A drug repurposing screen identifies decitabine as an HSV-1 antiviral

Herpes simplex virus type 1 (HSV-1) is a highly prevalent human pathogen that causes a range of clinical manifestations, including oral and genital herpes, keratitis, encephalitis, and disseminated neonatal disease. Despite its significant health and economic burden, there is currently only a handful of approved antiviral drugs to treat HSV-1 infection. Acyclovir and its analogs are the first-line treatment, but resistance often arises during prolonged treatment periods, such as in immunocompromised patients. Therefore, there is a critical need to identify novel antiviral agents against HSV-1. Here, we performed a drug repurposing screen, testing the ability of 1,900 safe-in-human drugs to inhibit HSV-1 infection in vitro. The screen identified decitabine, a cytidine analog that is used to treat myelodysplastic syndromes and acute myeloid leukemia, as a potent anti-HSV-1 agent. We show that decitabine is effective in inhibiting HSV-1 infection in multiple cell types, including human keratinocytes, that it synergizes with acyclovir, and acyclovir-resistant HSV-1 is still sensitive to decitabine. We further show that decitabine causes G > C and C > G transversions across the viral genome, suggesting it exerts its antiviral activity by lethal mutagenesis, although a role for decitabine's known targets, DNA methyl-transferases, has not been ruled out.