Development of broad-spectrum antiviral therapies is critical for outbreak and pandemic preparedness against emerging and reemerging viruses. Viruses inducing hemorrhagic fevers cause high morbidity and mortality in humans and are associated with several recent international outbreaks, but approved therapies for treating most of these pathogens are lacking. Here, we show that 4′-fluorouridine (4′-FlU; EIDD-2749), an orally available ribonucleoside analog, has antiviral activity against multiple hemorrhagic fever viruses in cell culture, including Nipah virus, Crimean-Congo hemorrhagic fever virus, orthohantaviruses, and arenaviruses. We performed preclinical in vivo evaluation of oral 4′-FlU against two arenaviruses, Old World Lassa virus (LASV) and New World Junín virus (JUNV), in guinea pig models of lethal disease. 4′-FlU demonstrated both advantageous pharmacokinetic characteristics and high efficacy in both of these lethal disease guinea pig models. Additional experiments supported protection of the infected animals even when 4′-FlU delivery was reduced to a low dose of 0.5 milligram per kilogram. To demonstrate clinical utility, 4′-FlU treatment was evaluated when initiated late in the course of infection (12 or 9 days after infection for LASV and JUNV, respectively). Delayed treatment resulted in rapid resolution of clinical signs, demonstrating an extended window for therapeutic intervention. These data support the use of 4′-FlU as a potent and efficacious treatment against highly pathogenic arenaviruses of public health concern with a virus inhibition profile suggesting broad-spectrum utility as an orally available antiviral drug against a wide variety of viral pathogens.

中文翻译：

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延迟低剂量口服 4′-氟尿苷在致死性疾病动物模型中抑制致病性沙粒病毒


广谱抗病毒疗法的开发对于针对新出现和重新出现的病毒的疫情和大流行准备至关重要。诱发出血热的病毒在人类中导致高发病率和死亡率，并与最近的几次国际暴发有关，但缺乏治疗大多数这些病原体的批准疗法。在这里，我们表明 4′-氟尿嘧啶 （4′-FlU;EIDD-2749） 是一种口服核糖核苷类似物，对细胞培养物中的多种出血热病毒具有抗病毒活性，包括尼帕病毒、克里米亚-刚果出血热病毒、正位汉坦病毒和沙粒病毒。我们在致命疾病的豚鼠模型中对两种沙粒病毒，旧世界拉沙病毒 （LASV） 和新世界胡宁病毒 （JUNV） 进行了口服 4′-FlU 的临床前体内评估。4'-FlU 在这两种致命疾病豚鼠模型中均表现出有利的药代动力学特性和高效性。额外的实验支持对感染动物的保护，即使 4'-FlU 递送减少到每公斤 0.5 毫克的低剂量。为了证明临床实用性，在感染后期 （LASV 和 JUNV 分别为感染后 12 或 9 天） 开始评估 4′-FlU 治疗。延迟治疗导致临床症状迅速消退，表明治疗干预的窗口延长。这些数据支持使用 4'-FlU 作为针对公共卫生关注的高致病性沙粒病毒的有效治疗方法，其病毒抑制特征表明作为针对多种病毒病原体的口服抗病毒药物具有广谱效用。