The anti-diabetic drug acarbose modulates the nucleation dependent amyloid fibrillation of wild-type α-synuclein.

Parkinson's disease (PD) is a prevalent, age-associated neurodegenerative disorder characterized by the loss of dopaminergic neurons and the accumulation of intracellular Lewy bodies, primarily composed of aggregated α-synuclein protein. In the present study we have examined Acarbose, an anti-diabetic drug, as a potential structure-based inhibitor of α-synuclein aggregation to advance therapeutic strategies for synucleinopathies. Using an integrated computational and experimental approach, we demonstrate that acarbose binds to key amyloidogenic residues within the amyloid core of α-synuclein, disrupting native hydrogen bonds, reduces β-sheet propensity and stabilizes the protein in an extended, aggregation-resistant conformation. Acarbose significantly affects α-synuclein fibrillation, substantiated by reducing the Thioflavin T fluorescence by 67.29%, 81.13%, and 90.36% at 20, 60, and 100 µM concentrations, respectively. The dose dependent increase in lag phase of amyloid fibrillation kinetics in presence of Acarbose further suggests that it interferes with the primary nucleation event. Further structural characterization using CD spectroscopy, high-end microscopy and dynamic light scattering confirmed that Acarbose inhibits the structural transitions of the protein into mature cross-β-sheet-rich amyloid fibrils. Collectively, these results establish the strong potential of Acarbose for repurposing against Parkinson's disease. Its targeted modulation of α-synuclein aggregation also positions it as a promising scaffold for the design of next-generation amyloid inhibitors.