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.
Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan.
Antiviral Res. 2024 Sep;229:105977. doi: 10.1016/j.antiviral.2024.105977. Epub 2024 Jul 31.
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-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.
狂犬病是一种由狂犬病病毒（RABV）感染引起的致命神经疾病。每年约有 6 万名患者死于狂犬病，目前尚无有效的治疗方法。基于其广谱抗病毒特性，核苷类似物被用作抗病毒药物，并且已经有报道称某些核苷类似物具有抗 RABV 活性。核苷类似物β-d-N-羟基胞苷（NHC）对多种 RNA 病毒具有抗病毒作用。NHC 的前药莫那比拉韦（MPV）已在临床上用作冠状病毒感染的口服抗病毒药物。尽管具有广谱活性，但 NHC 对 RABV 的抗病毒活性仍不清楚。在这项研究中，我们揭示 NHC 在体外具有与利巴韦林和法匹拉韦（也称为 T-705）相当的抗 RABV 活性，在小鼠神经母细胞瘤细胞中的 90%有效浓度为 6 μM。NHC 以剂量依赖性方式降低神经元和非神经元细胞中的病毒载量。实验室和现场 RABV（分别为固定株和街毒株）均对 NHC 敏感。然而，在预防性用 MPV 治疗的 RABV 感染小鼠中，未观察到存活或大脑中病毒滴度的增加。这些发现突出了 NHC 在治疗 RABV 感染方面的潜力和挑战。
