Broad-spectrum antiviral screening reveals pyrimidine biosynthesis as a target for inhibiting measles virus replication

Measles virus (MeV) is highly contagious. Vaccination is the most effective strategy to prevent the infection; however, global measles vaccination coverage is declining, and the incidence of measles outbreaks is increasing. These trends highlight the unmet need for antiviral therapies, particularly for individuals who cannot rely solely on vaccination. In this study, we screened a library of safe-in-human broad-spectrum antiviral agents to identify inhibitors of MeV replication. Among the identified leading candidates, brequinar demonstrated potent antiviral activity, profoundly inhibiting MeV replication in both Vero cells expressing the MeV receptor and human B cells. Supplementation with uridine largely reversed the antiviral effect of brequinar, identifying pyrimidine biosynthesis as the mechanism of action. Furthermore, brequinar exhibited an additive antiviral effect when combined with remdesivir, a direct-acting antiviral drug. Collectively, these findings demonstrated brequinar as a potent inhibitor of MeV replication through targeting the pyrimidine biosynthetic pathway, supporting its potential of repurposing as a therapeutic candidate against MeV.