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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.
  • Basu S; Cell Cycle Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Mak T; Cell Cycle Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Ulferts R; Cell Biology of Infection Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Wu M; High Throughput Screening, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Deegan T; The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
  • Fujisawa R; The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
  • Tan KW; Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Lim CT; Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Basier C; Cell Cycle Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Canal B; Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Curran JF; Cell Cycle Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Drury LS; Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • McClure AW; Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Roberts EL; Cell Cycle Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Weissmann F; Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Zeisner TU; Cell Cycle Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Beale R; Cell Biology of Infection Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Cowling VH; Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
  • Howell M; High Throughput Screening, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
  • Labib K; The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
  • Diffley JFX; Chromosome Replication Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
Biochem J ; 478(13): 2481-2497, 2021 07 16.
Article in English | MEDLINE | ID: covidwho-1289949
Preprint
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ABSTRACT
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / RNA Caps / Viral Nonstructural Proteins / Drug Evaluation, Preclinical / Exoribonucleases / Small Molecule Libraries / SARS-CoV-2 / Methyltransferases Type of study: Diagnostic study / Prognostic study / Screening study Topics: Traditional medicine Language: English Journal: Biochem J Year: 2021 Document Type: Article Affiliation country: Bcj20210219

Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / RNA Caps / Viral Nonstructural Proteins / Drug Evaluation, Preclinical / Exoribonucleases / Small Molecule Libraries / SARS-CoV-2 / Methyltransferases Type of study: Diagnostic study / Prognostic study / Screening study Topics: Traditional medicine Language: English Journal: Biochem J Year: 2021 Document Type: Article Affiliation country: Bcj20210219