@article{TothNeumannBerthetetal.2019,
  author    = {Gergely T{\´o}th and Thomas Neumann and Amandine Berthet and Eliezer Masliah and Brian Spencer and Jiahui Tao and Michael Jobling and Shyra Gardai and Carlos Bertoncini and Nunilo Cremades and Michael Bova and Stephen Ballaron and Xiao-Hua Chen and Wenxian Mao and Phuong Nguyen and Mariano Tabios and Mitali Tambe and Jean-Christophe Rochet and Hans-Dieter Junker and Daniel Schwizer and Renate Sekul and Inge Ott and John Anderson and Balazs Szoke and Wherly Hoffman and John Christodoulou and Ted Yednock and David Agard and Dale Schenk and Lisa McConlogue},
  title     = {Novel Small Molecules Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein Protect Against Diverse α-Synuclein Mediated Dysfunctions},
  series   = {Scientific reports},
  volume    = {9},
  issn      = {2045-2322},
  doi       = {10.1038/s41598-019-52598-4},
  year      = {2019},
  abstract  = {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.},
  language  = {en}
}