M. Ferrie, M. Darmuzey, I. Tarillon, T. Tubiana, M. Khan, T. Roskams, B. Weynand, D. Thal, N. Cremers, S. Hendrickx, K. Donckers, T. M. Portal, B. Vanmechelen, V. Lemmens, J. Rocha-Pereira, C. Castilletti, P. Mombaerts, S. Bressanelli, M. Laporte, H. MALET, J. Neyts
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.