Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections
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...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-10-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-05317-9 |
| _version_ | 1827709041582800896 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Patrick Y. A. Reinke |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T17:14:19Z |
| format | Article |
| id | doaj.art-959ee7d783844cc0965882267049dc4f |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-03-10T17:14:19Z |
| publishDate | 2023-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-959ee7d783844cc0965882267049dc4f2023-11-20T10:33:26ZengNature PortfolioCommunications Biology2399-36422023-10-016111310.1038/s42003-023-05317-9Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infectionsPatrick Y. A. Reinke0Edmarcia Elisa de Souza1Sebastian Günther2Sven Falke3Julia Lieske4Wiebke Ewert5Jure Loboda6Alexander Herrmann7Aida Rahmani Mashhour8Katarina Karničar9Aleksandra Usenik10Nataša Lindič11Andreja Sekirnik12Viviane Fongaro Botosso13Gláucia Maria Machado Santelli14Josana Kapronezai15Marcelo Valdemir de Araújo16Taiana Tainá Silva-Pereira17Antônio Francisco de Souza Filho18Mariana Silva Tavares19Lizdany Flórez-Álvarez20Danielle Bruna Leal de Oliveira21Edison Luiz Durigon22Paula Roberta Giaretta23Marcos Bryan Heinemann24Maurice Hauser25Brandon Seychell26Hendrik Böhler27Wioletta Rut28Marcin Drag29Tobias Beck30Russell Cox31Henry N. Chapman32Christian Betzel33Wolfgang Brehm34Winfried Hinrichs35Gregor Ebert36Sharissa L. Latham37Ana Marcia de Sá Guimarães38Dusan Turk39Carsten Wrenger40Alke Meents41Center for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESYDepartment of Parasitology, Institute of Biomedical Sciences at the University of São PauloCenter for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESYCenter for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESYCenter for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESYCenter for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESYDepartment of Biochemistry and Molecular and Structural Biology, Jozef Stefan InstituteInstitute of Virology, Helmholtz MunichCenter for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESYDepartment of Biochemistry and Molecular and Structural Biology, Jozef Stefan InstituteDepartment of Biochemistry and Molecular and Structural Biology, Jozef Stefan InstituteDepartment of Biochemistry and Molecular and Structural Biology, Jozef Stefan InstituteDepartment of Biochemistry and Molecular and Structural Biology, Jozef Stefan InstituteVirology Laboratory, Center of Development and Innovation, Butantan InstituteDepartment of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São PauloVirology Laboratory, Center of Development and Innovation, Butantan InstituteVirology Laboratory, Center of Development and Innovation, Butantan InstituteDepartment of Microbiology, Institute of Biomedical Sciences, University of São PauloDepartment of Microbiology, Institute of Biomedical Sciences, University of São PauloDepartment of Microbiology, Institute of Biomedical Sciences, University of São PauloDepartment of Parasitology, Institute of Biomedical Sciences at the University of São PauloDepartment of Microbiology, Institute of Biomedical Sciences, University of São PauloDepartment of Microbiology, Institute of Biomedical Sciences, University of São PauloGastrointestinal Laboratory, Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M UniversityDepartment of Preventive Veterinary Medicine and Animal Health, College of Veterinary Medicine, University of São PauloInstitute for Organic Chemistry and BMWZ, Leibniz University of HannoverDepartment of Chemistry, Institute of Physical Chemistry, Universität HamburgDepartment of Chemistry, Institute of Physical Chemistry, Universität HamburgDepartment of Chemical Biology and Bioimaging, Faculty of Chemistry, Wrocław University of Science and TechnologyDepartment of Chemical Biology and Bioimaging, Faculty of Chemistry, Wrocław University of Science and TechnologyDepartment of Chemistry, Institute of Physical Chemistry, Universität HamburgInstitute for Organic Chemistry and BMWZ, Leibniz University of HannoverCenter for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESYHamburg Centre for Ultrafast Imaging, Universität HamburgCenter for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESYUniversität Greifswald, Institute of BiochemistryInstitute of Virology, Helmholtz MunichThe Kinghorn Cancer Centre, Garvan Institute of Medical ResearchDepartment of Microbiology, Institute of Biomedical Sciences, University of São PauloDepartment of Biochemistry and Molecular and Structural Biology, Jozef Stefan InstituteDepartment of Parasitology, Institute of Biomedical Sciences at the University of São PauloCenter for Free-Electron Laser Science CFEL, Deutsches Elektronen-Synchrotron DESYAbstract 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.https://doi.org/10.1038/s42003-023-05317-9 |
| spellingShingle | 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 Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections Communications Biology |
| title | Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections |
| title_full | Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections |
| title_fullStr | Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections |
| title_full_unstemmed | Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections |
| title_short | Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections |
| title_sort | calpeptin is a potent cathepsin inhibitor and drug candidate for sars cov 2 infections |
| url | https://doi.org/10.1038/s42003-023-05317-9 |
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