Enhancing the Antiviral Efficacy of RNA-Dependent RNA Polymerase Inhibition by Combination with Modulators of Pyrimidine Metabolism
| Autor: | Curt R. Fischer, Qi Liu, Jan E. Carette, Chaitan Khosla, Mark W. Smith, Michael C. Bassik, Amita Gupta, Wenjie Qiao, Ayse Okesli-Armlovich |
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| Rok vydání: | 2020 |
| Předmět: |
Male
dihydroorotate dehydrogenase Clinical Biochemistry Dengue virus Virus Replication medicine.disease_cause 01 natural sciences Biochemistry chemistry.chemical_compound RNA polymerase antiviral therapy Chlorocebus aethiops Drug Discovery Enzyme Inhibitors Cells Cultured 0303 health sciences Gene knockdown Molecular Structure 3. Good health cytidine monophosphate kinase Pyrimidine metabolism Molecular Medicine Female Carbazoles RNA-dependent RNA polymerase Microbial Sensitivity Tests Biology Antiviral Agents Article 03 medical and health sciences medicine Animals Humans Uridine Gene Molecular Biology 030304 developmental biology combination Pharmacology 010405 organic chemistry Uracil Dengue Virus uridine-cytidine kinase RNA-Dependent RNA Polymerase dengue pyrimidine metabolism 0104 chemical sciences Pyrimidines chemistry Dihydroorotate dehydrogenase |
| Zdroj: | Cell Chemical Biology |
| ISSN: | 2451-9456 |
| Popis: | Summary 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. Graphical Abstract Highlights • Cyclopentenyl uracil and analogs inhibit pyrimidine salvage in vitro and in cells • A host-targeting antiviral strategy combining DHODH inhibitors with CPU is explored • The strategy rescues the antiviral efficacy of a DHODH inhibitor in 20 μM uridine • Modulating pyrimidine metabolism boosts the antiviral activity of an RdRp inhibitor Many RNA virus infections lack suitable treatments. Liu et al. identified a host-targeting antiviral strategy of modulating pyrimidine metabolism with cyclopentenyl uracil, an inhibitor of pyrimidine salvage, and GSK983, an inhibitor of de novo biosynthesis. This combination also increased the potency of an RNA-dependent RNA polymerase inhibitor, against dengue virus. |
| Databáze: | OpenAIRE |
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