Communications Biology (Oct 2023)
Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections
- Patrick Y. A. Reinke,
- Edmarcia Elisa de Souza,
- Sebastian Günther,
- Sven Falke,
- Julia Lieske,
- Wiebke Ewert,
- Jure Loboda,
- Alexander Herrmann,
- Aida Rahmani Mashhour,
- Katarina Karničar,
- Aleksandra Usenik,
- Nataša Lindič,
- Andreja Sekirnik,
- Viviane Fongaro Botosso,
- Gláucia Maria Machado Santelli,
- Josana Kapronezai,
- Marcelo Valdemir de Araújo,
- Taiana Tainá Silva-Pereira,
- Antônio Francisco de Souza Filho,
- Mariana Silva Tavares,
- Lizdany Flórez-Álvarez,
- Danielle Bruna Leal de Oliveira,
- Edison Luiz Durigon,
- Paula Roberta Giaretta,
- Marcos Bryan Heinemann,
- Maurice Hauser,
- Brandon Seychell,
- Hendrik Böhler,
- Wioletta Rut,
- Marcin Drag,
- Tobias Beck,
- Russell Cox,
- Henry N. Chapman,
- Christian Betzel,
- Wolfgang Brehm,
- Winfried Hinrichs,
- Gregor Ebert,
- Sharissa L. Latham,
- Ana Marcia de Sá Guimarães,
- Dusan Turk,
- Carsten Wrenger,
- Alke Meents
Affiliations
- Patrick Y. A. Reinke
- Center for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESY
- Edmarcia Elisa de Souza
- Department of Parasitology, Institute of Biomedical Sciences at the University of São Paulo
- Sebastian Günther
- Center for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESY
- Sven Falke
- Center for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESY
- Julia Lieske
- Center for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESY
- Wiebke Ewert
- Center for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESY
- Jure Loboda
- Department of Biochemistry and Molecular and Structural Biology, Jozef Stefan Institute
- Alexander Herrmann
- Institute of Virology, Helmholtz Munich
- Aida Rahmani Mashhour
- Center for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESY
- Katarina Karničar
- Department of Biochemistry and Molecular and Structural Biology, Jozef Stefan Institute
- Aleksandra Usenik
- Department of Biochemistry and Molecular and Structural Biology, Jozef Stefan Institute
- Nataša Lindič
- Department of Biochemistry and Molecular and Structural Biology, Jozef Stefan Institute
- Andreja Sekirnik
- Department of Biochemistry and Molecular and Structural Biology, Jozef Stefan Institute
- Viviane Fongaro Botosso
- Virology Laboratory, Center of Development and Innovation, Butantan Institute
- Gláucia Maria Machado Santelli
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo
- Josana Kapronezai
- Virology Laboratory, Center of Development and Innovation, Butantan Institute
- Marcelo Valdemir de Araújo
- Virology Laboratory, Center of Development and Innovation, Butantan Institute
- Taiana Tainá Silva-Pereira
- Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo
- Antônio Francisco de Souza Filho
- Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo
- Mariana Silva Tavares
- Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo
- Lizdany Flórez-Álvarez
- Department of Parasitology, Institute of Biomedical Sciences at the University of São Paulo
- Danielle Bruna Leal de Oliveira
- Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo
- Edison Luiz Durigon
- Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo
- Paula Roberta Giaretta
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University
- Marcos Bryan Heinemann
- Department of Preventive Veterinary Medicine and Animal Health, College of Veterinary Medicine, University of São Paulo
- Maurice Hauser
- Institute for Organic Chemistry and BMWZ, Leibniz University of Hannover
- Brandon Seychell
- Department of Chemistry, Institute of Physical Chemistry, Universität Hamburg
- Hendrik Böhler
- Department of Chemistry, Institute of Physical Chemistry, Universität Hamburg
- Wioletta Rut
- Department of Chemical Biology and Bioimaging, Faculty of Chemistry, Wrocław University of Science and Technology
- Marcin Drag
- Department of Chemical Biology and Bioimaging, Faculty of Chemistry, Wrocław University of Science and Technology
- Tobias Beck
- Department of Chemistry, Institute of Physical Chemistry, Universität Hamburg
- Russell Cox
- Institute for Organic Chemistry and BMWZ, Leibniz University of Hannover
- Henry N. Chapman
- Center for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESY
- Christian Betzel
- Hamburg Centre for Ultrafast Imaging, Universität Hamburg
- Wolfgang Brehm
- Center for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESY
- Winfried Hinrichs
- Universität Greifswald, Institute of Biochemistry
- Gregor Ebert
- Institute of Virology, Helmholtz Munich
- Sharissa L. Latham
- The Kinghorn Cancer Centre, Garvan Institute of Medical Research
- Ana Marcia de Sá Guimarães
- Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo
- Dusan Turk
- Department of Biochemistry and Molecular and Structural Biology, Jozef Stefan Institute
- Carsten Wrenger
- Department of Parasitology, Institute of Biomedical Sciences at the University of São Paulo
- Alke Meents
- Center for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESY
- DOI
- https://doi.org/10.1038/s42003-023-05317-9
- Journal volume & issue
-
Vol. 6,
no. 1
pp. 1 – 13
Abstract
Abstract Several drug screening campaigns identified Calpeptin as a drug candidate against SARS-CoV-2. Initially reported to target the viral main protease (Mpro), its moderate activity in Mpro inhibition assays hints at a second target. Indeed, we show that Calpeptin is an extremely potent cysteine cathepsin inhibitor, a finding additionally supported by X-ray crystallography. Cell infection assays proved Calpeptin’s efficacy against SARS-CoV-2. Treatment of SARS-CoV-2-infected Golden Syrian hamsters with sulfonated Calpeptin at a dose of 1 mg/kg body weight reduces the viral load in the trachea. Despite a higher risk of side effects, an intrinsic advantage in targeting host proteins is their mutational stability in contrast to highly mutable viral targets. Here we show that the inhibition of cathepsins, a protein family of the host organism, by calpeptin is a promising approach for the treatment of SARS-CoV-2 and potentially other viral infections.
