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

Significant progress in the development of antiviral drugs has come by targeting viral proteins with small molecules (Jordheim et al., 2013; Lou et al., 2014) . For examples, compounds like aciclovir and zidovudine block viral reverse transcriptase to treat herpes simplex virus and HIV infections, respectively, and RNA-dependent RNA polymerase (RdRp) inhibitors like dasabuvir and sofosbuvir are used to treat hepatitis C virus infections (Nováková et al., 2018) . More recently, the broadspectrum RdRp inhibitor remdesivir (Gordon et al., 2020) has entered clinical trials for coronavirus disease 2019 . Meanwhile, targeting host proteins required for viral propagation is emerging as an attractive alternative that may circumvent the emergence of resistance (Bekerman and Einav, 2015) . For example, maraviroc inhibits the human chemokine receptor CCR5, and is therefore used to treat multidrug-resistant HIV (Lieberman-Blum et al., 2008) . Additionally, pyrimidine biosynthesis has emerged as a potential host-targeting strategy for antivirals (Okesli et al., 2017) . Here, we focus on devising a host-targeting antiviral approach for the treatment of RNA viruses, which cause many serious diseases such as hepatitis, influenza, Ebola, dengue, and Covid-19.