Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants
Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants
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DOI：
10.1038/nature06956
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发表时间：
2008-06-26
期刊：
影响因子：
64.8
通讯作者：
Gamblin, Steven J.
中科院分区：
文献类型：
--
作者：
Collins, Patrick J.;Haire, Lesley F.;Gamblin, Steven J.
大流行性流感的潜在影响使得采取有效措施限制病毒感染的传播和发病率成为公共卫生的优先事项。抗病毒药物被视为控制由新病毒引起的最初流感暴发的基本要求，在大流行前的计划中，严重依赖药物储备。这些药物的主要靶点是病毒表面糖蛋白神经氨酸酶，它促进新生病毒的释放，从而促进感染的传播。奥司他韦（达菲）和扎那米韦（瑞乐沙）是两种目前使用的神经氨酸酶抑制剂，它们是利用酶结构的知识开发的（1，2）。有人提出，这种抑制剂越接近天然底物，它们越不可能选择保留活力的耐药突变病毒（3）。然而，已有体外（4）和从受感染的人（5，6）中选择耐药突变体的报道.我们在这里报告的酶的性质和晶体结构的神经氨酸酶突变体从H5N1感染的患者，解释耐药的分子基础。我们的研究结果表明，这些突变体对奥司他韦有抗性，但由于奥司他韦结合所需的酶活性位点中的疏水口袋改变，扎那米韦仍强烈抑制这些突变体。结合最近关于神经氨酸酶携带这些突变的H5N1（参考文献7）和H1N1（参考文献8）病毒的生存能力和发病机制的报道，我们的研究结果表明，通过额外的抗病毒药物（包括扎那米韦）来增加奥司他韦的大流行储备是谨慎的。
The potential impact of pandemic influenza makes effective measures to limit the spread and morbidity of virus infection a public health priority. Antiviral drugs are seen as essential requirements for control of initial influenza outbreaks caused by a new virus, and in pre- pandemic plans there is a heavy reliance on drug stockpiles. The principal target for these drugs is a virus surface glycoprotein, neuraminidase, which facilitates the release of nascent virus and thus the spread of infection. Oseltamivir (Tamiflu) and zanamivir ( Relenza) are two currently used neuraminidase inhibitors that were developed using knowledge of the enzyme structure(1,2). It has been proposed that the closer such inhibitors resemble the natural substrate, the less likely they are to select drug- resistant mutant viruses that retain viability(3). However, there have been reports of drug- resistant mutant selection in vitro(4) and from infected humans(5,6). We report here the enzymatic properties and crystal structures of neuraminidase mutants from H5N1- infected patients that explain the molecular basis of resistance. Our results show that these mutants are resistant to oseltamivir but still strongly inhibited by zanamivir owing to an altered hydrophobic pocket in the active site of the enzyme required for oseltamivir binding. Together with recent reports of the viability and pathogenesis of H5N1 ( ref. 7) and H1N1 ( ref. 8) viruses with neuraminidases carrying these mutations, our results indicate that it would be prudent for pandemic stockpiles of oseltamivir to be augmented by additional antiviral drugs, including zanamivir.