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Nat Chem Biol

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Abstract

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.K99 CA181494/CA/NCI NIH HHS/United StatesDP2 HD084069/HD/NICHD NIH HHS/United StatesR00 CA181494/CA/NCI NIH HHS/United StatesDP2 AI104557/AI/NIAID NIH HHS/United StatesT32 GM008284/GM/NIGMS NIH HHS/United StatesT32 GM007618/GM/NIGMS NIH HHS/United StatesK99/R00 CA181494/CA/NCI NIH HHS/United States1DP2HD084069-01/DP/NCCDPHP CDC HHS/United StatesT32 EB009383/EB/NIBIB NIH HHS/United StatesU19 AI109662/AI/NIAID NIH HHS/United StatesU19-AI109662/AI/NIAID NIH HHS/United States2016-09-28T00:00:00Z27018887PMC48369737487vault:1854

Topics: Article, Antiviral Agents, CRISPR-Cas Systems, Carbazoles, Cell Line, Tumor, Cloning, Molecular, Humans, Lentivirus, RNA, Small Interfering
OAI identifier: oai:cdc.stacks:cdc:40994
Provided by: CDC Stacks
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