Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp14 RNA cap methyltransferase
| Autor: | Kang Wei Tan, Emma L. Roberts, Tiffany Mak, Lucy S. Drury, Souradeep Basu, Berta Canal, Michael Howell, Joseph F. Curran, Florian Weissmann, Karim Labib, Tom D Deegan, John F.X. Diffley, Allison W McClure, Ryo Fujisawa, Mary Wu, Victoria H. Cowling, Rachel Ulferts, Clovis Basier, Rupert Beale, Theresa U. Zeisner, Chew Theng Lim |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Methyltransferase
Indoles coronavirus Drug Evaluation Preclinical Viral Nonstructural Proteins medicine.disease_cause Biochemistry Substrate Specificity Phenothiazines Chlorocebus aethiops Fluorescence Resonance Energy Transfer Coronaviridae Viral Regulatory and Accessory Proteins Research Articles Coronavirus 0303 health sciences Alanine Translation (biology) Small molecule covid-19 Indenes mRNA cap RNA Caps Indazoles Viral protein Biology Chlorobenzenes Antiviral Agents Small Molecule Libraries 03 medical and health sciences Biochemical Techniques & Resources Trifluperidol Virology Nitriles medicine Animals Molecular Biology Vero Cells 030304 developmental biology Enzyme Assays 030306 microbiology SARS-CoV-2 RNA Reproducibility of Results Cell Biology Methyltransferases biology.organism_classification Adenosine Monophosphate High-Throughput Screening Assays Viral replication Purines Exoribonucleases methyltransferase |
| Zdroj: | Biochemical Journal |
| ISSN: | 1470-8728 0264-6021 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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