Therapeutic efficacy of favipiravir against henipavirus infections

摘要 尼帕病毒和亨德拉病毒是最近出现的蝙蝠传播的副粘病毒（亨帕病毒属），引起严重的 脑炎和呼吸道疾病，死亡率为40- 75%。尽管严重的 由于这些病毒的致病性及其大流行的可能性，目前还没有批准治疗或疫苗 用于人类。法匹拉韦（T-705）是一种嘌呤类似物抗病毒药物，在日本获批用于治疗新出现的 流感病毒株;美国和欧洲正在进行几项2期和3期临床试验。 此前，已证实法匹拉韦对大量RNA具有广谱抗病毒活性。 病毒，包括副粘病毒科、丝状病毒科、沙粒病毒科和布尼亚病毒科的成员。与 在持续的COVID-19大流行中，法匹拉韦也被讨论为一种潜在的抗病毒药物用于治疗 轻度至中度症状的SARS-CoV-2感染患者，目前正在几项临床试验中进行测试。 我们能够证明法匹拉韦在细胞培养物中对亨尼帕病毒具有有效的抗病毒活性， EC 50在低微摩尔范围内。此外，我们可以证明，用法匹拉韦治疗导致完全的 保护尼帕病毒感染的仓鼠，这表明法匹拉韦应作为抗病毒药物进行进一步评估。 亨尼帕病毒感染的治疗选择。这项申请的总体目标是开发抗病毒治疗 由亨尼帕病毒引起的感染的选择。我们的假设是法匹拉韦将证明治疗 在一种疾病相关的， 广泛接受的小动物模型，将在暴露后环境中有效，并中断传播。 为了质疑我们的驱动假说，我们提出了以下具体目标：（1）优化治疗方案， 法匹拉韦对叙利亚仓鼠模型中亨尼帕病毒感染的疗效;和（2）评价 法匹拉韦可通过致死性诱变引起尼帕病毒的灭绝。拟议的研究将 为进一步开发法匹拉韦作为广谱抗病毒药物提供基础信息， 最终导致抗亨尼帕病毒感染的对策的发展。

ABSTRACT Nipah and Hendra viruses are recently emerged bat-borne paramyxoviruses (genus Henipavirus) causing severe encephalitis and respiratory disease in humans with fatality rates ranging from 40-75%. Despite the severe pathogenicity of these viruses and their pandemic potential, no therapeutics or vaccines are currently approved for use in humans. Favipiravir (T-705) is a purine analogue antiviral approved for use in Japan against emerging influenza strains; and several phase 2 and 3 clinical trials are ongoing in the United States and Europe. Previously, broad-spectrum antiviral activity of favipiravir has been demonstrated against a large number of RNA viruses, including members of the Paramyxoviridae, Filoviridae, Arenaviridae, and Bunyaviridae families. With the ongoing COVID-19 pandemic, favipiravir has also been discussed as a potential antiviral drug for treatment of mild to moderate symptomatic SARS-CoV-2-infected patients and is currently tested in several clinical trials. We were able to demonstrate that favipiravir has potent antiviral activity against henipaviruses in cell culture with EC50's in the low micromolar range. Furthermore, we could show that treatment with favipiravir resulted in full protection of Nipah virus-infected hamsters, suggesting that favipiravir should be further evaluated as an antiviral treatment option for henipavirus infections. The overall goal of this application is to develop antiviral treatment options for infections caused by henipaviruses. Our hypothesis is that favipiravir will demonstrate therapeutic antiviral efficacy against all human pathogenic Nipah virus strains and Hendra virus in a disease-relevant and widely accepted small animal model, will be efficacious in a post-exposure setting, and interrupt transmission. To interrogate our driving hypothesis, we propose the following Specific Aims: (1) Optimize the therapeutic efficacy of favipiravir against henipavirus infection in the Syrian hamster model; and (2) Evaluate if favipiravir can evoke extinction of Nipah virus through lethal mutagenesis. The proposed studies will provide fundamental information for the further development of favipiravir as a broad-spectrum antiviral, and ultimately lead to the development of countermeasures against henipavirus infections.