1. Novel highly selective inhibitors of ubiquitin specific protease 30 (USP30) accelerate mitophagy
- Author
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Bharat Lagu, Michael Webb, Pranab Maiti, Arthur F. Kluge, Jyoti Malhotra, P. Akhila Srinivas, James E. Thompson, Ashley Mallat, and Mahaboobi Jaleel
- Subjects
0301 basic medicine ,Ubiquitin-Protein Ligases ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Parkin ,Mitochondrial Proteins ,03 medical and health sciences ,Mice ,Structure-Activity Relationship ,Drug Discovery ,Mitophagy ,Ubiquitin specific protease ,Animals ,Protease Inhibitors ,Molecular Biology ,Mitochondrial protein ,chemistry.chemical_classification ,biology ,Chemistry ,Organic Chemistry ,Ubiquitination ,Highly selective ,Protein ubiquitination ,Ubiquitin ligase ,Cell biology ,Mitochondria ,030104 developmental biology ,Enzyme ,biology.protein ,Molecular Medicine ,Thiolester Hydrolases - Abstract
Mitophagy is one of the processes that cells use to maintain overall health. An E3 ligase, parkin, ubiquitinates mitochondrial proteins prior to their degradation by autophagasomes. USP30 is an enzyme that de-ubiquitinates mitochondrial proteins; therefore, inhibiting this enzyme could foster mitophagy. Herein, we disclose the structure-activity relationships (SAR) within a novel series of highly selective USP30 inhibitors. Two structurally similar compounds, MF-094 (a potent and selective USP30 inhibitor) and MF-095 (a significantly less potent USP30 inhibitor), serve as useful controls for biological evaluation. We show that MF-094 increases protein ubiquitination and accelerates mitophagy.
- Published
- 2018