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Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp14 RNA cap methyltransferase
The COVID-19 pandemic has presented itself as one of the most critical public health challenges of the century, with SARS-CoV-2 being the third member of the Coronaviridae family to cause a fatal disease in humans. There is currently only one antiviral compound, remdesivir, that can be used for the...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286817/ https://www.ncbi.nlm.nih.gov/pubmed/34198328 http://dx.doi.org/10.1042/BCJ20210219 |
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author | Basu, Souradeep Mak, Tiffany Ulferts, Rachel Wu, Mary Deegan, Tom Fujisawa, Ryo Tan, Kang Wei Lim, Chew Theng Basier, Clovis Canal, Berta Curran, Joseph F. Drury, Lucy S. McClure, Allison W. Roberts, Emma L. Weissmann, Florian Zeisner, Theresa U. Beale, Rupert Cowling, Victoria H. Howell, Michael Labib, Karim Diffley, John F.X. |
author_facet | Basu, Souradeep Mak, Tiffany Ulferts, Rachel Wu, Mary Deegan, Tom Fujisawa, Ryo Tan, Kang Wei Lim, Chew Theng Basier, Clovis Canal, Berta Curran, Joseph F. Drury, Lucy S. McClure, Allison W. Roberts, Emma L. Weissmann, Florian Zeisner, Theresa U. Beale, Rupert Cowling, Victoria H. Howell, Michael Labib, Karim Diffley, John F.X. |
author_sort | Basu, Souradeep |
collection | PubMed |
description | The COVID-19 pandemic has presented itself as one of the most critical public health challenges of the century, with SARS-CoV-2 being the third member of the Coronaviridae family to cause a fatal disease in humans. There is currently only one antiviral compound, remdesivir, that can be used for the treatment of COVID-19. To identify additional potential therapeutics, we investigated the enzymatic proteins encoded in the SARS-CoV-2 genome. In this study, we focussed on the viral RNA cap methyltransferases, which play key roles in enabling viral protein translation and facilitating viral escape from the immune system. We expressed and purified both the guanine-N7 methyltransferase nsp14, and the nsp16 2′-O-methyltransferase with its activating cofactor, nsp10. We performed an in vitro high-throughput screen for inhibitors of nsp14 using a custom compound library of over 5000 pharmaceutical compounds that have previously been characterised in either clinical or basic research. We identified four compounds as potential inhibitors of nsp14, all of which also showed antiviral capacity in a cell-based model of SARS-CoV-2 infection. Three of the four compounds also exhibited synergistic effects on viral replication with remdesivir. |
format | Online Article Text |
id | pubmed-8286817 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Portland Press Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82868172021-08-02 Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp14 RNA cap methyltransferase Basu, Souradeep Mak, Tiffany Ulferts, Rachel Wu, Mary Deegan, Tom Fujisawa, Ryo Tan, Kang Wei Lim, Chew Theng Basier, Clovis Canal, Berta Curran, Joseph F. Drury, Lucy S. McClure, Allison W. Roberts, Emma L. Weissmann, Florian Zeisner, Theresa U. Beale, Rupert Cowling, Victoria H. Howell, Michael Labib, Karim Diffley, John F.X. Biochem J Biochemical Techniques & Resources The COVID-19 pandemic has presented itself as one of the most critical public health challenges of the century, with SARS-CoV-2 being the third member of the Coronaviridae family to cause a fatal disease in humans. There is currently only one antiviral compound, remdesivir, that can be used for the treatment of COVID-19. To identify additional potential therapeutics, we investigated the enzymatic proteins encoded in the SARS-CoV-2 genome. In this study, we focussed on the viral RNA cap methyltransferases, which play key roles in enabling viral protein translation and facilitating viral escape from the immune system. We expressed and purified both the guanine-N7 methyltransferase nsp14, and the nsp16 2′-O-methyltransferase with its activating cofactor, nsp10. We performed an in vitro high-throughput screen for inhibitors of nsp14 using a custom compound library of over 5000 pharmaceutical compounds that have previously been characterised in either clinical or basic research. We identified four compounds as potential inhibitors of nsp14, all of which also showed antiviral capacity in a cell-based model of SARS-CoV-2 infection. Three of the four compounds also exhibited synergistic effects on viral replication with remdesivir. Portland Press Ltd. 2021-07-16 2021-07-02 /pmc/articles/PMC8286817/ /pubmed/34198328 http://dx.doi.org/10.1042/BCJ20210219 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Biochemical Techniques & Resources Basu, Souradeep Mak, Tiffany Ulferts, Rachel Wu, Mary Deegan, Tom Fujisawa, Ryo Tan, Kang Wei Lim, Chew Theng Basier, Clovis Canal, Berta Curran, Joseph F. Drury, Lucy S. McClure, Allison W. Roberts, Emma L. Weissmann, Florian Zeisner, Theresa U. Beale, Rupert Cowling, Victoria H. Howell, Michael Labib, Karim Diffley, John F.X. Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp14 RNA cap methyltransferase |
title | Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp14 RNA cap methyltransferase |
title_full | Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp14 RNA cap methyltransferase |
title_fullStr | Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp14 RNA cap methyltransferase |
title_full_unstemmed | Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp14 RNA cap methyltransferase |
title_short | Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp14 RNA cap methyltransferase |
title_sort | identifying sars-cov-2 antiviral compounds by screening for small molecule inhibitors of nsp14 rna cap methyltransferase |
topic | Biochemical Techniques & Resources |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286817/ https://www.ncbi.nlm.nih.gov/pubmed/34198328 http://dx.doi.org/10.1042/BCJ20210219 |
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