2. Academic Validation
  3. Structural Elucidation and Antiviral Activity of Covalent Cathepsin L Inhibitors

Structural Elucidation and Antiviral Activity of Covalent Cathepsin L Inhibitors

  • J Med Chem. 2024 May 9;67(9):7048-7067. doi: 10.1021/acs.jmedchem.3c02351.
Sven Falke 1,  Julia Lieske 1,  Alexander Herrmann 2,  Jure Loboda 3,  Katarina Karničar 3 4,  Sebastian Günther 1,  Patrick Y A Reinke 1,  Wiebke Ewert 1,  Aleksandra Usenik 3 4,  Nataša Lindič 3,  Andreja Sekirnik 3,  Klemen Dretnik 3 5,  Hideaki Tsuge 6,  Vito Turk 3,  Henry N Chapman 1 7 8,  Winfried Hinrichs 9,  Gregor Ebert 2 10,  Dušan Turk 3 4,  Alke Meents 1
Affiliations

Affiliations

  • 1 Center for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESY, Notkestraße 85, 22607 Hamburg, Germany.
  • 2 Institute of Virology, Helmholtz Munich, Ingolstädter Landstraße 1, 85764 Neuherberg, Munich, Germany.
  • 3 Department of Biochemistry and Molecular and Structural Biology, Jozef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia.
  • 4 Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, Jamova 39, 1000 Ljubljana, Slovenia.
  • 5 The Jožef Stefan International Postgraduate School, Jamova cesta 39, 1000 Ljubljana, Slovenia.
  • 6 Faculty of Life Sciences, Kyoto Sangyo University, Kyoto 603-8555, Japan.
  • 7 Hamburg Centre for Ultrafast Imaging, Universität Hamburg, Luruper Chaussee 149, 22761 Hamburg, Germany.
  • 8 Department of Physics, Universität Hamburg, Luruper Chaussee 149, 22761 Hamburg, Germany.
  • 9 Institute of Biochemistry, Universität Greifswald, Felix-Hausdorff-Str. 4, 17489 Greifswald, Germany.
  • 10 Institute of Virology, Technical University of Munich, Trogerstraße 30, 81675 Munich, Germany.
PMID: 38630165 DOI: 10.1021/acs.jmedchem.3c02351
Abstract

Emerging RNA viruses, including SARS-CoV-2, continue to be a major threat. Cell entry of SARS-CoV-2 particles via the endosomal pathway involves cysteine cathepsins. Due to ubiquitous expression, Cathepsin L (CatL) is considered a promising drug target in the context of different viral and lysosome-related diseases. We characterized the anti-SARS-CoV-2 activity of a set of carbonyl- and succinyl epoxide-based inhibitors, which were previously identified as inhibitors of cathepsins or related cysteine proteases. Calpain inhibitor XII, MG-101, and CatL inhibitor IV possess Antiviral activity in the very low nanomolar EC50 range in Vero E6 cells and inhibit CatL in the picomolar Ki range. We show a relevant off-target effect of CatL inhibition by the coronavirus main protease α-ketoamide inhibitor 13b. Crystal structures of CatL in complex with 14 compounds at resolutions better than 2 Å present a solid basis for structure-guided understanding and optimization of CatL inhibitors toward protease drug development.

Figures