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Discovery of Triple Inhibitors of Both SARS-CoV-2 Proteases and Human Cathepsin L

One inhibitor of the main SARS-CoV-2 protease has been approved recently by the FDA, yet it targets only SARS-CoV-2 main protease (Mpro). Here, we discovered inhibitors containing thiuram disulfide or dithiobis-(thioformate) tested against three key proteases involved in SARS-CoV-2 replication, incl...

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Autores principales: Meewan, Ittipat, Kattoula, Jacob, Kattoula, Julius Y., Skinner, Danielle, Fajtová, Pavla, Giardini, Miriam A., Woodworth, Brendon, McKerrow, James H., Lage de Siqueira-Neto, Jair, O’Donoghue, Anthony J., Abagyan, Ruben
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9230533/
https://www.ncbi.nlm.nih.gov/pubmed/35745663
http://dx.doi.org/10.3390/ph15060744
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author Meewan, Ittipat
Kattoula, Jacob
Kattoula, Julius Y.
Skinner, Danielle
Fajtová, Pavla
Giardini, Miriam A.
Woodworth, Brendon
McKerrow, James H.
Lage de Siqueira-Neto, Jair
O’Donoghue, Anthony J.
Abagyan, Ruben
author_facet Meewan, Ittipat
Kattoula, Jacob
Kattoula, Julius Y.
Skinner, Danielle
Fajtová, Pavla
Giardini, Miriam A.
Woodworth, Brendon
McKerrow, James H.
Lage de Siqueira-Neto, Jair
O’Donoghue, Anthony J.
Abagyan, Ruben
author_sort Meewan, Ittipat
collection PubMed
description One inhibitor of the main SARS-CoV-2 protease has been approved recently by the FDA, yet it targets only SARS-CoV-2 main protease (Mpro). Here, we discovered inhibitors containing thiuram disulfide or dithiobis-(thioformate) tested against three key proteases involved in SARS-CoV-2 replication, including Mpro, SARS-CoV-2 papain-like protease (PLpro), and human cathepsin L. The use of thiuram disulfide and dithiobis-(thioformate) covalent inhibitor warheads was inspired by an idea to find a better alternative than disulfiram, an approved treatment for chronic alcoholism that is currently in phase 2 clinical trials against SARS-CoV-2. Our goal was to find more potent inhibitors that target both viral proteases and one essential human protease to reduce the dosage, improve the efficacy, and minimize the adverse effects associated with these agents. We found that compounds coded as RI175, RI173, and RI172 were the most potent inhibitors in an enzymatic assay against SARS-CoV-2 Mpro, SARS-CoV-2 PLpro, and human cathepsin L, with IC(50)s of 300, 200, and 200 nM, which is about 5-, 19-, and 11-fold more potent than disulfiram, respectively. In addition, RI173 was tested against SARS-CoV-2 in a cell-based and toxicity assay and was shown to have a greater antiviral effect than disulfiram. The identified compounds demonstrated the promising potential of thiuram disulfide or dithiobis-(thioformate) as a reactive functional group in small molecules that could be further developed for treatment of the COVID-19 virus or related variants.
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spelling pubmed-92305332022-06-25 Discovery of Triple Inhibitors of Both SARS-CoV-2 Proteases and Human Cathepsin L Meewan, Ittipat Kattoula, Jacob Kattoula, Julius Y. Skinner, Danielle Fajtová, Pavla Giardini, Miriam A. Woodworth, Brendon McKerrow, James H. Lage de Siqueira-Neto, Jair O’Donoghue, Anthony J. Abagyan, Ruben Pharmaceuticals (Basel) Article One inhibitor of the main SARS-CoV-2 protease has been approved recently by the FDA, yet it targets only SARS-CoV-2 main protease (Mpro). Here, we discovered inhibitors containing thiuram disulfide or dithiobis-(thioformate) tested against three key proteases involved in SARS-CoV-2 replication, including Mpro, SARS-CoV-2 papain-like protease (PLpro), and human cathepsin L. The use of thiuram disulfide and dithiobis-(thioformate) covalent inhibitor warheads was inspired by an idea to find a better alternative than disulfiram, an approved treatment for chronic alcoholism that is currently in phase 2 clinical trials against SARS-CoV-2. Our goal was to find more potent inhibitors that target both viral proteases and one essential human protease to reduce the dosage, improve the efficacy, and minimize the adverse effects associated with these agents. We found that compounds coded as RI175, RI173, and RI172 were the most potent inhibitors in an enzymatic assay against SARS-CoV-2 Mpro, SARS-CoV-2 PLpro, and human cathepsin L, with IC(50)s of 300, 200, and 200 nM, which is about 5-, 19-, and 11-fold more potent than disulfiram, respectively. In addition, RI173 was tested against SARS-CoV-2 in a cell-based and toxicity assay and was shown to have a greater antiviral effect than disulfiram. The identified compounds demonstrated the promising potential of thiuram disulfide or dithiobis-(thioformate) as a reactive functional group in small molecules that could be further developed for treatment of the COVID-19 virus or related variants. MDPI 2022-06-13 /pmc/articles/PMC9230533/ /pubmed/35745663 http://dx.doi.org/10.3390/ph15060744 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Meewan, Ittipat
Kattoula, Jacob
Kattoula, Julius Y.
Skinner, Danielle
Fajtová, Pavla
Giardini, Miriam A.
Woodworth, Brendon
McKerrow, James H.
Lage de Siqueira-Neto, Jair
O’Donoghue, Anthony J.
Abagyan, Ruben
Discovery of Triple Inhibitors of Both SARS-CoV-2 Proteases and Human Cathepsin L
title Discovery of Triple Inhibitors of Both SARS-CoV-2 Proteases and Human Cathepsin L
title_full Discovery of Triple Inhibitors of Both SARS-CoV-2 Proteases and Human Cathepsin L
title_fullStr Discovery of Triple Inhibitors of Both SARS-CoV-2 Proteases and Human Cathepsin L
title_full_unstemmed Discovery of Triple Inhibitors of Both SARS-CoV-2 Proteases and Human Cathepsin L
title_short Discovery of Triple Inhibitors of Both SARS-CoV-2 Proteases and Human Cathepsin L
title_sort discovery of triple inhibitors of both sars-cov-2 proteases and human cathepsin l
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9230533/
https://www.ncbi.nlm.nih.gov/pubmed/35745663
http://dx.doi.org/10.3390/ph15060744
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