T-705 (Favipiravir) Inhibition of Arenavirus Replication in Cell Culture
T-705 (Favipiravir) Inhibition of Arenavirus Replication in Cell Culture
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DOI：
10.1128/aac.01219-10
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发表时间：
2011-02-01
影响因子：
4.9
通讯作者：
Gowen, Brian B.
中科院分区：
文献类型：
--
作者：
Mendenhall, Michelle;Russell, Andrew;Gowen, Brian B.
许多新世界沙粒病毒（朱宁[JUNV]、马丘波[MACV]和瓜纳里托[GTOV]病毒）可引起人类疾病，从轻度发热性疾病到严重且通常致命的出血热综合征。这些高致病性病毒和旧大陆拉沙热病毒对公共卫生和国家安全构成重大威胁。唯一许可的抗病毒药物对这些病毒的活性，利巴韦林，在治疗严重的沙粒病毒病方面取得了混合的成功，并与显着的毒性。目前用于治疗流感病毒感染的临床试验中的新型吡嗪衍生物T-705（法匹拉韦）已证明对许多RNA病毒（包括沙粒病毒）具有广谱活性。T-705也已被证明在仓鼠模型中对皮钦德沙粒病毒感染有效。在这里，我们证明了T-705在细胞培养中对真实的高致病性沙粒病毒的强大抗病毒活性。我们发现，T-705破坏病毒复制的早期或中期阶段，不同于吸收或释放，其在细胞培养中的抗病毒活性通过加入嘌呤碱基和核苷逆转，但不与嘧啶。使用淋巴细胞性脉络丛脑膜炎沙粒病毒复制子系统证明T-705对病毒复制/转录的特异性抑制。我们的研究结果表明，T-705的行为，以抑制沙粒病毒复制/转录，并可能直接靶向病毒RNA依赖的RNA聚合酶。
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.