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.
摘要：
狂犬病是由狂犬病病毒（RABV）感染引起的一种致命的神经系统疾病。每年大约有6万名病人死于狂犬病,这种疾病没有有效的治疗方法。核苷类似物基于其广泛的抗病毒谱被用作抗病毒药物，和某些核苷类似物已被报道表现出抗RABV活性。核苷类似物β-d-N4-羟胞苷(NHC)对一系列RNA病毒具有抗病毒作用。Molnupiravir(MPV),NHC的前药，临床上用作冠状病毒感染的口服抗病毒药物。尽管其广谱活动，NHC对RABV的抗病毒活性尚不清楚.在这项研究中,我们揭示了NHC在体外表现出与利巴韦林和法培韦（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6μM。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。实验室和野外RABV(固定菌株和街头菌株，分别)易感NHC。然而,在接受MPV预防性治疗的RABV感染小鼠中,未观察到脑内存活率增加或病毒滴度降低.这些发现突出了NHC在治疗RABV感染中的潜力和挑战。
