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Life sciences · Journal article
Emerging Microbes & Infections · September 22, 2026
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Mpox remains a critical public health threat worldwide, and currently available therapeutics against orthopoxvirus infections remain very limited. In this study, we identified 2'-deoxy-2'-fluoro-5-methyl-1-β-D-arabinofuranosyluracil (FMAU) as a broad-spectrum anti-orthopoxvirus candidate through nucleos(t)ide analogue library screening combined with a structure-guided hit expansion strategy. In Vero cells, FMAU exerted potent in vitro antiviral activity against vaccinia virus (VACV) and monkeypox virus (MPXV), with EC₅₀ values of 1.99 μM and 30 nM, respectively, while exhibiting no apparent cytotoxicity, as reflected by a CC₅₀ value greater than 200 μM. In vivo mouse studies further showed that FMAU treatment provided full protection against lethal VACV and MPXV challenges, while significantly reducing viral loads in lung tissues. Importantly, oral FMAU administration retained potent therapeutic efficacy against MPXV in a mouse model of MPXV infection. Collectively, our findings identify FMAU as a promising oral anti-orthopoxvirus drug candidate and support its further preclinical evaluation.