Enhancing the Antiviral Efficacy of RNA-Dependent RNA Polymerase Inhibition by Combination with Modulators of Pyrimidine Metabolism.,Cell Chemical Biology

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Enhancing the Antiviral Efficacy of RNA-Dependent RNA Polymerase Inhibition by Combination with Modulators of Pyrimidine Metabolism.
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2020-05-21 , 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

Affiliation

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.
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.
Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
Stanford Chemistry, Engineering and Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA 94305, USA.
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.
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.
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.

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.

中文翻译：

通过与嘧啶代谢调节剂组合增强 RNA 依赖性 RNA 聚合酶抑制的抗病毒功效。

对 GSK983（一种有效的抗病毒剂）作用模式的全基因组分析，确定了二氢乳清酸脱氢酶作为其靶标，并发现嘧啶挽救的基因敲低使细胞对 GSK983 敏感。由于 GSK983 在生理尿苷浓度存在下是一种无效的抗病毒药物，因此我们探索了将 GSK983 与嘧啶补救抑制剂联合使用。我们合成并评估了环戊烯基尿嘧啶 (CPU) 的类似物，它是一种尿苷补救抑制剂。我们发现CPU在细胞内转化为三磷酸盐。当与 GSK983 结合使用时，CPU 导致蜂窝 UTP 和 CTP 池大幅下降。因此，CPU-GSK983 在生理浓度的尿苷存在下抑制登革热病毒复制。此外，CPU-GSK983组合显着增强了RNA依赖性RNA聚合酶（RdRp）对病毒感染的抑制作用。我们的研究结果强调了一种新的宿主靶向策略，可增强 RdRp 抑制剂的抗病毒活性。

更新日期：2020-06-18

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