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T-705 (favipiravir) inhibition of arenavirus replication in cell culture.

机译:T-705(favipiravir)在细胞培养物中抑制沙粒病毒复制。

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A number of New World arenaviruses (Junin [JUNV], Machupo [MACV], and Guanarito [GTOV] viruses) can cause human disease ranging from mild febrile illness to a severe and often fatal hemorrhagic fever syndrome. These highly pathogenic viruses and the Old World Lassa fever virus pose a significant threat to public health and national security. The only licensed antiviral agent with activity against these viruses, ribavirin, has had mixed success in treating severe arenaviral disease and is associated with significant toxicities. A novel pyrazine derivative currently in clinical trials for the treatment of influenza virus infections, T-705 (favipiravir), has demonstrated broad-spectrum activity against a number of RNA viruses, including arenaviruses. T-705 has also been shown to be effective against Pichinde arenavirus infection in a hamster model. Here, we demonstrate the robust antiviral activity of T-705 against authentic highly pathogenic arenaviruses in cell culture. We show that T-705 disrupts an early or intermediate stage in viral replication, distinct from absorption or release, and that its antiviral activity in cell culture is reversed by the addition of purine bases and nucleosides, but not with pyrimidines. Specific inhibition of viral replication/transcription by T-705 was demonstrated using a lymphocytic choriomeningitis arenavirus replicon system. Our findings indicate that T-705 acts to inhibit arenavirus replication/transcription and may directly target the viral RNA-dependent RNA polymerase.
机译:许多新世界性鼻病毒(Junin [JUNV],Machupo [MACV]和Guanarito [GTOV]病毒)可以引起人类疾病,从轻度高热疾病到严重的致命性出血热综合症。这些高致病性病毒和旧世界拉萨热病毒对公共卫生和国家安全构成了重大威胁。唯一对这些病毒具有活性的抗病毒药利巴韦林在治疗严重的沙雷亚病毒病方面取得了不同的成功,并伴有明显的毒性。目前正在临床试验中用于治疗流感病毒感染的新型吡嗪衍生物T-705(favipiravir)对多种RNA病毒(包括沙粒病毒)表现出广谱活性。在仓鼠模型中,T-705也被证明可有效抵抗Pichinde沙门氏菌感染。在这里,我们证明了T-705对细胞培养中真正的高致病性沙粒病毒的强大抗病毒活性。我们显示,T-705破坏了病毒复制的早期或中间阶段,不同于吸收或释放,并且其抗病毒活性在细胞培养中可通过添加嘌呤碱基和核苷(而非嘧啶)来逆转。使用淋巴细胞性脉络膜脑膜炎沙门氏病毒复制系统,证明了T-705对病毒复制/转录的特异性抑制。我们的发现表明,T-705可以抑制类病毒的复制/转录,并且可以直接靶向依赖病毒RNA的RNA聚合酶。

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