TY - JOUR T1 - Identification of SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of the nsp14 RNA Cap Methyltransferase JF - bioRxiv DO - 10.1101/2021.04.07.438810 SP - 2021.04.07.438810 AU - Souradeep Basu AU - Tiffany Mak AU - Rachel Ulferts AU - Mary Wu AU - Tom Deegan AU - Ryo Fujisawa AU - Kang Wei Tan AU - Chew Theng Lim AU - Clovis Basier AU - Berta Canal AU - Joseph F. Curran AU - Lucy Drury AU - Allison W. McClure AU - Emma L. Roberts AU - Florian Weissmann AU - Theresa U. Zeisner AU - Rupert Beale AU - Victoria H. Cowling AU - Michael Howell AU - Karim Labib AU - John F.X. Diffley Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/04/08/2021.04.07.438810.abstract N2 - 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 fatal disease in humans. There is currently only one antiviral compound, remdesivir, that can be used for the treatment of COVID-19. In order 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 a key role 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 5,000 pharmaceutical compounds that have previously been characterised in either clinical or basic research. We identified 4 compounds as potential inhibitors of nsp14, all of which also show antiviral capacity in a cell based model of SARS-CoV-2 infection. Three of the 4 compounds also exhibited synergistic effects on viral replication with remdesivir.Competing Interest StatementThe authors have declared no competing interest. ER -