Potent in vitro antiviral activity of 4'-Fluorouridine against diverse orthohantaviruses including Andes virus.

Hantaviruses are emerging pathogens responsible for severe and often fatal diseases, including hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), for which no FDA-approved antivirals currently exist. Using a Seoul virus minigenome system, we first confirmed that the ribonucleoside analog 4'-fluorouridine (EIDD-2749) effectively targets the hantavirus polymerase complex, inhibiting viral RNA transcription and replication. We subsequently evaluated its antiviral activity against a comprehensive panel of 16 hantaviruses representing both Old and New World lineages including both the Chilean and Argentinian strains of Andes virus. 4'-fluorouridine demonstrated potent, dose-dependent inhibition across all viruses tested, with EC50 values uniformly in the low-to sub-micromolar range. Collectively, these findings establish 4'-fluorouridine as a highly potent, pan-hantavirus inhibitor and a promising candidate for further preclinical development.