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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.

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Author:Gergely Tóth, Thomas Neumann, Amandine Berthet, Eliezer Masliah, Brian Spencer, Jiahui Tao, Michael Jobling, Shyra Gardai, Carlos Bertoncini, Nunilo Cremades, Michael Bova, Stephen Ballaron, Xiao-Hua Chen, Wenxian Mao, Phuong Nguyen, Mariano Tabios, Mitali Tambe, Jean-Christophe Rochet, Hans-Dieter Junker, Daniel Schwizer, Renate Sekul, Inge Ott, John Anderson, Balazs Szoke, Wherly Hoffman, John Christodoulou, Ted Yednock, David Agard, Dale Schenk, Lisa McConlogue
Institutional Author:Hans-Dieter Junker
Source Title (English):Scientific reports
Document Type:Article
Year of Completion:2019
Release Date:2021/05/11
Number of Pages:32
Open Access:Open Access
Relevance:peer reviewed