Isobavachalcone inhibits α-synuclein fibrillogenesis and its Parkinson's disease variants, disassembles the mature fibrils and alleviates cellular toxicity.

The accumulation of α-Synuclein (α-Syn) aggregates into neuronal inclusions is a hallmark of Parkinson's disease (PD), making α-Syn a key target for PD therapeutics. Here, we demonstrate that the chalcone compound isobavachalcone (IBC) inhibits α-Syn aggregation and remodels mature fibrils into fragmented filaments. IBC exhibits dose-dependent inhibition of wild-type α-Syn and PD-linked mutants (E46K, H50Q, G51D and A53T) while effectively abrogating seeded fibrillization. Biophysical characterization using circular dichroism (CD), transmission electron microscopy (TEM), dynamic light scattering (DLS), and nuclear magnetic resonance (NMR) revealed that IBC prevents the formation of β-sheet-enriched α-Syn aggregates. In silico docking suggests that IBC binds to the protofilament interface, blocking aggregation. Additionally, IBC disassembles α-Syn fibrils into fragmented filaments and mitigates α-Syn-induced cytotoxicity in CCK-8 cell viability assays. Our findings establish IBC as a chalcone-based molecule capable of binding α-Syn and remodeling its fibrillogenesis, providing a potential molecular template for developing PD inhibitors targeting α-Syn aggregation.