This is an early access version
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Physiology, Faculty of Medicine, Cyprus International University , Nicosia , Cyprus
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Physiology, Faculty of Medicine, Cyprus Health and Social Sciences University , Guzelyurt , Cyprus
Human Anatomy, Faculty of Medicine, Cyprus International University , Nicosia , Cyprus
Human Anatomy, Faculty of Basic Medical Sciences, University of Maiduguri , Maiduguri , Nigeria
Monkeypox virus (MPXV) replicates in the host cell cytoplasm and must therefore encode its own messenger RNA capping machinery, which makes the viral cap methyltransferases attractive antiviral targets. Folic acid has recently been proposed as an inhibitor of these enzymes and, on that basis, as a candidate treatment for MPXV. This narrative review examines that proposition and the level of evidence supporting it. PubMed, Scopus, and Google Scholar were searched through May 2026; no original experimental work was undertaken. The proposal rests almost entirely on a single virtual screening study in which folic acid emerged as a high-scoring ligand in molecular docking and molecular dynamics simulations, supported indirectly by reports that folates and folate antagonists modulate the replication of unrelated viruses. No published study demonstrates concentration-dependent inhibition of a purified orthopoxvirus methyltransferase by folic acid, and no kinetic parameters have been determined. Folate biochemistry offers no straightforward mechanism because S-adenosylmethionine, rather than folate, is the methyl donor for these enzymes and folate contributes only indirectly by supplying that pool. Furthermore, reported antiviral activity at millimolar concentrations exceeds achievable plasma exposures by approximately three orders of magnitude. By contrast, sinefungin-derived inhibitors of the MPXV 2′-O-methyltransferase VP39 have been characterized structurally, inhibit the purified enzyme at submicromolar concentrations, and suppress viral replication in cell culture, confirming that this machinery is druggable. Folic acid is therefore best described as a computationally derived hypothesis requiring enzymatic validation, rather than an established methyltransferase inhibitor or a therapy for MPXV.
Conceptualization, A.A., L.A. and M.O.O.A.; Data curation, A.A.; Formal Analysis, A.A. and M.O.O.A.; Methodology, A.A., L.A. and M.O.O.A.; Validation, A.A., L.A. and M.O.O.A.; Visualization, A.A., L.A. and M.O.O.A.; Writing – original draft, A.A., L.A. and M.O.O.A.; Writing – review & editing, A.A., L.A. and M.O.O.A.; Investigation, L.A. and M.O.O.A. All authors have read and agreed to the published version of the manuscript.
The study was not supported by any sponsor or funder.
No new datasets were generated or analyzed during this study. All analyzed data are included in this published article and its cited references.
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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