Details
| Original language | English |
|---|---|
| Article number | 1058 |
| Journal | Communications Biology |
| Volume | 6 |
| Early online date | 18 Oct 2023 |
| Publication status | Published - 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.
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In: Communications Biology, Vol. 6, 1058, 2023.
Research output: Contribution to journal › Article › Research › peer review
}
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 -