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A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic

The COVID-19 pandemic caused by the SARS-CoV-2 virus remains a global public health crisis. Although widespread vaccination campaigns are underway, their efficacy is reduced owing to emerging variants of concern(1,2). Development of host-directed therapeutics and prophylactics could limit such resis...

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Autores principales: Shapira, Tirosh, Monreal, I. Abrrey, Dion, Sébastien P., Buchholz, David W., Imbiakha, Brian, Olmstead, Andrea D., Jager, Mason, Désilets, Antoine, Gao, Guang, Martins, Mathias, Vandal, Thierry, Thompson, Connor A. H., Chin, Aaleigha, Rees, William D., Steiner, Theodore, Nabi, Ivan Robert, Marsault, Eric, Sahler, Julie, Diel, Diego G., Van de Walle, Gerlinde R., August, Avery, Whittaker, Gary R., Boudreault, Pierre-Luc, Leduc, Richard, Aguilar, Hector C., Jean, François
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9095466/
https://www.ncbi.nlm.nih.gov/pubmed/35344983
http://dx.doi.org/10.1038/s41586-022-04661-w
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author Shapira, Tirosh
Monreal, I. Abrrey
Dion, Sébastien P.
Buchholz, David W.
Imbiakha, Brian
Olmstead, Andrea D.
Jager, Mason
Désilets, Antoine
Gao, Guang
Martins, Mathias
Vandal, Thierry
Thompson, Connor A. H.
Chin, Aaleigha
Rees, William D.
Steiner, Theodore
Nabi, Ivan Robert
Marsault, Eric
Sahler, Julie
Diel, Diego G.
Van de Walle, Gerlinde R.
August, Avery
Whittaker, Gary R.
Boudreault, Pierre-Luc
Leduc, Richard
Aguilar, Hector C.
Jean, François
author_facet Shapira, Tirosh
Monreal, I. Abrrey
Dion, Sébastien P.
Buchholz, David W.
Imbiakha, Brian
Olmstead, Andrea D.
Jager, Mason
Désilets, Antoine
Gao, Guang
Martins, Mathias
Vandal, Thierry
Thompson, Connor A. H.
Chin, Aaleigha
Rees, William D.
Steiner, Theodore
Nabi, Ivan Robert
Marsault, Eric
Sahler, Julie
Diel, Diego G.
Van de Walle, Gerlinde R.
August, Avery
Whittaker, Gary R.
Boudreault, Pierre-Luc
Leduc, Richard
Aguilar, Hector C.
Jean, François
author_sort Shapira, Tirosh
collection PubMed
description The COVID-19 pandemic caused by the SARS-CoV-2 virus remains a global public health crisis. Although widespread vaccination campaigns are underway, their efficacy is reduced owing to emerging variants of concern(1,2). Development of host-directed therapeutics and prophylactics could limit such resistance and offer urgently needed protection against variants of concern(3,4). Attractive pharmacological targets to impede viral entry include type-II transmembrane serine proteases (TTSPs) such as TMPRSS2; these proteases cleave the viral spike protein to expose the fusion peptide for cell entry, and thus have an essential role in the virus lifecycle(5,6). Here we identify and characterize a small-molecule compound, N-0385, which exhibits low nanomolar potency and a selectivity index of higher than 10(6) in inhibiting SARS-CoV-2 infection in human lung cells and in donor-derived colonoids(7). In Calu-3 cells it inhibits the entry of the SARS-CoV-2 variants of concern B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta). Notably, in the K18-human ACE2 transgenic mouse model of severe COVID-19, we found that N-0385 affords a high level of prophylactic and therapeutic benefit after multiple administrations or even after a single administration. Together, our findings show that TTSP-mediated proteolytic maturation of the spike protein is critical for SARS-CoV-2 infection in vivo, and suggest that N-0385 provides an effective early treatment option against COVID-19 and emerging SARS-CoV-2 variants of concern.
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spelling pubmed-90954662022-05-13 A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic Shapira, Tirosh Monreal, I. Abrrey Dion, Sébastien P. Buchholz, David W. Imbiakha, Brian Olmstead, Andrea D. Jager, Mason Désilets, Antoine Gao, Guang Martins, Mathias Vandal, Thierry Thompson, Connor A. H. Chin, Aaleigha Rees, William D. Steiner, Theodore Nabi, Ivan Robert Marsault, Eric Sahler, Julie Diel, Diego G. Van de Walle, Gerlinde R. August, Avery Whittaker, Gary R. Boudreault, Pierre-Luc Leduc, Richard Aguilar, Hector C. Jean, François Nature Article The COVID-19 pandemic caused by the SARS-CoV-2 virus remains a global public health crisis. Although widespread vaccination campaigns are underway, their efficacy is reduced owing to emerging variants of concern(1,2). Development of host-directed therapeutics and prophylactics could limit such resistance and offer urgently needed protection against variants of concern(3,4). Attractive pharmacological targets to impede viral entry include type-II transmembrane serine proteases (TTSPs) such as TMPRSS2; these proteases cleave the viral spike protein to expose the fusion peptide for cell entry, and thus have an essential role in the virus lifecycle(5,6). Here we identify and characterize a small-molecule compound, N-0385, which exhibits low nanomolar potency and a selectivity index of higher than 10(6) in inhibiting SARS-CoV-2 infection in human lung cells and in donor-derived colonoids(7). In Calu-3 cells it inhibits the entry of the SARS-CoV-2 variants of concern B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta). Notably, in the K18-human ACE2 transgenic mouse model of severe COVID-19, we found that N-0385 affords a high level of prophylactic and therapeutic benefit after multiple administrations or even after a single administration. Together, our findings show that TTSP-mediated proteolytic maturation of the spike protein is critical for SARS-CoV-2 infection in vivo, and suggest that N-0385 provides an effective early treatment option against COVID-19 and emerging SARS-CoV-2 variants of concern. Nature Publishing Group UK 2022-03-28 2022 /pmc/articles/PMC9095466/ /pubmed/35344983 http://dx.doi.org/10.1038/s41586-022-04661-w Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Shapira, Tirosh
Monreal, I. Abrrey
Dion, Sébastien P.
Buchholz, David W.
Imbiakha, Brian
Olmstead, Andrea D.
Jager, Mason
Désilets, Antoine
Gao, Guang
Martins, Mathias
Vandal, Thierry
Thompson, Connor A. H.
Chin, Aaleigha
Rees, William D.
Steiner, Theodore
Nabi, Ivan Robert
Marsault, Eric
Sahler, Julie
Diel, Diego G.
Van de Walle, Gerlinde R.
August, Avery
Whittaker, Gary R.
Boudreault, Pierre-Luc
Leduc, Richard
Aguilar, Hector C.
Jean, François
A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic
title A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic
title_full A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic
title_fullStr A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic
title_full_unstemmed A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic
title_short A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic
title_sort a tmprss2 inhibitor acts as a pan-sars-cov-2 prophylactic and therapeutic
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9095466/
https://www.ncbi.nlm.nih.gov/pubmed/35344983
http://dx.doi.org/10.1038/s41586-022-04661-w
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