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A novel class of broad-spectrum active-site-directed 3C-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive SARS-CoV-2 Omicron subvariants

Antivirals with broad coronavirus activity are important for treating high-risk individuals exposed to the constantly evolving SARS-CoV-2 variants of concern (VOCs) as well as emerging drug-resistant variants. We developed and characterized a novel class of active-site-directed 3-chymotrypsin-like p...

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Autores principales: Pérez-Vargas, Jimena, Worrall, Liam J., Olmstead, Andrea D., Ton, Anh-Tien, Lee, Jaeyong, Villanueva, Ivan, Thompson, Connor A. H., Dudek, Svenja, Ennis, Siobhan, Smith, Jason R., Shapira, Tirosh, De Guzman, Joshua, Gang, Shutong, Ban, Fuqiang, Vuckovic, Marija, Bielecki, Michael, Kovacic, Suzana, Kenward, Calem, Hong, Christopher Yee, Gordon, Danielle G., Levett, Paul N., Krajden, Mel, Leduc, Richard, Boudreault, Pierre-Luc, Niikura, Masahiro, Paetzel, Mark, Young, Robert N., Cherkasov, Artem, Strynadka, Natalie C. J., Jean, François
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10453993/
https://www.ncbi.nlm.nih.gov/pubmed/37555275
http://dx.doi.org/10.1080/22221751.2023.2246594
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author Pérez-Vargas, Jimena
Worrall, Liam J.
Olmstead, Andrea D.
Ton, Anh-Tien
Lee, Jaeyong
Villanueva, Ivan
Thompson, Connor A. H.
Dudek, Svenja
Ennis, Siobhan
Smith, Jason R.
Shapira, Tirosh
De Guzman, Joshua
Gang, Shutong
Ban, Fuqiang
Vuckovic, Marija
Bielecki, Michael
Kovacic, Suzana
Kenward, Calem
Hong, Christopher Yee
Gordon, Danielle G.
Levett, Paul N.
Krajden, Mel
Leduc, Richard
Boudreault, Pierre-Luc
Niikura, Masahiro
Paetzel, Mark
Young, Robert N.
Cherkasov, Artem
Strynadka, Natalie C. J.
Jean, François
author_facet Pérez-Vargas, Jimena
Worrall, Liam J.
Olmstead, Andrea D.
Ton, Anh-Tien
Lee, Jaeyong
Villanueva, Ivan
Thompson, Connor A. H.
Dudek, Svenja
Ennis, Siobhan
Smith, Jason R.
Shapira, Tirosh
De Guzman, Joshua
Gang, Shutong
Ban, Fuqiang
Vuckovic, Marija
Bielecki, Michael
Kovacic, Suzana
Kenward, Calem
Hong, Christopher Yee
Gordon, Danielle G.
Levett, Paul N.
Krajden, Mel
Leduc, Richard
Boudreault, Pierre-Luc
Niikura, Masahiro
Paetzel, Mark
Young, Robert N.
Cherkasov, Artem
Strynadka, Natalie C. J.
Jean, François
author_sort Pérez-Vargas, Jimena
collection PubMed
description Antivirals with broad coronavirus activity are important for treating high-risk individuals exposed to the constantly evolving SARS-CoV-2 variants of concern (VOCs) as well as emerging drug-resistant variants. We developed and characterized a novel class of active-site-directed 3-chymotrypsin-like protease (3CLpro) inhibitors (C2–C5a). Our lead direct-acting antiviral (DAA), C5a, is a non-covalent, non-peptide with a dissociation constant of 170 nM against recombinant SARS-CoV-2 3CLpro. The compounds C2–C5a exhibit broad-spectrum activity against Omicron subvariants (BA.5, BQ.1.1, and XBB.1.5) and seasonal human coronavirus-229E infection in human cells. Notably, C5a has median effective concentrations of 30–50 nM against BQ.1.1 and XBB.1.5 in two different human cell lines. X-ray crystallography has confirmed the unique binding modes of C2–C5a to the 3CLpro, which can limit virus cross-resistance to emerging Paxlovid-resistant variants. We tested the effect of C5a with two of our newly discovered host-directed antivirals (HDAs): N-0385, a TMPRSS2 inhibitor, and bafilomycin D (BafD), a human vacuolar H(+)-ATPase [V-ATPase] inhibitor. We demonstrated a synergistic action of C5a in combination with N-0385 and BafD against Omicron BA.5 infection in human Calu-3 lung cells. Our findings underscore that a SARS-CoV-2 multi-targeted treatment for circulating Omicron subvariants based on DAAs (C5a) and HDAs (N-0385 or BafD) can lead to therapeutic benefits by enhancing treatment efficacy. Furthermore, the high-resolution structures of SARS-CoV-2 3CLpro in complex with C2–C5a will facilitate future rational optimization of our novel broad-spectrum active-site-directed 3C-like protease inhibitors.
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spelling pubmed-104539932023-08-26 A novel class of broad-spectrum active-site-directed 3C-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive SARS-CoV-2 Omicron subvariants Pérez-Vargas, Jimena Worrall, Liam J. Olmstead, Andrea D. Ton, Anh-Tien Lee, Jaeyong Villanueva, Ivan Thompson, Connor A. H. Dudek, Svenja Ennis, Siobhan Smith, Jason R. Shapira, Tirosh De Guzman, Joshua Gang, Shutong Ban, Fuqiang Vuckovic, Marija Bielecki, Michael Kovacic, Suzana Kenward, Calem Hong, Christopher Yee Gordon, Danielle G. Levett, Paul N. Krajden, Mel Leduc, Richard Boudreault, Pierre-Luc Niikura, Masahiro Paetzel, Mark Young, Robert N. Cherkasov, Artem Strynadka, Natalie C. J. Jean, François Emerg Microbes Infect Coronaviruses Antivirals with broad coronavirus activity are important for treating high-risk individuals exposed to the constantly evolving SARS-CoV-2 variants of concern (VOCs) as well as emerging drug-resistant variants. We developed and characterized a novel class of active-site-directed 3-chymotrypsin-like protease (3CLpro) inhibitors (C2–C5a). Our lead direct-acting antiviral (DAA), C5a, is a non-covalent, non-peptide with a dissociation constant of 170 nM against recombinant SARS-CoV-2 3CLpro. The compounds C2–C5a exhibit broad-spectrum activity against Omicron subvariants (BA.5, BQ.1.1, and XBB.1.5) and seasonal human coronavirus-229E infection in human cells. Notably, C5a has median effective concentrations of 30–50 nM against BQ.1.1 and XBB.1.5 in two different human cell lines. X-ray crystallography has confirmed the unique binding modes of C2–C5a to the 3CLpro, which can limit virus cross-resistance to emerging Paxlovid-resistant variants. We tested the effect of C5a with two of our newly discovered host-directed antivirals (HDAs): N-0385, a TMPRSS2 inhibitor, and bafilomycin D (BafD), a human vacuolar H(+)-ATPase [V-ATPase] inhibitor. We demonstrated a synergistic action of C5a in combination with N-0385 and BafD against Omicron BA.5 infection in human Calu-3 lung cells. Our findings underscore that a SARS-CoV-2 multi-targeted treatment for circulating Omicron subvariants based on DAAs (C5a) and HDAs (N-0385 or BafD) can lead to therapeutic benefits by enhancing treatment efficacy. Furthermore, the high-resolution structures of SARS-CoV-2 3CLpro in complex with C2–C5a will facilitate future rational optimization of our novel broad-spectrum active-site-directed 3C-like protease inhibitors. Taylor & Francis 2023-08-23 /pmc/articles/PMC10453993/ /pubmed/37555275 http://dx.doi.org/10.1080/22221751.2023.2246594 Text en © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group, on behalf of Shanghai Shangyixun Cultural Communication Co., Ltd https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
spellingShingle Coronaviruses
Pérez-Vargas, Jimena
Worrall, Liam J.
Olmstead, Andrea D.
Ton, Anh-Tien
Lee, Jaeyong
Villanueva, Ivan
Thompson, Connor A. H.
Dudek, Svenja
Ennis, Siobhan
Smith, Jason R.
Shapira, Tirosh
De Guzman, Joshua
Gang, Shutong
Ban, Fuqiang
Vuckovic, Marija
Bielecki, Michael
Kovacic, Suzana
Kenward, Calem
Hong, Christopher Yee
Gordon, Danielle G.
Levett, Paul N.
Krajden, Mel
Leduc, Richard
Boudreault, Pierre-Luc
Niikura, Masahiro
Paetzel, Mark
Young, Robert N.
Cherkasov, Artem
Strynadka, Natalie C. J.
Jean, François
A novel class of broad-spectrum active-site-directed 3C-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive SARS-CoV-2 Omicron subvariants
title A novel class of broad-spectrum active-site-directed 3C-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive SARS-CoV-2 Omicron subvariants
title_full A novel class of broad-spectrum active-site-directed 3C-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive SARS-CoV-2 Omicron subvariants
title_fullStr A novel class of broad-spectrum active-site-directed 3C-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive SARS-CoV-2 Omicron subvariants
title_full_unstemmed A novel class of broad-spectrum active-site-directed 3C-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive SARS-CoV-2 Omicron subvariants
title_short A novel class of broad-spectrum active-site-directed 3C-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive SARS-CoV-2 Omicron subvariants
title_sort novel class of broad-spectrum active-site-directed 3c-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive sars-cov-2 omicron subvariants
topic Coronaviruses
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10453993/
https://www.ncbi.nlm.nih.gov/pubmed/37555275
http://dx.doi.org/10.1080/22221751.2023.2246594
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