Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections

Research output: Contribution to journalArticleResearchpeer review

Authors

  • 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

External Research Organisations

  • Deutsches Elektronen-Synchrotron (DESY)
  • Universidade de Sao Paulo
  • Jožef Stefan Institute (JSI)
  • Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins (CIPKeBiP)
  • Instituto Butantan
  • Texas A&M University
  • Universität Hamburg
  • Wroclaw University of Technology
  • University of Greifswald
  • Technical University of Munich (TUM)
  • The Kinghorn Cancer Centre
  • St. Vincent's Hospital Sydney
  • Helmholtz Zentrum München - German Research Center for Environmental Health
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Details

Original languageEnglish
Article number1058
JournalCommunications Biology
Volume6
Early online date18 Oct 2023
Publication statusPublished - 2023

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.

Cite this

Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections. / Reinke, Patrick Y.A.; de Souza, Edmarcia Elisa; Günther, Sebastian et al.
In: Communications Biology, Vol. 6, 1058, 2023.

Research output: Contribution to journalArticleResearchpeer review

Reinke, PYA, de Souza, EE, Günther, S, Falke, S, Lieske, J, Ewert, W, Loboda, J, Herrmann, A, Rahmani Mashhour, A, Karničar, K, Usenik, A, Lindič, N, Sekirnik, A, Botosso, VF, Santelli, GMM, Kapronezai, J, de Araújo, MV, Silva-Pereira, TT, Filho, AFDS, Tavares, MS, Flórez-Álvarez, L, de Oliveira, DBL, Durigon, EL, Giaretta, PR, Heinemann, MB, Hauser, M, Seychell, B, Böhler, H, Rut, W, Drag, M, Beck, T, Cox, R, Chapman, HN, Betzel, C, Brehm, W, Hinrichs, W, Ebert, G, Latham, SL, Guimarães, AMDS, Turk, D, Wrenger, C & Meents, A 2023, 'Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections', Communications Biology, vol. 6, 1058. https://doi.org/10.1038/s42003-023-05317-9
Reinke, P. Y. A., de Souza, E. E., Günther, S., Falke, S., Lieske, J., Ewert, W., Loboda, J., Herrmann, A., Rahmani Mashhour, A., Karničar, K., Usenik, A., Lindič, N., Sekirnik, A., Botosso, V. F., Santelli, G. M. M., Kapronezai, J., de Araújo, M. V., Silva-Pereira, T. T., Filho, A. F. D. S., ... Meents, A. (2023). Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections. Communications Biology, 6, Article 1058. https://doi.org/10.1038/s42003-023-05317-9
Reinke PYA, de Souza EE, Günther S, Falke S, Lieske J, Ewert W et al. Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections. Communications Biology. 2023;6:1058. Epub 2023 Oct 18. doi: 10.1038/s42003-023-05317-9
Reinke, Patrick Y.A. ; de Souza, Edmarcia Elisa ; Günther, Sebastian et al. / Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections. In: Communications Biology. 2023 ; Vol. 6.
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title = "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 cathepsin inhibitor, a finding additionally supported by X-ray crystallography. Cell infection assays proved Calpeptin{\textquoteright}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.",
author = "Reinke, {Patrick Y.A.} and {de Souza}, {Edmarcia Elisa} and Sebastian G{\"u}nther and Sven Falke and Julia Lieske and Wiebke Ewert and Jure Loboda and Alexander Herrmann and {Rahmani Mashhour}, Aida and Katarina Karni{\v c}ar and Aleksandra Usenik and Nata{\v s}a Lindi{\v c} and Andreja Sekirnik and Botosso, {Viviane Fongaro} and Santelli, {Gl{\'a}ucia Maria Machado} and Josana Kapronezai and {de Ara{\'u}jo}, {Marcelo Valdemir} and Silva-Pereira, {Taiana Tain{\'a}} and Filho, {Ant{\^o}nio Francisco de Souza} and Tavares, {Mariana Silva} and Lizdany Fl{\'o}rez-{\'A}lvarez and {de Oliveira}, {Danielle Bruna Leal} and Durigon, {Edison Luiz} and Giaretta, {Paula Roberta} and Heinemann, {Marcos Bryan} and Maurice Hauser and Brandon Seychell and Hendrik B{\"o}hler and Wioletta Rut and Marcin Drag and Tobias Beck and Russell Cox and Chapman, {Henry N.} and Christian Betzel and Wolfgang Brehm and Winfried Hinrichs and Gregor Ebert and Latham, {Sharissa L.} and Guimar{\~a}es, {Ana Marcia de S{\'a}} and Dusan Turk and Carsten Wrenger and Alke Meents",
note = "Funding Information: We acknowledge DESY (Hamburg, Germany), a member of the Helmholtz Association HGF, for the provision of experimental facilities. Parts of this research were carried out at PETRA III beamline P11. This research was supported in part through the Maxwell computational resources operated at Deutsches Elektronen-Synchrotron DESY, Hamburg, Germany. We acknowledge the assistance of Marcel Lach. We acknowledge financial support obtained from the Helmholtz society through the projects FISCOV, SFragX and the Helmholtz Association Impulse and Networking funds InternLabs-0011 “HIR3X”. This work was further supported through BMBF funded projects “ConScience” (project 16GW0277) and the R{\"o}ntgen-Angstrom cluster project “X-ray drug design platform” (13K22CHB). Additional funding was received through the Cluster of Excellence “Advanced Imaging of Matter” of the Deutsche Forschungsgemeinschaft (DFG)— EXC 2056—project ID 390715994, via BMBF via projects 05K19GU4 and 05K20GUB. The Dr{\c a}g laboratory is supported by the “TEAM/2017-4/32” project, which is conducted within the TEAM program of the Foundation for Polish Science co-financed by the European Union under the European Regional Development Fund. The authors also thank the Funda{\c c}{\~a}o de Amparo {\`a} Pesquisa do Estado de S{\~a}o Paulo (FAPESP) (grants 2015/26722-8 (CW), 2020/12277-0 (EES), 2020/07251-2 (AMSG), 2020/09149-0, 2022/ 01812-8, and 2021/02736-0) and the collaborative network between the Universities S{\~a}o Paulo (USP) and Hamburg (UHH) via the UHH-USP-FAPESP Sprint Project 2019 (FAPESP 2019/00899-0). We also acknowledge the Butantan Institute (M.V.d.A. fellowship) and the Brazilian Ministry of Education, CAPES (88887.508739/2020-00, 000). D.T. group is supported by the Slovenian Research Agency (ARRS; research program P1- 0048, Infrastructural program IO-0048).",
year = "2023",
doi = "10.1038/s42003-023-05317-9",
language = "English",
volume = "6",

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Download

TY - JOUR

T1 - Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections

AU - Reinke, Patrick Y.A.

AU - de Souza, Edmarcia Elisa

AU - Günther, Sebastian

AU - Falke, Sven

AU - Lieske, Julia

AU - Ewert, Wiebke

AU - Loboda, Jure

AU - Herrmann, Alexander

AU - Rahmani Mashhour, Aida

AU - Karničar, Katarina

AU - Usenik, Aleksandra

AU - Lindič, Nataša

AU - Sekirnik, Andreja

AU - Botosso, Viviane Fongaro

AU - Santelli, Gláucia Maria Machado

AU - Kapronezai, Josana

AU - de Araújo, Marcelo Valdemir

AU - Silva-Pereira, Taiana Tainá

AU - Filho, Antônio Francisco de Souza

AU - Tavares, Mariana Silva

AU - Flórez-Álvarez, Lizdany

AU - de Oliveira, Danielle Bruna Leal

AU - Durigon, Edison Luiz

AU - Giaretta, Paula Roberta

AU - Heinemann, Marcos Bryan

AU - Hauser, Maurice

AU - Seychell, Brandon

AU - Böhler, Hendrik

AU - Rut, Wioletta

AU - Drag, Marcin

AU - Beck, Tobias

AU - Cox, Russell

AU - Chapman, Henry N.

AU - Betzel, Christian

AU - Brehm, Wolfgang

AU - Hinrichs, Winfried

AU - Ebert, Gregor

AU - Latham, Sharissa L.

AU - Guimarães, Ana Marcia de Sá

AU - Turk, Dusan

AU - Wrenger, Carsten

AU - Meents, Alke

N1 - Funding Information: We acknowledge DESY (Hamburg, Germany), a member of the Helmholtz Association HGF, for the provision of experimental facilities. Parts of this research were carried out at PETRA III beamline P11. This research was supported in part through the Maxwell computational resources operated at Deutsches Elektronen-Synchrotron DESY, Hamburg, Germany. We acknowledge the assistance of Marcel Lach. We acknowledge financial support obtained from the Helmholtz society through the projects FISCOV, SFragX and the Helmholtz Association Impulse and Networking funds InternLabs-0011 “HIR3X”. This work was further supported through BMBF funded projects “ConScience” (project 16GW0277) and the Röntgen-Angstrom cluster project “X-ray drug design platform” (13K22CHB). Additional funding was received through the Cluster of Excellence “Advanced Imaging of Matter” of the Deutsche Forschungsgemeinschaft (DFG)— EXC 2056—project ID 390715994, via BMBF via projects 05K19GU4 and 05K20GUB. The Drąg laboratory is supported by the “TEAM/2017-4/32” project, which is conducted within the TEAM program of the Foundation for Polish Science co-financed by the European Union under the European Regional Development Fund. The authors also thank the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (grants 2015/26722-8 (CW), 2020/12277-0 (EES), 2020/07251-2 (AMSG), 2020/09149-0, 2022/ 01812-8, and 2021/02736-0) and the collaborative network between the Universities São Paulo (USP) and Hamburg (UHH) via the UHH-USP-FAPESP Sprint Project 2019 (FAPESP 2019/00899-0). We also acknowledge the Butantan Institute (M.V.d.A. fellowship) and the Brazilian Ministry of Education, CAPES (88887.508739/2020-00, 000). D.T. group is supported by the Slovenian Research Agency (ARRS; research program P1- 0048, Infrastructural program IO-0048).

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85174463058&partnerID=8YFLogxK

U2 - 10.1038/s42003-023-05317-9

DO - 10.1038/s42003-023-05317-9

M3 - Article

C2 - 37853179

AN - SCOPUS:85174463058

VL - 6

JO - Communications Biology

JF - Communications Biology

M1 - 1058

ER -

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