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(亨尼帕病毒属)，引起严重的 人类感染脑炎和呼吸道疾病，病死率从40%到75%不等。尽管情况严峻 这些病毒的致病性及其大流行的可能性，目前没有治疗方法或疫苗被批准 在人类身上使用。法维拉韦(T-705)是一种嘌呤类似物，在日本被批准用于治疗新出现的 美国和欧洲正在进行几项2期和3期临床试验。 此前，法韦拉韦的广谱抗病毒活性已经被证明可以对抗大量的rna。 病毒，包括副粘病毒科、丝状病毒科、阿伦病毒科和布尼亚病毒科的成员。使用 正在进行的新冠肺炎大流行，法韦拉韦也被讨论为一种潜在的抗病毒药物 该产品适用于轻至中度有症状的SARS-CoV-2感染患者，目前正在几个临床试验中进行测试。 我们在细胞培养中证实了法韦拉韦对Heipav病毒具有有效的抗病毒活性。 EC50‘S在低微摩尔范围内。此外，我们可以证明，用法韦拉韦治疗后完全缓解 对感染尼帕病毒的仓鼠的保护作用，建议应进一步评估法韦拉韦作为抗病毒药物的作用 埃尼帕病毒感染的治疗选择。这个应用程序的总体目标是开发抗病毒治疗 埃尼帕病毒引起的感染的选择。我们的假设是法维拉韦将显示出治疗作用 对所有人类致病性尼帕病毒株和亨德拉病毒株的抗病毒效果 被广泛接受的小动物模型，将在曝光后设置有效，并中断传播。 为了验证我们的驾驶假说，我们提出了以下具体目标：(1)优化治疗 法韦拉韦在叙利亚仓鼠模型中对埃尼帕病毒感染的疗效；以及(2)评估是否 法韦拉韦可通过致死性突变引起尼帕病毒的灭绝。拟议的研究将 为法韦拉韦作为广谱抗病毒药物的进一步开发提供基本信息 最终导致制定针对埃尼帕病毒感染的对策。

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.