Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein by Small Molecules as a Potential Therapeutic Strategy for Parkinson's Disease

The misfolding of intrinsically disordered proteins such as alpha-synuclein, tau and the A beta peptide has been associated with many highly debilitating neurodegenerative syndromes including Parkinson's and Alzheimer's diseases. Therapeutic targeting of the monomeric state of such intrinsically disordered proteins by small molecules has, however, been a major challenge because of their heterogeneous conformational properties. We show here that a combination of computational and experimental techniques has led to the identification of a drug-like phenyl-sulfonamide compound (ELN484228), that targets alpha-synuclein, a key protein in Parkinson's disease. We found that this compound has substantial biological activity in cellular models of alpha-synuclein-mediated dysfunction, including rescue of alpha-synuclein-induced disruption of vesicle trafficking and dopaminergic neuronal loss and neurite retraction most likely by reducing the amount of alpha-synuclein targeted to sites of vesicle mobilization such as the synapse in neurons or the site of bead engulfment in microglial cells. These results indicate that targeting alpha-synuclein by small molecules represents a promising approach to the development of therapeutic treatments of Parkinson's disease and related conditions.