RT Journal Article
SR Electronic
T1 Identification of SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of the nsp14 RNA Cap Methyltransferase
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.04.07.438810
DO 10.1101/2021.04.07.438810
A1 Souradeep Basu
A1 Tiffany Mak
A1 Rachel Ulferts
A1 Mary Wu
A1 Tom Deegan
A1 Ryo Fujisawa
A1 Kang Wei Tan
A1 Chew Theng Lim
A1 Clovis Basier
A1 Berta Canal
A1 Joseph F. Curran
A1 Lucy Drury
A1 Allison W. McClure
A1 Emma L. Roberts
A1 Florian Weissmann
A1 Theresa U. Zeisner
A1 Rupert Beale
A1 Victoria H. Cowling
A1 Michael Howell
A1 Karim Labib
A1 John F.X. Diffley
YR 2021
UL http://biorxiv.org/content/early/2021/04/08/2021.04.07.438810.abstract
AB 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.