TY  - JOUR
U1  - Zeitschriftenartikel, wissenschaftlich - begutachtet (reviewed)
A1  - Tóth, Gergely
A1  - Neumann, Thomas
A1  - Berthet, Amandine
A1  - Masliah, Eliezer
A1  - Spencer, Brian
A1  - Tao, Jiahui
A1  - Jobling, Michael
A1  - Gardai, Shyra
A1  - Bertoncini, Carlos
A1  - Cremades, Nunilo
A1  - Bova, Michael
A1  - Ballaron, Stephen
A1  - Chen, Xiao-Hua
A1  - Mao, Wenxian
A1  - Nguyen, Phuong
A1  - Tabios, Mariano
A1  - Tambe, Mitali
A1  - Rochet, Jean-Christophe
A1  - Junker, Hans-Dieter
A1  - Schwizer, Daniel
A1  - Sekul, Renate
A1  - Ott, Inge
A1  - Anderson, John
A1  - Szoke, Balazs
A1  - Hoffman, Wherly
A1  - Christodoulou, John
A1  - Yednock, Ted
A1  - Agard, David
A1  - Schenk, Dale
A1  - McConlogue, Lisa
T1  - Novel Small Molecules Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein Protect Against Diverse α-Synuclein Mediated Dysfunctions
JF  - Scientific reports
N2  - 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.
Y1  - 2019
SN  - 2045-2322
SS  - 2045-2322
U6  - https://doi.org/10.1038/s41598-019-52598-4
DO  - https://doi.org/10.1038/s41598-019-52598-4
VL  - 9
SP  - 32
S1  - 32
ER  -