Structure-based discovery of anti-influenza virus A compounds among medicines
Structure-based discovery of anti-influenza virus A compounds among medicines
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DOI：
10.1016/j.bbagen.2011.11.003
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发表时间：
2012-02-01
影响因子：
3
通讯作者：
Kuwata, Kazuo
中科院分区：
文献类型：
--
作者：
Fukuoka, Mayuko;Minakuchi, Moeko;Kuwata, Kazuo
背景：甲型流感病毒(IAV)感染是当今一个主要的公共卫生问题，特别是自2009年H1N1流感大流行以来。对针对神经氨酸酶的奥司他韦或扎那米韦等现有药物产生抗药性的IAV毒株的暴发，对人类和动物都是一个真正的威胁。因此，开发具有新的作用机制的抗IAV药物可能是一个紧迫的主题。方法：我们利用包含4000个类似化合物的药物数据库，针对PA与PB1相互作用的界面进行了对接模拟。然后用IAV/WSN/33进行细胞存活率和空斑实验。结果：苯溴马龙、地克珠利、曲宁隆具有较强的抗IAV活性。结论：苯溴马隆和地克珠利具有较强的抗IAV活性，作用机制新颖，即抑制病毒RNA聚合酶。一般意义：由于苯溴马龙和地克珠利已经作为药物用于公共场合，因此可以作为IAV暴发时的替代药物。(C)2011爱思唯尔B.V.保留所有权利。
Background: Influenza A virus (IAV) infection is nowadays a major public health concern, in particular since the 2009 H1N1 flu pandemic. The outbreak of IAV strains resistant to currently available drugs, such as oseltamivir or zanamivir targeting the neuraminidase, is a real threat for humans as well as for animals. Thus the development of anti-IAV drugs with a novel action mechanism may be an urgent theme.Methods: We performed a docking simulation targeting the interface of PA interacting with PB1 using a drug database including similar to 4000 compounds. We then conducted cell viability assay and plaque assay using IAV/WSN/33. Finally we examined their anti-IAV mechanism by surface plasmon resonance and IAV replicon assay.Results: We found that benzbromarone, diclazuril, and trenbolone acetate had strong anti-IAV activities. We confirmed that benzbromarone and diclazuril bound with PA subunit, and decreased the transcriptional activity of the viral RNA polymerase.Conclusions: Benzbromarone and diclazuril had strong anti-IAV activities with novel action mechanism, i.e. inhibition of viral RNA polymerase.General significance: Since benzbromarone and diclazuril are already used in public as medicines, these could be the candidates for alternatives in case of an outbreak of IAV which is resistant to pre-existing anti-IAV drugs. (C) 2011 Elsevier B.V. All rights reserved.