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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Published inACS chemical neuroscience Vol. 12; no. 24; pp. 4512 - 4523
Main Authors Maestro, Inés, de la Ballina, Laura R, Simonsen, Anne, Boya, Patricia, Martinez, Ana
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 15.12.2021
Subjects
Autophagy
Humans
Mitochondria
Mitophagy
Parkinson Disease - drug therapy
mitophagy inducers
mitophagy
drug discovery
phenotypic assay
Parkinson’s disease
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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.
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content type line 23
NFR/314684
ISSN:1948-7193
1948-7193
DOI:10.1021/acschemneuro.1c00529