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Chemical Blockage of the Mitochondrial Rhomboid Protease PARL by Novel Ketoamide Inhibitors Reveals Its Role in PINK1/Parkin-Dependent Mitophagy
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SYSNO ASEP 0566618 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Chemical Blockage of the Mitochondrial Rhomboid Protease PARL by Novel Ketoamide Inhibitors Reveals Its Role in PINK1/Parkin-Dependent Mitophagy Author(s) Poláchová, Edita (UOCHB-X) ORCID
Bach, Kathrin (UOCHB-X)
Heuten, E. (DE)
Stanchev, Stancho (UOCHB-X) RID, ORCID
Tichá, Anežka (UOCHB-X) ORCID, RID
Lampe, P. (DE)
Majer, Pavel (UOCHB-X)
Langer, T. (DE)
Lemberg, M. K. (DE)
Stříšovský, Kvido (UOCHB-X) RID, ORCIDSource Title Journal of Medicinal Chemistry. - : American Chemical Society - ISSN 0022-2623
Roč. 66, č. 1 (2023), s. 251-265Number of pages 15 s. Language eng - English Country US - United States Keywords lipid bilayer nanodiscs ; membrane proteins ; PINK1 OECD category Biochemistry and molecular biology R&D Projects LO1302 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF16_019/0000729 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UOCHB-X - RVO:61388963 UT WOS 000904355800001 EID SCOPUS 85144343182 DOI 10.1021/acs.jmedchem.2c01092 Annotation The mitochondrial rhomboid protease PARL regulates mitophagy by balancing intramembrane proteolysis of PINK1 and PGAM5. It has been implicated in the pathogenesis of Parkinson's disease, but its investigation as a possible therapeutic target is challenging in this context because genetic deficiency of PARL may result in compensatory mechanisms. To address this problem, we undertook a hitherto unavailable chemical biology strategy. We developed potent PARL-targeting ketoamide inhibitors and investigated the effects of acute PARL suppression on the processing status of PINK1 intermediates and on Parkin activation. This approach revealed that PARL inhibition leads to a robust activation of the PINK1/Parkin pathway without major secondary effects on mitochondrial properties, which demonstrates that the pharmacological blockage of PARL to boost PINK1/Parkin-dependent mitophagy is a feasible approach to examine novel therapeutic strategies for Parkinson's disease. More generally, this study showcases the power of ketoamide inhibitors for cell biological studies of rhomboid proteases. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2024 Electronic address https://doi.org/10.1021/acs.jmedchem.2c01092
Number of the records: 1