The mechanism of resistance to favipiravir in influenza.
The mechanism of resistance to favipiravir in influenza.
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DOI：
10.1073/pnas.1811345115
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发表时间：
2018-11-06
影响因子：
11.1
通讯作者：
Barclay WS
中科院分区：
文献类型：
--
作者：
Goldhill DH;Te Velthuis AJW;Fletcher RA;Langat P;Zambon M;Lackenby A;Barclay WS
法匹拉韦是一种广谱抗病毒药物，在治疗流感病毒感染方面显示出前景，特别是由于在细胞培养或动物研究中明显缺乏对该药物的耐药性突变。我们在此证明，病毒RNA聚合酶保守区的突变可在体外和细胞培养中对法匹拉韦产生耐药性。耐药突变对病毒适应性有代价，但这可以通过聚合酶中的补偿突变来恢复。我们的研究结果支持开发法匹拉韦耐药性诊断和监测检测策略，并加强了考虑联合治疗流感感染的重要性。法匹拉韦是一种广谱抗病毒药物，已显示出治疗流感病毒感染的前景。虽然已观察到许多抗流感药物出现耐药性，但迄今为止，法匹拉韦的临床试验和实验室研究尚未产生耐药性病毒。在这里，我们展示了在实验室环境中大流行性H1N1甲型流感病毒对法匹拉韦耐药性的演变。我们发现，对法匹拉韦的强耐药性需要两个突变。我们证明了流感病毒RNA依赖性RNA聚合酶（RdRP）PB1亚基基F基序中的K229R突变在体外和细胞培养中赋予对法匹拉韦的耐药性。这种突变对病毒适应性有代价，但适应性可以通过聚合酶的PA亚基中的P653L突变来恢复。K229 R还赋予法匹拉韦对其他甲型流感病毒株RNA聚合酶的耐药性，其在RdRP高度保守结构特征中的位置表明其他RNA病毒也可能通过基序F突变获得耐药性。这里鉴定的突变可用于筛选接受法匹拉韦治疗的流感病毒感染患者是否出现耐药性。
Favipiravir is a broad-spectrum antiviral that has shown promise in treatment of influenza virus infections, in particular due to the apparent lack of emergence of resistance mutations against the drug in cell culture or animal studies. We demonstrate here that a mutation in a conserved region of the viral RNA polymerase confers resistance to favipiravir in vitro and in cell culture. The resistance mutation has a cost to viral fitness, but this can be restored by a compensatory mutation in the polymerase. Our findings support the development of favipiravir-resistance diagnostic and surveillance testing strategies and reinforce the importance of considering combinations of therapies to treat influenza infections. Favipiravir is a broad-spectrum antiviral that has shown promise in treatment of influenza virus infections. While emergence of resistance has been observed for many antiinfluenza drugs, to date, clinical trials and laboratory studies of favipiravir have not yielded resistant viruses. Here we show evolution of resistance to favipiravir in the pandemic H1N1 influenza A virus in a laboratory setting. We found that two mutations were required for robust resistance to favipiravir. We demonstrate that a K229R mutation in motif F of the PB1 subunit of the influenza virus RNA-dependent RNA polymerase (RdRP) confers resistance to favipiravir in vitro and in cell culture. This mutation has a cost to viral fitness, but fitness can be restored by a P653L mutation in the PA subunit of the polymerase. K229R also conferred favipiravir resistance to RNA polymerases of other influenza A virus strains, and its location within a highly conserved structural feature of the RdRP suggests that other RNA viruses might also acquire resistance through mutations in motif F. The mutations identified here could be used to screen influenza virus-infected patients treated with favipiravir for the emergence of resistance.
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DOI：
10.2183/pjab.93.027
发表时间：
2017
期刊：
Proceedings of the Japan Academy. Series B, Physical and biological sciences
影响因子：
--
作者：
Furuta Y;Komeno T;Nakamura T
通讯作者：
Nakamura T
影响因子：
16.6
作者：
Cheung, Peter P. H.;Watson, Simon J.;Choy, Ka-Tim;Sia, Sin Fun;Wong, Diana D. Y.;Poon, Leo L. M.;Kellam, Paul;Guan, Yi;Peiris, J. S. Malik;Yen, Hui-Ling
通讯作者：
Yen, Hui-Ling
影响因子：
7.6
作者：
Furuta, Yousuke;Gowen, Brian B.;Takahashi, Kazumi;Shiraki, Kimiyasu;Smee, Donald F.;Barnard, Dale L.
通讯作者：
Barnard, Dale L.
影响因子：
5.2
作者：
Delang, Leen;Segura Guerrero, Nidya;Leyssen, Pieter
通讯作者：
Leyssen, Pieter
T-705（法匹拉韦）呋喃核糖基 5'-三磷酸对甲型流感病毒聚合酶的模糊碱基配对和高底物效率。
影响因子：
3.7
作者：
Jin Z;Smith LK;Rajwanshi VK;Kim B;Deval J
通讯作者：
Deval J