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Pathogenic bunyavirus infections can cause severe hemorrhagic fevers and other life-threatening diseases, posing threats to human health and social stability; however, therapeutic strategies for treating bunyavirus infections remain limited. Here, we report that VV251 hydrochloride salt (VV251), an optimized oral prodrug derivative of 4\u2032-fluorouridine (EIDD-2794), exhibits potent efficacy against severe fever with thrombocytopenia syndrome virus (SFTSV) and lymphocytic choriomeningitis virus (LCMV) both\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      . In various cell lines, VV251 inhibits SFTSV and LCMV with EC\n                      <jats:sub>50<\/jats:sub>\n                      values in the nanomolar to micromolar range. In lethal rodent models, once-daily oral administration of VV251 at low doses (10 mg\/kg for SFTSV; 1 mg\/kg for LCMV) achieves complete protection (100% survival), matching the efficacy of T-705 at 300 mg\/kg. Additional pharmacokinetic analysis indicates that VV251 has favorable absorption and exposure profiles in both Sprague-Dawley rat and cynomolgus monkey models. This study evaluates the antiviral profile of VV251 and supports its further development as a promising therapeutic candidate.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>Bunyaviruses encompass numerous highly pathogenic agents that pose significant threats to human health, including the causative agents of Crimean-Congo hemorrhagic fever, Lassa fever, and Rift Valley fever. The World Health Organization has identified Lassa fever as a priority pathogen requiring urgent research and development efforts in emergency contexts, underscoring the critical need for effective oral antiviral therapies to enhance pandemic preparedness. Here, we report that VV251 hydrochloride salt (VV251), an optimized oral prodrug derivative of 4\u2032-fluorouridine (4\u2032-FlU, EIDD-2794), shows significant efficacy against severe fever with thrombocytopenia syndrome virus and lymphocytic choriomeningitis virus infections, with inhibitory activity in cell culture and protective effects in lethal animal models. Building on the established broad-spectrum antiviral activity of 4\u2032-FlU against multiple high-consequence pathogens (including severe acute respiratory syndrome coronavirus 2, respiratory syncytial virus, Lassa virus, and Junin virus), VV251 emerges as a promising next-generation oral antiviral candidate, offering an orally available therapeutic option to combat these formidable pathogens.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01172-25","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T13:00:27Z","timestamp":1758027627000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["An orally available 4\n                    <i>'<\/i>\n                    -fluorouridine prodrug inhibits SFTSV and LCMV 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