SOD1 fibrils. Experimental data also show the anti-amyloidogenic potential of both the flavonoids against A4V SOD1 mutant fibrillation. Thus, our findings may provide a direction for designing effective therapeutic agents against ALS which can act as promising anti-amyloidogenic and fibril destabilizing agents.