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Non-covalent SARS-CoV-2 M(pro) inhibitors developed from in silico screen hits

M(pro), the main protease of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is essential for the viral life cycle. Accordingly, several groups have performed in silico screens to identify M(pro) inhibitors that might be used to treat SARS-CoV-2 infections. We selected more than fi...

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Autores principales: Rossetti, Giacomo G., Ossorio, Marianna A., Rempel, Stephan, Kratzel, Annika, Dionellis, Vasilis S., Barriot, Samia, Tropia, Laurence, Gorgulla, Christoph, Arthanari, Haribabu, Thiel, Volker, Mohr, Peter, Gamboni, Remo, Halazonetis, Thanos D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8847420/
https://www.ncbi.nlm.nih.gov/pubmed/35169179
http://dx.doi.org/10.1038/s41598-022-06306-4
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author Rossetti, Giacomo G.
Ossorio, Marianna A.
Rempel, Stephan
Kratzel, Annika
Dionellis, Vasilis S.
Barriot, Samia
Tropia, Laurence
Gorgulla, Christoph
Arthanari, Haribabu
Thiel, Volker
Mohr, Peter
Gamboni, Remo
Halazonetis, Thanos D.
author_facet Rossetti, Giacomo G.
Ossorio, Marianna A.
Rempel, Stephan
Kratzel, Annika
Dionellis, Vasilis S.
Barriot, Samia
Tropia, Laurence
Gorgulla, Christoph
Arthanari, Haribabu
Thiel, Volker
Mohr, Peter
Gamboni, Remo
Halazonetis, Thanos D.
author_sort Rossetti, Giacomo G.
collection PubMed
description M(pro), the main protease of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is essential for the viral life cycle. Accordingly, several groups have performed in silico screens to identify M(pro) inhibitors that might be used to treat SARS-CoV-2 infections. We selected more than five hundred compounds from the top-ranking hits of two very large in silico screens for on-demand synthesis. We then examined whether these compounds could bind to M(pro) and inhibit its protease activity. Two interesting chemotypes were identified, which were further evaluated by characterizing an additional five hundred synthesis on-demand analogues. The compounds of the first chemotype denatured M(pro) and were considered not useful for further development. The compounds of the second chemotype bound to and enhanced the melting temperature of M(pro). The most active compound from this chemotype inhibited M(pro) in vitro with an IC(50) value of 1 μM and suppressed replication of the SARS-CoV-2 virus in tissue culture cells. Its mode of binding to M(pro) was determined by X-ray crystallography, revealing that it is a non-covalent inhibitor. We propose that the inhibitors described here could form the basis for medicinal chemistry efforts that could lead to the development of clinically relevant inhibitors.
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spelling pubmed-88474202022-02-17 Non-covalent SARS-CoV-2 M(pro) inhibitors developed from in silico screen hits Rossetti, Giacomo G. Ossorio, Marianna A. Rempel, Stephan Kratzel, Annika Dionellis, Vasilis S. Barriot, Samia Tropia, Laurence Gorgulla, Christoph Arthanari, Haribabu Thiel, Volker Mohr, Peter Gamboni, Remo Halazonetis, Thanos D. Sci Rep Article M(pro), the main protease of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is essential for the viral life cycle. Accordingly, several groups have performed in silico screens to identify M(pro) inhibitors that might be used to treat SARS-CoV-2 infections. We selected more than five hundred compounds from the top-ranking hits of two very large in silico screens for on-demand synthesis. We then examined whether these compounds could bind to M(pro) and inhibit its protease activity. Two interesting chemotypes were identified, which were further evaluated by characterizing an additional five hundred synthesis on-demand analogues. The compounds of the first chemotype denatured M(pro) and were considered not useful for further development. The compounds of the second chemotype bound to and enhanced the melting temperature of M(pro). The most active compound from this chemotype inhibited M(pro) in vitro with an IC(50) value of 1 μM and suppressed replication of the SARS-CoV-2 virus in tissue culture cells. Its mode of binding to M(pro) was determined by X-ray crystallography, revealing that it is a non-covalent inhibitor. We propose that the inhibitors described here could form the basis for medicinal chemistry efforts that could lead to the development of clinically relevant inhibitors. Nature Publishing Group UK 2022-02-15 /pmc/articles/PMC8847420/ /pubmed/35169179 http://dx.doi.org/10.1038/s41598-022-06306-4 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Rossetti, Giacomo G.
Ossorio, Marianna A.
Rempel, Stephan
Kratzel, Annika
Dionellis, Vasilis S.
Barriot, Samia
Tropia, Laurence
Gorgulla, Christoph
Arthanari, Haribabu
Thiel, Volker
Mohr, Peter
Gamboni, Remo
Halazonetis, Thanos D.
Non-covalent SARS-CoV-2 M(pro) inhibitors developed from in silico screen hits
title Non-covalent SARS-CoV-2 M(pro) inhibitors developed from in silico screen hits
title_full Non-covalent SARS-CoV-2 M(pro) inhibitors developed from in silico screen hits
title_fullStr Non-covalent SARS-CoV-2 M(pro) inhibitors developed from in silico screen hits
title_full_unstemmed Non-covalent SARS-CoV-2 M(pro) inhibitors developed from in silico screen hits
title_short Non-covalent SARS-CoV-2 M(pro) inhibitors developed from in silico screen hits
title_sort non-covalent sars-cov-2 m(pro) inhibitors developed from in silico screen hits
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8847420/
https://www.ncbi.nlm.nih.gov/pubmed/35169179
http://dx.doi.org/10.1038/s41598-022-06306-4
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