β-d-N4-hydroxycytidine, a metabolite of molnupiravir, exhibits in vitro antiviral activity against rabies virus

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 nuc...

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Veröffentlicht in:Antiviral research 2024-09, Vol.229, p.105977, Article 105977
Hauptverfasser: Konishi, Kei, Kusakabe, Shinji, Kawaguchi, Nijiho, Shishido, Takao, Ito, Naoto, Harada, Michiko, Inoue, Satoshi, Maeda, Ken, Hall, William W., Orba, Yasuko, Sawa, Hirofumi, Sasaki, Michihito, Sato, Akihiko
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Sprache:eng
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Zusammenfassung: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-N4-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. •β-d-N4-hydroxycytidine (NHC) exhibited antiviral activity and inhibited rabies virus (RABV) infection in cultured cells.•NHC had a comparable 90% effective concentration as ribavirin and T-705 in cultured cells.•No therapeutic effect was observed for oral molnupiravir, a prodrug of NHC, in RABV-infected mice.
ISSN:0166-3542
1872-9096
1872-9096
DOI:10.1016/j.antiviral.2024.105977