Unknown

Dataset Information

0

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


ABSTRACT: The over-expression and aggregation of ?-synuclein (?Syn) are linked to the onset and pathology of Parkinson's 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 Parkinson's disease.

SUBMITTER: Toth G 

PROVIDER: S-EPMC6861283 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Tóth Gergely G   Neumann Thomas T   Berthet Amandine A   Masliah Eliezer E   Spencer Brian B   Tao Jiahui J   Jobling Michael F MF   Gardai Shyra J SJ   Bertoncini Carlos W CW   Cremades Nunilo N   Bova Michael M   Ballaron Stephen S   Chen Xiao-Hua XH   Mao Wenxian W   Nguyen Phuong P   Tabios Mariano C MC   Tambe Mitali A MA   Rochet Jean-Christophe JC   Junker Hans-Dieter HD   Schwizer Daniel D   Sekul Renate R   Ott Inge I   Anderson John P JP   Szoke Balazs B   Hoffman Wherly W   Christodoulou John J   Yednock Ted T   Agard David A DA   Schenk Dale D   McConlogue Lisa L  

Scientific reports 20191118 1


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 pl  ...[more]

Similar Datasets

| S-EPMC3925190 | biostudies-literature
| S-EPMC11352843 | biostudies-literature
| S-EPMC10634714 | biostudies-literature
| S-EPMC6447293 | biostudies-literature
| S-EPMC3177054 | biostudies-literature
| S-EPMC5232785 | biostudies-literature
| S-EPMC5941170 | biostudies-literature
| S-EPMC7277182 | biostudies-literature
| S-EPMC7190594 | biostudies-literature
| S-EPMC8851865 | biostudies-literature