Novel Small Molecules Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein Protect Against Diverse α-Synuclein Mediated Dysfunctions

Abstract

The over-expression and aggregation of -synuclein (Syn) are linked to the onset and pathology of Parkinsons disease. Native monomeric Syn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of Syn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric Syn is incubated with microchips arrayed with tethered compounds, we identified novel Syn interacting drug-like compounds. Because these small molecules could impact a variety of Syn forms present in the ensemble, we tested representative hits for impact on multiple Syn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits Syn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by Syn overexpression, and a compound blocking cellular transmission of Syn. Our studies demonstrate that drug-like small molecules that interact with native Syn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of Syn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinsons disease.