Phenotypic Assay Leads to Discovery of Mitophagy Inducers with Therapeutic Potential for Parkinson’s Disease

Mitophagy, the selective degradation of mitochondria by autophagy, involved in important physiological processes and defects in pathways has been reported in pathological conditions, such as neurodegeneration. Thus, mitophagy is an interesting target for drug discovery programs. In this investigatio...

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Bibliographic Details
Published in:ACS chemical neuroscience 2021-12, Vol.12 (24), p.4512-4523
Main Authors: Maestro, Inés, de la Ballina, Laura R, Simonsen, Anne, Boya, Patricia, Martinez, Ana
Format: Article
Language:English
Subjects:
Autophagy
Humans
Mitochondria
Mitophagy
Parkinson Disease - drug therapy
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Summary:Mitophagy, the selective degradation of mitochondria by autophagy, involved in important physiological processes and defects in pathways has been reported in pathological conditions, such as neurodegeneration. Thus, mitophagy is an interesting target for drug discovery programs. In this investigation, we used robust phenotypic assay to screen a set of 50 small heterocyclic compounds to identify inducers of mitophagy. We identified two compounds, VP07 and JAR1.39, that induce Parkin-dependent mitophagy. Based on structure–activity relationship studies, we proposed the ability of the compounds to act as light chain 3 (LC3) interactors, similar to cardiolipin or ceramide, triggering mitophagy via Pink1/Parkin. Finally, we show promising therapeutic applicability in a cellular model of Parkinson’s disease.
ISSN:1948-7193
1948-7193
DOI:10.1021/acschemneuro.1c00529