In Vitro Synergistic Antiviral Effects of β‐D‐N4‐hydroxycytidine and Teriflunomide in Combination against a Broad Range of RNA Viruses

Emerging and important endemic viral diseases without effective antiviral are important public health threat. An effective broad-spectrum antiviral can be a pivotal tool to mitigate future epidemics and provide a solution for endemic viral diseases. Molnupiravir, a pyrimidine analog, is known for the COVID-19 treatment. It has been shown to inhibit a broad range of RNA viruses. Inhibition of de novo pyrimidine synthesis by teriflunomide, a dihydroorotate dehydrogenase inhibitor, also showed potent antiviral activity against various RNA viruses. Mechanistically, pyrimidine synthesis inhibition should enhance the activity of molnupiravir as it reduces competition of native nucleotides to incorporate into nascent viral RNA. Molnupiravir and teriflunomide combination has been recently shown to have synergistic effect against SARS-CoV-2. Here we show that the combination of β-D-N4-hydroxycytidine, the active form of molnupiravir, and teriflunomide also showed synergistic activity against many RNA viruses. This combination may offer an effective antiviral regimen not only for future emerging viral diseases but also existing important viral diseases.