Potency of nucleoside analogs against Powassan virus replication and identification of 4′-fluorouridine as a therapeutic candidate for tick-borne orthoflavivirus encephalitis
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Powassan virus (POWV) is an emerging tick-borne orthoflavivirus that causes severe encephalitis, long-term neurologic sequelae, and death, yet no approved antiviral therapies exist. Here, we evaluated several previously characterized nucleoside analogs as candidate countermeasures for POWV encephalitis. Favipiravir, molnupiravir, 4′-fluorouridine (4’-FlU), and GS-441524 inhibited POWV replication in vitro and demonstrated comparable activity against West Nile virus (WNV). We established C3H/HeNCrl mice as a stringent POWV disease model, showing increased susceptibility, higher day 7 brain titers, and more pronounced neurologic signs resembling severe human disease, compared with C57BL/6 mice. In prophylactic and therapeutic studies, 4′-fluorouridine was the most efficacious compound tested, significantly reducing brain viral burden even when treatment was delayed. Direct comparison with molnupiravir, favipiravir, and GS-441524 in mice confirmed superior survival benefit and antiviral activity for 4′-FlU against both POWV and WNV. These data identify 4′-fluorouridine as a promising therapeutic candidate for neurotropic flavivirus disease.
Importance
Powassan virus is an emerging tick-borne orthoflavivirus that causes severe neuroinvasive disease, but there are no approved antivirals for treatment after exposure or onset of neurologic disease. This study addresses that gap by comparing multiple clinically relevant nucleoside analogs against POWV and WNV in cell culture and mouse models of encephalitic orthoflavivirus infection. We identify C3H/HeNCrl mice as a stringent POWV disease model that develops increased brain viral burden and neurologic signs compared with C57BL/6 mice, providing a useful platform for antiviral efficacy studies. Across prophylactic and delayed-treatment experiments, 4′-fluorouridine showed the strongest activity, reducing brain viral titers and improving survival more effectively than favipiravir, molnupiravir, or GS-441524. These findings support 4′-fluorouridine as a lead therapeutic candidate for POWV and WNV and establish a framework for evaluating direct-acting antivirals against neurotropic orthoflavivirus disease.
