期刊
BIOCHEMICAL JOURNAL
卷 478, 期 1, 页码 2481-2497出版社
PORTLAND PRESS LTD
DOI: 10.1042/BCJ20210219
关键词
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资金
- Francis Crick Institute from Cancer Research U. K. [FC001066]
- U.K. Medical Research Council [FC001066]
- Wellcome Trust [FC001066, 106252/Z/14/Z, 204678/Z/16/Z]
- Lord Leonard and Lady Estelle Wolfson Foundation
- Boehringer Ingelheim Fonds
- European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant [895786, 844211]
- Medical Research Council [MC_UU_12016/13]
- Cancer Research U.K. [C578/A24558]
- Wellcome Trust [204678/Z/16/Z] Funding Source: Wellcome Trust
- Marie Curie Actions (MSCA) [844211] Funding Source: Marie Curie Actions (MSCA)
Researchers have identified four potential SARS-CoV-2 nsp14 inhibitors, all of which showed antiviral capacity in a cell-based model. Three of these compounds exhibited synergistic effects on viral replication with remdesivir.
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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