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

CPU is known to be safe in vitro (Blaney et al., 1992; Ford et al., 1991; Song et al., 2001) , and does The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.24.992230 doi: bioRxiv preprint not show appreciable toxicity in mice (Cysyk et al., 1995) or non-human primates (Blaney et al., 1990) . While the safety profile of GSK983 remains less clear, other DHODH inhibitors like teriflunomide and brequinar have been extensively studied in humans, and are generally welltolerated (Aly et al., 2017) . Meanwhile, many RdRp inhibitors have been evaluated in clinical trials against dengue. While a preliminary study combining CPU with a de novo synthesis inhibitor in vivo resulted in toxicity (Cysyk et al., 1995) , there is precedent for combining inhibitors of de novo pyrimidine synthesis with nucleoside transport inhibitors in humans (Casper et al., 1991) . With careful dose optimization, our results suggest that a combination strategy targeting both host pyrimidine biosynthesis and viral RdRp holds promise as a potential therapy against RNA viruses. In light of the growing interest in RdRp and DHODH inhibitors as antiviral agents, our findings shine light on a promising way to enhance their clinical utility by combining them with modulators of mammalian pyrimidine metabolism.