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Sci Rep. 2019 Nov 18;9(1):16947. doi: 10.1038/s41598-019-52598-4.

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

Author information

1
Elan Pharmaceuticals, 700 Gateway Boulevard, South San Francisco, CA, 94080, USA.
2
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
3
MTA-TTK-NAP B - Drug Discovery Research Group - Neurodegenerative Diseases, Institute of Organic Chemistry, Research, Center for Natural Sciences, Hungarian Academy of Sciences, 1245, Budapest, Hungary.
4
Cantabio Pharmaceuticals, 1250 Oakmead Pkwy, Sunnyvale, CA, 94085, USA.
5
NovAliX: Building B: Biology BioParc, bld Sébastien Brant BP 30170, F-67405, Illkirch Cedex, France.
6
Gladstone Institute of Neurological Disease, San Francisco, CA, 94158, USA.
7
Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
8
Division of Neurosciences and Molecular Neuropathology Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
9
Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, 94158, USA.
10
IBR - Instituto de Biología Molecular y Celular de Rosario, National Scientific and Technical Research Council, Buenos Aires, Argentina.
11
Laboratory of Molecular Biophysics, Institute for Research in Biomedicine, Baldiri Reixac 10, 08028, Barcelona, Spain.
12
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.
13
Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN, USA.
14
Aalen University (Hochschule Aalen), Beethovenstraße 1, 73430, Aalen, DE, Germany.
15
Institute of Structural & Molecular Biology, University College London, Gower Street, London, WC1E 6BT, UK.
16
Prothena Biosciences Inc, 331 Oyster Point Blvd, South San Francisco, CA, 94080, USA.
17
Elan Pharmaceuticals, 700 Gateway Boulevard, South San Francisco, CA, 94080, USA. lisam@trp.ucsf.edu.
18
Gladstone Institute of Neurological Disease, San Francisco, CA, 94158, USA. lisam@trp.ucsf.edu.
19
Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, 94158, USA. lisam@trp.ucsf.edu.

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.

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