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

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