Effective treatment of advanced Oropouche virus, Rift Valley fever virus, and Dabie bandavirus infections with 4'-fluorouridine.

Oropouche virus (OROV), Rift Valley fever virus (RVFV), and Dabie bandavirus (DBV) are significant re-emerging and emerging human pathogens with major public health implications. Notably, the ongoing OROV disease epidemic spanning South America, Central America, and the Caribbean now exceeds 11,000 cases, including several fatalities and reports of neurological disease and congenital abnormalities associated with infection. Rift Valley fever outbreaks continue to plague sub-Saharan Africa, and DBV, the etiologic agent of severe fever with thrombocytopenia syndrome (SFTS), is expanding its reach throughout several Asian countries. No vaccines or approved therapies are available to prevent or treat these viral infections. Here, we report on the antiviral activity and protective efficacy of the ribonucleoside analog, 4'-fluorouridine (4'-FlU), against OROV, RVFV, and DBV in cell culture and murine models of infection and disease. In cell culture, the potency of 4'-FlU was in the low nanomolar (OROV) to low micromolar (RVFV and DBV) range. In vivo, prophylactic oral dosing of the compound was fully protective against all three viruses in their respective mouse infection models. Importantly, post-exposure and therapeutic interventions of advanced infections in mice also responded remarkably well to treatments. Our findings extend the broad-spectrum antiviral capacity of 4'-FlU and support the compound's further development for treating severe bunyaviral infections.

Importance: Re-emerging and emerging viral diseases, for which no approved vaccines or therapeutics exist, pose a significant public health threat in affected areas of the world. Antiviral drugs that are broadly active against multiple pathogenic viruses are much needed. Our findings demonstrating robust protection conferred by treatment with 4'-fluorouridine (4'-FlU) in viral infection models for Oropouche fever, Rift Valley fever, and severe fever with thrombocytopenia syndrome support the continuing development of this promising broad-spectrum antiviral drug candidate for the treatment of these notable viral diseases.