Potency of nucleoside analogs against Powassan virus replication and identification of 4'-fluorouridine as a therapeutic candidate for tick-borne orthoflavivirus encephalitis
- 1Georgia State University Institute for Biomedical Sciences
Abstract
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.
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BibTeX
@misc{lewis2026potency,
title = {{Potency of nucleoside analogs against Powassan virus replication and identification of 4'-fluorouridine as a therapeutic candidate for tick-borne orthoflavivirus encephalitis}},
author = {D. S. M. Lewis and T. Moore and R. Patel and R. Cox},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.24.754293},
url = {https://www.biorxiv.org/content/10.64898/2026.09.24.754293v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Potency of nucleoside analogs against Powassan virus replication and identification of 4'-fluorouridine as a therapeutic candidate for tick-borne orthoflavivirus encephalitis
AU - D. S. M. Lewis
AU - T. Moore
AU - R. Patel
AU - R. Cox
PY - 2026
DA - 2026/09/24
PB - bioRxiv
DO - 10.64898/2026.09.24.754293
UR - https://www.biorxiv.org/content/10.64898/2026.09.24.754293v1
AB - 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.
ER -