Novel small molecules targeting the intrinsically disordered structural ensemble of α-Synuclein protect against diverse α-Synuclein mediated dysfunctions

The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson’s disease. Native monomeric αSyn 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 αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn. Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson’s disease.Fil: Tóth, Gergely. Elan Pharmaceuticals; Estados Unidos. University of Cambridge; Estados Unidos. Hungarian Academy of Sciences; Hungría. Cantabio Pharmaceuticals; Estados UnidosFil: Neumann, Thomas. NovAliX; FranciaFil: Berthet, Amandine. Gladstone Institute of Neurological Disease; Estados UnidosFil: Masliah, Eliezer. University of California at San Diego; Estados Unidos. National Institutes of Health; Estados UnidosFil: Spencer, Brian. University of California at San Diego; Estados UnidosFil: Tao, Jiahui. University of California; Estados UnidosFil: Jobling, Michael F.. Elan Pharmaceuticals; Estados UnidosFil: Gardai, Shyra J.. Elan Pharmaceuticals; Estados UnidosFil: Bertoncini, Carlos Walter. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina. University of Cambridge; Reino Unido. Institute for Research in Biomedicine; EspañaFil: Cremades, Nunilo. University of Cambridge; Reino UnidoFil: Bova, Michael. Elan Pharmaceuticals; Estados UnidosFil: Ballaron, Stephen. Elan Pharmaceuticals; Estados UnidosFil: Chen, Xiao-Hua. Elan Pharmaceuticals; Estados UnidosFil: Mao, Wenxian. Elan Pharmaceuticals; Estados UnidosFil: Nguyen, Phuong. University of California; Estados UnidosFil: Tabios, Mariano C.. University of California; Estados UnidosFil: Tambe, Mitali A.. Purdue University; Estados UnidosFil: Rochet, Jean Christophe. Purdue University; Estados UnidosFil: Junker, Hans Dieter. Aalen University; Alemania. NovAliX; FranciaFil: Schwizer, Daniel. NovAliX; FranciaFil: Sekul, Renate. NovAliX; FranciaFil: Ott, Inge. NovAliX; FranciaFil: Anderson, John P.. Elan Pharmaceuticals; Estados UnidosFil: Szoke, Balazs. Elan Pharmaceuticals; Estados UnidosFil: Hoffman, Wherly. Elan Pharmaceuticals; Estados UnidosFil: Christodoulou, John. Colegio Universitario de Londres; Reino UnidoFil: Yednock, Ted. Elan Pharmaceuticals; Estados UnidosFil: Agard, David A.. University of California; Estados UnidosFil: Schenk, Dale. Elan Pharmaceuticals; Estados UnidosFil: McConlogue, Lisa. Elan Pharmaceuticals; Estados Unidos. Gladstone Institute of Neurological Disease; Estados Unidos. University of California; Estados Unido