1. β-d-N 4 -hydroxycytidine, a metabolite of molnupiravir, exhibits in vitro antiviral activity against rabies virus.
- Author
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Konishi K, Kusakabe S, Kawaguchi N, Shishido T, Ito N, Harada M, Inoue S, Maeda K, Hall WW, Orba Y, Sawa H, Sasaki M, and Sato A
- Subjects
- Animals, Mice, Pyrazines pharmacology, Ribavirin pharmacology, Hydroxylamines pharmacology, Cell Line, Tumor, Cell Line, Antiviral Agents pharmacology, Cytidine analogs & derivatives, Cytidine pharmacology, Rabies virus drug effects, Rabies drug therapy, Rabies virology, Amides pharmacology, Viral Load drug effects
- Abstract
Rabies is a fatal neurological disorder caused by rabies virus (RABV) infection. Approximately 60,000 patients die from rabies annually, and there are no effective treatments for this disease. Nucleoside analogs are employed as antiviral drugs based on their broad antiviral spectrum, and certain nucleoside analogs have been reported to exhibit anti-RABV activity. The nucleoside analog β-d-N
4 -hydroxycytidine (NHC) has antiviral effects against a range of RNA viruses. Molnupiravir (MPV), a prodrug of NHC, is clinically used as an oral antiviral drug for coronavirus infections. Despite its broad-spectrum activity, the antiviral activity of NHC against RABV remains unclear. In this study, we reveal that NHC exhibits comparable in vitro anti-RABV activity as ribavirin and favipiravir (also known as T-705) with a 90% effective concentration of 6 μM in mouse neuroblastoma cells. NHC reduced viral loads in neuronal and nonneuronal cells in a dose-dependent manner. Both laboratory and field RABVs (fixed and street strains, respectively) were susceptible to NHC. However, no increase in survival or reduction in viral titers in the brain was observed in RABV-infected mice treated prophylactically with MPV. These findings highlight the potential and challenges of NHC in the treatment of RABV infection., Competing Interests: Declaration of competing interest All experiments reported in this paper was financially supported by Shionogi & Co., Ltd. The authors K.K., S.K., S.T. and A.S. are employees of Shionogi & Co., Ltd. The remaining authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)- Published
- 2024
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