Oral 4-fluorouridine completely suppresses epidemic Oropouche virus replication in mice and confers protection against virus-induced disease.

Ferrie, M.; Darmuzey, M.; Tubiana, T.; Khan, M.; Roskams, T.; Weynand, B.; Cremers, N.; Hendrickx, S.; Donckers, K.; Portal, T. M.; Vanmechelen, B.; Rocha-Pereira, J.; Castilletti, C.; Mombaerts, P.; Bressanelli, S.; Laporte, M.; Neyts, J.

doi:10.1101/2025.09.22.677733

bioRxiv · 10.1101/2025.09.22.677733

Oral 4-fluorouridine completely suppresses epidemic Oropouche virus replication in mice and confers protection against virus-induced disease.

Ferrie, M.·Darmuzey, M.·Tubiana, T.·Khan, M.·Roskams, T.·Weynand, B.·Cremers, N.·Hendrickx, S.·Donckers, K.·Portal, T. M.·Vanmechelen, B.·Rocha-Pereira, J.·Castilletti, C.·Mombaerts, P.·Bressanelli, S.·Laporte, M.·Neyts, J.

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Abstract

Oropouche virus (OROV) is an orthobunyavirus that causes increasingly frequent and severe outbreaks in Central and South America. We report that 4'-fluorouridine (4'-FlU) inhibits the in vitro replication of epidemic and pre-epidemic OROV strains in multiple cell lines. In vitro polymerase assays demonstrate that 4'-FlU (as its triphosphate) targets the Peribunyaviridae L protein, is incorporated during RNA synthesis and causes premature chain termination. Following 69 consecutive days of in vitro passages of OROV in the presence of suboptimal concentrations of 4'-FlU, no drug-resistant variants were identified in the viral polymerase. In stringent mouse (AG129) or Syrian hamster OROV-infection models, oral administration of 4'-FlU completely blocked viral replication and virus-induced disease, even when administration was delayed until 72 hours after infection. Our findings support exploring the potential of 4'-FlU for the management of OROV infections in humans.

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Ferrie, M., Darmuzey, M., Tubiana, T., Khan, M., Roskams, T., Weynand, B., Cremers, N., Hendrickx, S., Donckers, K., Portal, T. M., Vanmechelen, B., Rocha-Pereira, J., Castilletti, C., Mombaerts, P., Bressanelli, S., Laporte, M., Neyts, J.. 2025-09-22. Oral 4-fluorouridine completely suppresses epidemic Oropouche virus replication in mice and confers protection against virus-induced disease.. https://doi.org/10.1101/2025.09.22.677733

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