2. Academic Validation
  3. Chemical Blockage of the Mitochondrial Rhomboid Protease PARL by Novel Ketoamide Inhibitors Reveals Its Role in PINK1/Parkin-Dependent Mitophagy

Chemical Blockage of the Mitochondrial Rhomboid Protease PARL by Novel Ketoamide Inhibitors Reveals Its Role in PINK1/Parkin-Dependent Mitophagy

  • J Med Chem. 2023 Jan 12;66(1):251-265. doi: 10.1021/acs.jmedchem.2c01092.
Edita Poláchová 1 2,  Kathrin Bach 1 3,  Elena Heuten 4 5,  Stancho Stanchev 1,  Anežka Tichá 1,  Philipp Lampe 6,  Pavel Majer 1,  Thomas Langer 6 7 8,  Marius K Lemberg 4 5,  Kvido Stříšovský 1
Affiliations

Affiliations

  • 1 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, Flemingovo n. 2, Prague 160 00, Czech Republic.
  • 2 First Faculty of Medicine, Charles University, Kateřinská 32, Prague 121 08, Czech Republic.
  • 3 Department of Molecular Genetics, Faculty of Science, Charles University, Viničná 5, Prague 128 44, Czech Republic.
  • 4 Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 282, Heidelberg 69120, Germany.
  • 5 Center for Biochemistry and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Medical Faculty, University of Cologne, Joseph-Stelzmann-Strasse 52, Cologne 50931, Germany.
  • 6 Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Medical Faculty, University of Cologne, Joseph-Stelzmann-Strasse 52, Cologne 50931, Germany.
  • 7 Center for Molecular Medicine (CMMC), Medical Faculty, University of Cologne, Joseph-Stelzmann-Strasse 52, Cologne 50931, Germany.
  • 8 Max-Planck-Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, Cologne 50931, Germany.
PMID: 36540942 DOI: 10.1021/acs.jmedchem.2c01092
Abstract

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.

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