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

  • Cell Chem Biol. 2020 Jun 18;27(6):668-677.e9. doi: 10.1016/j.chembiol.2020.05.002.
Qi Liu  1 ,  Amita Gupta  2 ,  Ayse Okesli-Armlovich  1 ,  Wenjie Qiao  3 ,  Curt R Fischer  4 ,  Mark Smith  4 ,  Jan E Carette  5 ,  Michael C Bassik  6 ,  Chaitan Khosla  7
Affiliations
  • 1. Department of Chemistry, Stanford University, Stanford, CA 94305, USA; Stanford Chemistry, Engineering and Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA 94305, USA.
  • 2. Stanford Chemistry, Engineering and Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA 94305, USA; Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA.
  • 3. Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
  • 4. Stanford Chemistry, Engineering and Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA 94305, USA.
  • 5. Stanford Chemistry, Engineering and Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
  • 6. Stanford Chemistry, Engineering and Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
  • 7. Department of Chemistry, Stanford University, Stanford, CA 94305, USA; Stanford Chemistry, Engineering and Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA 94305, USA; Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA. Electronic address: [email protected].
PMID: 32442424 DOI: 10.1016/j.chembiol.2020.05.002
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.

Keywords
RNA-dependent RNA polymerase; antiviral therapy; combination; cytidine monophosphate kinase; dengue; dihydroorotate dehydrogenase; pyrimidine metabolism; uridine-cytidine kinase.
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