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Enhancing the Antiviral Efficacy of RNA-Dependent RNA Polymerase Inhibition by Combination With Modulators of Pyrimidine Metabolism

Enhancing the Antiviral Efficacy of RNA-Dependent RNA Polymerase Inhibition by Combination With Modulators of Pyrimidine Metabolism

Qi Liu, Amita Gupta, Ayse Okesli-Armlovich, Wenjie Qiao, Curt R Fischer, Mark Smith, Jan E Carette, Michael C Bassik, Chaitan Khosla

Cell Chem Biol. 2020 Jun 18;27(6):668-677.e9.

PMID: 32442424

Abstract:

Genome-wide analysis of the mode of action of GSK983, a potent antiviral agent, led to the identification of dihydroorotate dehydrogenase as its target along with the discovery that genetic knockdown of pyrimidine salvage sensitized cells to GSK983. Because GSK983 is an ineffective antiviral in the presence of physiological uridine concentrations, we explored combining GSK983 with pyrimidine salvage inhibitors. We synthesized and evaluated analogs of cyclopentenyl uracil (CPU), an inhibitor of uridine salvage. We found that CPU was converted into its triphosphate in cells. When combined with GSK983, CPU resulted in large drops in cellular UTP and CTP pools. Consequently, CPU-GSK983 suppressed dengue virus replication in the presence of physiological concentrations of uridine. In addition, the CPU-GSK983 combination markedly enhanced the effect of RNA-dependent RNA polymerase (RdRp) inhibition on viral infection. Our findings highlight a new host-targeting strategy for potentiating the antiviral activity of RdRp inhibitors.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP827591026	GSK983		827591-02-6	Price

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