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

This distinctive antiviral activity of CPU could conceivably originate from both host-targeting modulation of pyrimidine metabolism as well as potential direct acting antiviral activity of its triphosphate on viral replication. Intracellular nucleotide depletion appears correlated with antiviral activity given that the structurally unrelated nucleoside transport inhibitor DPY also suppressed intracellular nucleotide levels and viral replication ( Figure S5 ). Additionally, while 250 µM CPU in the absence of GSK983 did slightly potentiate the effects of R1479 on viral replication (Figure 7) , this did not translate to decreased viral infection at the same time point ( Figure S6A ). Nevertheless, further investigation of inhibitory effects of CPU-TP on dengue RdRp is warranted. Indeed, as noted previously, NIs are the largest class of RdRp inhibitors (Klumpp et al., 2008) . Additionally, a multifactorial approach that incorporates information about interactions with multiple host and viral enzymes will likely be useful for future SAR around CPU as this compound remained the most efficacious in our panel.