TY - JOUR
AU - Basu, Souradeep
AU - Mak, Tiffany
AU - Ulferts, Rachel
AU - Wu, Mary
AU - Deegan, Tom D.
AU - Fujisawa, Ryo
AU - Tan, Kang Wei
AU - Lim, Chew Theng
AU - Basier, Clovis
AU - Canal, Berta
AU - Curran, J.
AU - Drury, Lucy S.
AU - McClure, Allison W.
AU - Roberts, Emma L.
AU - Weissmann, Florian
AU - Zeisner, Theresa U.
AU - Beale, Rupert
AU - Cowling, Victoria H.
AU - Howell, Michael
AU - Labib, Karim
AU - Diffley, John F. X.
PY - 2021
DA - July
TI - Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp14 RNA cap methyltransferase
JO - Biochemical Journal
EP - 2497
VL - 478
IS - 13
DO - https://doi.org/10.1042/BCJ20210219
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 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.
PB - Portland Press
UR - https://discovery.dundee.ac.uk/en/publications/de900c26-482a-4d56-b770-851c34d0ee92
KW - Coronavirus (COVID-19)
ER