2′-Fluoro-2′-deoxycytidine is a broad-spectrum inhibitor of bunyaviruses in vitro and in phleboviral disease mouse models

2'-Fluoro-2'-deoxycytidine (2'-FdC) was reported to inhibit various viruses in vitro, including Borna disease, hepatitis C, Lassa fever, influenza and certain herpes viruses, and is inhibitory to influenza viruses in mice. We investigated the antiviral activity of 2'-FdC against several unrelated bunyaviruses in 50% cytopathic effect (CPE) inhibition assays and, with viruses that cause limited CPE, 90% virus yield reduction (VYR) assays. La Crosse (LACV), Maporal, Punta Toro, Rift Valley fever (RVFV), and San Angelo viruses were inhibited in CPE assays at 2.2-9.7 mu M concentrations. In VYR assays, Heartland and severe fever with thrombocytopenia syndrome (SFTSV) viruses were inhibited at 0.9 and 3.7 mu M, respectively. In contrast, ribavirin inhibited these viruses at an average of 47 mu M. Antiviral efficacy studies were also conducted in mice infected with RVFV, SFTSV, and LACV. Against RVFV, 2'-FdC (100 and 200 mg/kg/day) and ribavirin (100 mg/kg/day) treatments each delayed mortality by approximately 6 days compared to placebo. Liver, spleen, and serum viral titers were significantly reduced by antiviral treatments. 2'-FdC (100 and 200 mg/kg/day) prevented death in SFTSV-infected mice, but was not as effective as favipiravir (100 mg/kg/day) based on body weight loss during infection. The 100 mg/kg/day doses of 2'-FdC and favipiravir significantly reduced liver, spleen, and serum viral titers. 2'-FdC and ribavirin afforded no protection against LACV infection in mice, which is encephalitic and thus inherently more difficult to treat. Taken together, our data suggest that 2'-FdC may be a viable candidate for treating certain non-encephalitic bunyavirus infections such as those caused by phleboviruses.