Journal
NATURE CHEMICAL BIOLOGY
Volume 12, Issue 5, Pages 361-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.2050
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Funding
- NIH/NCI [K99/R00 CA181494]
- National Science Foundation Graduate Research Fellowship [DGE-114747]
- Burt and DeeDee McMurtry Stanford Graduate Fellowship
- US National Institues of Health [U19-AI109662]
- Director's New Innovator Award Program [1DP2HD084069-01]
- seed grant from Stanford ChEM-H
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Broad-spectrum antiviral drugs targeting host processes could potentially treat a wide range of viruses while reducing the likelihood of emergent resistance. Despite great promise as therapeutics, such drugs remain largely elusive. Here we used parallel genome-wide high-coverage short hairpin RNA (shRNA) and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screens to identify the cellular target and mechanism of action of GSK983, a potent broad-spectrum antiviral with unexplained cytotoxicity. We found that GSK983 blocked cell proliferation and dengue virus replication by inhibiting the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH). Guided by mechanistic insights from both genomic screens, we found that exogenous deoxycytidine markedly reduced GSK983 cytotoxicity but not antiviral activity, providing an attractive new approach to improve the therapeutic window of DHODH inhibitors against RNA viruses. Our results highlight the distinct advantages and limitations of each screening method for identifying drug targets, and demonstrate the utility of parallel knockdown and knockout screens for comprehensive probing of drug activity.
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