2. Academic Validation
  3. β-d-N4-hydroxycytidine, a metabolite of molnupiravir, exhibits in vitro antiviral activity against rabies virus

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

  • Antiviral Res. 2024 Sep:229:105977. doi: 10.1016/j.antiviral.2024.105977.
Kei Konishi 1,  Shinji Kusakabe 1,  Nijiho Kawaguchi 2,  Takao Shishido 3,  Naoto Ito 4,  Michiko Harada 5,  Satoshi Inoue 5,  Ken Maeda 5,  William W Hall 6,  Yasuko Orba 7,  Hirofumi Sawa 8,  Michihito Sasaki 9,  Akihiko Sato 10
Affiliations

Affiliations

  • 1 Laboratory for Drug Discovery & Disease Research, Shionogi & Co., Ltd., Osaka, Japan; Division of Anti-Virus Drug Research, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan.
  • 2 Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan.
  • 3 Laboratory for Drug Discovery & Disease Research, Shionogi & Co., Ltd., Osaka, Japan.
  • 4 Laboratory of Zoonotic Diseases, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan.
  • 5 Department of Veterinary Science, National Institute of Infectious Diseases (NIID), Tokyo, Japan.
  • 6 International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; National Virus Reference Laboratory, School of Medicine, University College of Dublin, Ireland; Global Virus Network, Baltimore, MD, USA; Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan.
  • 7 Division of Anti-Virus Drug Research, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan; One Health Research Center, Hokkaido University, Sapporo, Japan.
  • 8 Division of Anti-Virus Drug Research, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; Global Virus Network, Baltimore, MD, USA; Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan; One Health Research Center, Hokkaido University, Sapporo, Japan.
  • 9 Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan. Electronic address: m-sasaki@czc.hokudai.ac.jp.
  • 10 Laboratory for Drug Discovery & Disease Research, Shionogi & Co., Ltd., Osaka, Japan; Division of Anti-Virus Drug Research, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan. Electronic address: akihiko.sato@shionogi.co.jp.
PMID: 39089332 DOI: 10.1016/j.antiviral.2024.105977
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-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.

Keywords

Antiviral; Molnupiravir; Nucleoside analog; Rabies virus; β-d-N(4)-hydroxycytidine.

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