Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp14 RNA cap methyltransferase

Souradeep Basu (Lead / Corresponding author), Tiffany Mak (Lead / Corresponding author), Rachel Ulferts, Mary Wu, Tom Deegan, Ryo Fujisawa, Kang Wei Tan, Chew Theng Lim, Clovis Basier, Berta Canal, Joseph F. Curran, Lucy S. Drury, Allison W. McClure, Emma L. Roberts, Florian Weissmann, Theresa U. Zeisner, Rupert Beale, Victoria H. Cowling, Michael Howell, Karim LabibJohn F. X. Diffley

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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.

Original languageEnglish
Pages (from-to)2481-2497
Number of pages17
JournalBiochemical Journal
Volume478
Issue number13
Early online date11 May 2021
DOIs
Publication statusPublished - 2 Jul 2021

Keywords

  • coronavirus
  • covid-19
  • methyltransferase
  • mRNA cap

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