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Screening of small molecules using the inhibition of oligomer formation in α-synuclein aggregation as a selection parameter.

Accepted version
Peer-reviewed

Type

Article

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Authors

Michaels, Thomas CT 
Flagmeier, Patrick 
Chia, Sean 

Abstract

The aggregation of α-synuclein is a central event in Parkinsons's disease and related synucleinopathies. Since pharmacologically targeting this process, however, has not yet resulted in approved disease-modifying treatments, there is an unmet need of developing novel methods of drug discovery. In this context, the use of chemical kinetics has recently enabled accurate quantifications of the microscopic steps leading to the proliferation of protein misfolded oligomers. As these species are highly neurotoxic, effective therapeutic strategies may be aimed at reducing their numbers. Here, we exploit this quantitative approach to develop a screening strategy that uses the reactive flux toward α-synuclein oligomers as a selection parameter. Using this approach, we evaluate the efficacy of a library of flavone derivatives, identifying apigenin as a compound that simultaneously delays and reduces the formation of α-synuclein oligomers. These results demonstrate a compound selection strategy based on the inhibition of the formation of α-synuclein oligomers, which may be key in identifying small molecules in drug discovery pipelines for diseases associated with α-synuclein aggregation.

Description

Keywords

3404 Medicinal and Biomolecular Chemistry, 34 Chemical Sciences, Neurosciences, Parkinson's Disease, Neurodegenerative, Brain Disorders, 5.1 Pharmaceuticals, 5 Development of treatments and therapeutic interventions

Journal Title

Commun Chem

Conference Name

Journal ISSN

2399-3669
2399-3669

Volume Title

3

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved
Sponsorship
Wellcome Trust (203249/Z/16/Z)
The Wellcome Trust grant no. 203249/Z/16/Z