Lambert Kristiansen Sørensen

Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity

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Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity. / Hoffmann, Markus; Hofmann-Winkler, Heike; Smith, Joan C.; Krüger, Nadine; Arora, Prerna; Sørensen, Lambert K.; Søgaard, Ole S.; Hasselstrøm, Jørgen Bo; Winkler, Michael; Hempel, Tim; Raich, Lluís; Olsson, Simon; Danov, Olga; Jonigk, Danny; Yamazoe, Takashi; Yamatsuta, Katsura; Mizuno, Hirotaka; Ludwig, Stephan; Noé, Frank; Kjolby, Mads; Braun, Armin; Sheltzer, Jason M.; Pöhlmann, Stefan.

In: EBioMedicine, Vol. 65, 103255, 03.2021.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Hoffmann, M, Hofmann-Winkler, H, Smith, JC, Krüger, N, Arora, P, Sørensen, LK, Søgaard, OS, Hasselstrøm, JB, Winkler, M, Hempel, T, Raich, L, Olsson, S, Danov, O, Jonigk, D, Yamazoe, T, Yamatsuta, K, Mizuno, H, Ludwig, S, Noé, F, Kjolby, M, Braun, A, Sheltzer, JM & Pöhlmann, S 2021, 'Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity', EBioMedicine, vol. 65, 103255. https://doi.org/10.1016/j.ebiom.2021.103255

APA

Hoffmann, M., Hofmann-Winkler, H., Smith, J. C., Krüger, N., Arora, P., Sørensen, L. K., Søgaard, O. S., Hasselstrøm, J. B., Winkler, M., Hempel, T., Raich, L., Olsson, S., Danov, O., Jonigk, D., Yamazoe, T., Yamatsuta, K., Mizuno, H., Ludwig, S., Noé, F., ... Pöhlmann, S. (2021). Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity. EBioMedicine, 65, [103255]. https://doi.org/10.1016/j.ebiom.2021.103255

CBE

Hoffmann M, Hofmann-Winkler H, Smith JC, Krüger N, Arora P, Sørensen LK, Søgaard OS, Hasselstrøm JB, Winkler M, Hempel T, Raich L, Olsson S, Danov O, Jonigk D, Yamazoe T, Yamatsuta K, Mizuno H, Ludwig S, Noé F, Kjolby M, Braun A, Sheltzer JM, Pöhlmann S. 2021. Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity. EBioMedicine. 65:Article 103255. https://doi.org/10.1016/j.ebiom.2021.103255

MLA

Vancouver

Author

Hoffmann, Markus ; Hofmann-Winkler, Heike ; Smith, Joan C. ; Krüger, Nadine ; Arora, Prerna ; Sørensen, Lambert K. ; Søgaard, Ole S. ; Hasselstrøm, Jørgen Bo ; Winkler, Michael ; Hempel, Tim ; Raich, Lluís ; Olsson, Simon ; Danov, Olga ; Jonigk, Danny ; Yamazoe, Takashi ; Yamatsuta, Katsura ; Mizuno, Hirotaka ; Ludwig, Stephan ; Noé, Frank ; Kjolby, Mads ; Braun, Armin ; Sheltzer, Jason M. ; Pöhlmann, Stefan. / Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity. In: EBioMedicine. 2021 ; Vol. 65.

Bibtex

@article{500a057406774be598cd15216c50f3ac,
title = "Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity",
abstract = "Background: Antivirals are needed to combat the COVID-19 pandemic, which is caused by SARS-CoV-2. The clinically-proven protease inhibitor Camostat mesylate inhibits SARS-CoV-2 infection by blocking the virus-activating host cell protease TMPRSS2. However, antiviral activity of Camostat mesylate metabolites and potential viral resistance have not been analyzed. Moreover, antiviral activity of Camostat mesylate in human lung tissue remains to be demonstrated. Methods: We used recombinant TMPRSS2, reporter particles bearing the spike protein of SARS-CoV-2 or authentic SARS-CoV-2 to assess inhibition of TMPRSS2 and viral entry, respectively, by Camostat mesylate and its metabolite GBPA. Findings: We show that several TMPRSS2-related proteases activate SARS-CoV-2 and that two, TMPRSS11D and TMPRSS13, are robustly expressed in the upper respiratory tract. However, entry mediated by these proteases was blocked by Camostat mesylate. The Camostat metabolite GBPA inhibited recombinant TMPRSS2 with reduced efficiency as compared to Camostat mesylate. In contrast, both inhibitors exhibited similar antiviral activity and this correlated with the rapid conversion of Camostat mesylate into GBPA in the presence of serum. Finally, Camostat mesylate and GBPA blocked SARS-CoV-2 spread in human lung tissue ex vivo and the related protease inhibitor Nafamostat mesylate exerted augmented antiviral activity. Interpretation: Our results suggest that SARS-CoV-2 can use TMPRSS2 and closely related proteases for spread in the upper respiratory tract and that spread in the human lung can be blocked by Camostat mesylate and its metabolite GBPA. Funding: NIH, Damon Runyon Foundation, ACS, NYCT, DFG, EU, Berlin Mathematics center MATH+, BMBF, Lower Saxony, Lundbeck Foundation, Novo Nordisk Foundation.",
keywords = "Camostat, FOY-251, GBPA, SARS-CoV-2, TMPRSS2",
author = "Markus Hoffmann and Heike Hofmann-Winkler and Smith, {Joan C.} and Nadine Kr{\"u}ger and Prerna Arora and S{\o}rensen, {Lambert K.} and S{\o}gaard, {Ole S.} and Hasselstr{\o}m, {J{\o}rgen Bo} and Michael Winkler and Tim Hempel and Llu{\'i}s Raich and Simon Olsson and Olga Danov and Danny Jonigk and Takashi Yamazoe and Katsura Yamatsuta and Hirotaka Mizuno and Stephan Ludwig and Frank No{\'e} and Mads Kjolby and Armin Braun and Sheltzer, {Jason M.} and Stefan P{\"o}hlmann",
note = "Funding Information: We are grateful for in-depth discussions with Katarina Elez, Tuan Le, Moritz Hoffmann (FU Berlin) and the members of the JEDI COVID-19 grand challenge. We further thank Inga Nehlmeier for excellent technical support. Research in the Sheltzer Lab was supported by NIH grants 1DP5OD021385 and R01CA237652-01, a Damon Runyon-Rachleff Innovation award, an American Cancer Society Research Scholar Grant, and a grant from the New York Community Trust. The No? lab was supported by Deutsche Forschungsgemeinschaft DFG (SFB/TRR 186, Project A12), the European Commission (ERC CoG 772230 {"}ScaleCell{"}), the Berlin Mathematics center MATH+ (AA1-6) and the federal ministry of education and research BMBF (BIFOLD). The P?hlmann lab was supported by the Bundesministerium f?r Bildung und Forschung (RAPID Consortium, 01KI1723D; RENACO consortium, 01KI20328A; SARS_S1S2, 01KI20396 ), Deutsche Forschungsgemeinschaft (PO 716/11-1) and the Country of Lower Saxony. The Kjolby lab was supported by the Lundbeck Foundation (M.K. O.S.) and the Novo Nordisk Foundation (M.K.). The work in the Braun lab was partly funded by the Fraunhofer Internal Programs under Grant No. Anti-Corona 840260 DRECOR (Drug Repurposing for Corona). Publisher Copyright: {\textcopyright} 2021 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = mar,
doi = "10.1016/j.ebiom.2021.103255",
language = "English",
volume = "65",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity

AU - Hoffmann, Markus

AU - Hofmann-Winkler, Heike

AU - Smith, Joan C.

AU - Krüger, Nadine

AU - Arora, Prerna

AU - Sørensen, Lambert K.

AU - Søgaard, Ole S.

AU - Hasselstrøm, Jørgen Bo

AU - Winkler, Michael

AU - Hempel, Tim

AU - Raich, Lluís

AU - Olsson, Simon

AU - Danov, Olga

AU - Jonigk, Danny

AU - Yamazoe, Takashi

AU - Yamatsuta, Katsura

AU - Mizuno, Hirotaka

AU - Ludwig, Stephan

AU - Noé, Frank

AU - Kjolby, Mads

AU - Braun, Armin

AU - Sheltzer, Jason M.

AU - Pöhlmann, Stefan

N1 - Funding Information: We are grateful for in-depth discussions with Katarina Elez, Tuan Le, Moritz Hoffmann (FU Berlin) and the members of the JEDI COVID-19 grand challenge. We further thank Inga Nehlmeier for excellent technical support. Research in the Sheltzer Lab was supported by NIH grants 1DP5OD021385 and R01CA237652-01, a Damon Runyon-Rachleff Innovation award, an American Cancer Society Research Scholar Grant, and a grant from the New York Community Trust. The No? lab was supported by Deutsche Forschungsgemeinschaft DFG (SFB/TRR 186, Project A12), the European Commission (ERC CoG 772230 "ScaleCell"), the Berlin Mathematics center MATH+ (AA1-6) and the federal ministry of education and research BMBF (BIFOLD). The P?hlmann lab was supported by the Bundesministerium f?r Bildung und Forschung (RAPID Consortium, 01KI1723D; RENACO consortium, 01KI20328A; SARS_S1S2, 01KI20396 ), Deutsche Forschungsgemeinschaft (PO 716/11-1) and the Country of Lower Saxony. The Kjolby lab was supported by the Lundbeck Foundation (M.K. O.S.) and the Novo Nordisk Foundation (M.K.). The work in the Braun lab was partly funded by the Fraunhofer Internal Programs under Grant No. Anti-Corona 840260 DRECOR (Drug Repurposing for Corona). Publisher Copyright: © 2021 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/3

Y1 - 2021/3

N2 - Background: Antivirals are needed to combat the COVID-19 pandemic, which is caused by SARS-CoV-2. The clinically-proven protease inhibitor Camostat mesylate inhibits SARS-CoV-2 infection by blocking the virus-activating host cell protease TMPRSS2. However, antiviral activity of Camostat mesylate metabolites and potential viral resistance have not been analyzed. Moreover, antiviral activity of Camostat mesylate in human lung tissue remains to be demonstrated. Methods: We used recombinant TMPRSS2, reporter particles bearing the spike protein of SARS-CoV-2 or authentic SARS-CoV-2 to assess inhibition of TMPRSS2 and viral entry, respectively, by Camostat mesylate and its metabolite GBPA. Findings: We show that several TMPRSS2-related proteases activate SARS-CoV-2 and that two, TMPRSS11D and TMPRSS13, are robustly expressed in the upper respiratory tract. However, entry mediated by these proteases was blocked by Camostat mesylate. The Camostat metabolite GBPA inhibited recombinant TMPRSS2 with reduced efficiency as compared to Camostat mesylate. In contrast, both inhibitors exhibited similar antiviral activity and this correlated with the rapid conversion of Camostat mesylate into GBPA in the presence of serum. Finally, Camostat mesylate and GBPA blocked SARS-CoV-2 spread in human lung tissue ex vivo and the related protease inhibitor Nafamostat mesylate exerted augmented antiviral activity. Interpretation: Our results suggest that SARS-CoV-2 can use TMPRSS2 and closely related proteases for spread in the upper respiratory tract and that spread in the human lung can be blocked by Camostat mesylate and its metabolite GBPA. Funding: NIH, Damon Runyon Foundation, ACS, NYCT, DFG, EU, Berlin Mathematics center MATH+, BMBF, Lower Saxony, Lundbeck Foundation, Novo Nordisk Foundation.

AB - Background: Antivirals are needed to combat the COVID-19 pandemic, which is caused by SARS-CoV-2. The clinically-proven protease inhibitor Camostat mesylate inhibits SARS-CoV-2 infection by blocking the virus-activating host cell protease TMPRSS2. However, antiviral activity of Camostat mesylate metabolites and potential viral resistance have not been analyzed. Moreover, antiviral activity of Camostat mesylate in human lung tissue remains to be demonstrated. Methods: We used recombinant TMPRSS2, reporter particles bearing the spike protein of SARS-CoV-2 or authentic SARS-CoV-2 to assess inhibition of TMPRSS2 and viral entry, respectively, by Camostat mesylate and its metabolite GBPA. Findings: We show that several TMPRSS2-related proteases activate SARS-CoV-2 and that two, TMPRSS11D and TMPRSS13, are robustly expressed in the upper respiratory tract. However, entry mediated by these proteases was blocked by Camostat mesylate. The Camostat metabolite GBPA inhibited recombinant TMPRSS2 with reduced efficiency as compared to Camostat mesylate. In contrast, both inhibitors exhibited similar antiviral activity and this correlated with the rapid conversion of Camostat mesylate into GBPA in the presence of serum. Finally, Camostat mesylate and GBPA blocked SARS-CoV-2 spread in human lung tissue ex vivo and the related protease inhibitor Nafamostat mesylate exerted augmented antiviral activity. Interpretation: Our results suggest that SARS-CoV-2 can use TMPRSS2 and closely related proteases for spread in the upper respiratory tract and that spread in the human lung can be blocked by Camostat mesylate and its metabolite GBPA. Funding: NIH, Damon Runyon Foundation, ACS, NYCT, DFG, EU, Berlin Mathematics center MATH+, BMBF, Lower Saxony, Lundbeck Foundation, Novo Nordisk Foundation.

KW - Camostat

KW - FOY-251

KW - GBPA

KW - SARS-CoV-2

KW - TMPRSS2

UR - http://www.scopus.com/inward/record.url?scp=85102025796&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2021.103255

DO - 10.1016/j.ebiom.2021.103255

M3 - Journal article

C2 - 33676899

AN - SCOPUS:85102025796

VL - 65

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

M1 - 103255

ER -