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

The flaviviruses, including dengue virus, are an important class of clinically-relevant viral pathogens with limited treatment options (Boldescu et al., 2017) . In particular, dengue causes hundreds of millions of symptomatic infections annually yet lacks any antiviral treatment while the sole approved vaccine has limited use because of safety risks associated with vaccination of individuals not previously exposed to dengue (Lim et al., 2013; Sridhar et al., 2018) . A series of high-throughput phenotypic cell-based screens have recently identified DHODH inhibition as a potent, broadspectrum antiviral strategy in vitro (Hoffmann et al., 2011; Lucas-Hourani et al., 2013; Luthra et al., 2018; Wang et al., 2011) . Furthermore, a DHODH inhibitor was recently shown to suppress SARS-CoV-2 in vitro (Xiong et al., 2020) . However, DHODH inhibitors often lose antiviral activity upon extracellular uridine addition due presumably to pyrimidine salvage (Deans et al., 2016) .