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Their global distribution paired with multiple routes of transmission by arthropods and rodents cause risks to public health. However, effective antiviral drugs are not yet approved. Molnupiravir is an orally available prodrug of \u03b2-D-N4-hydroxycytidine (NHC) and shows a broad spectrum of antiviral activity. This includes severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and also several members of the Bunyavirales, such as Crimean\u2013Congo hemorrhagic fever virus (CCHFV). For SARS-CoV-2, the active triphosphate form of NHC (NHC-TP) targets the viral RNA-dependent RNA polymerase (RdRp) and causes lethal mutagenesis; however, the mechanism of inhibition of CCHFV RdRp remains elusive. To address this problem, we employed a combination of biochemical studies, structural modeling, and cell-based, antiviral assays. The results of this study support a unifying mechanism consistent with lethal mutagenesis. Binding and\/or incorporation of NHC-TP by CCHFV RdRp is likely facilitated by a conserved glutamine in close proximity to the active site. Next-generation sequencing revealed that NHC induced predominantly G-to-A and C-to-U transitions in CCHFV. Collectively, these results provide mechanistic evidence to consider the development of mutagenic nucleotides as possible treatments for CCHFV infection.<\/jats:p>","DOI":"10.1093\/narmme\/ugaf041","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T13:02:21Z","timestamp":1764766941000},"source":"Crossref","is-referenced-by-count":5,"title":["Inhibitory effects of molnupiravir on Crimean\u2013Congo hemorrhagic fever virus polymerase"],"prefix":"10.1093","volume":"3","author":[{"given":"Angela","family":"Sloan","sequence":"first","affiliation":[{"name":"Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada , Winnipeg, Manitoba R3E 3R2 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Calvin J","family":"Gordon","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of Alberta , Edmonton, Alberta T6G 2R3 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