Department of Biological Sciences, Purdue University, West Lafayette, IN 47907-2032, USA.
Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5463-7. doi: 10.1073/pnas.1222379110. Epub 2013 Mar 18.
Human enterovirus 71 is a picornavirus causing hand, foot, and mouth disease that may progress to fatal encephalitis in infants and small children. As of now, no cure is available for enterovirus 71 infections. Small molecule inhibitors binding into a hydrophobic pocket within capsid viral protein 1 were previously shown to effectively limit infectivity of many picornaviruses. Here we report a 3.2-Å-resolution X-ray structure of the enterovirus 71 virion complexed with the capsid-binding inhibitor WIN 51711. The inhibitor replaced the natural pocket factor within the viral protein 1 pocket without inducing any detectable rearrangements in the structure of the capsid. Furthermore, we show that the compound stabilizes enterovirus 71 virions and limits its infectivity, probably through restricting dynamics of the capsid necessary for genome release. Thus, our results provide a structural basis for development of antienterovirus 71 capsid-binding drugs.
肠道病毒 71 型是一种小核糖核酸病毒，可引起手足口病，在婴幼儿中可进展为致命性脑炎。目前，尚无针对肠道病毒 71 感染的治疗方法。先前的研究表明，与衣壳病毒蛋白 1 内的疏水口袋结合的小分子抑制剂能有效限制多种小核糖核酸病毒的感染性。在此，我们报道了肠道病毒 71 病毒粒子与衣壳结合抑制剂 WIN 51711 形成复合物的 3.2 Å 分辨率的 X 射线结构。该抑制剂取代了病毒蛋白 1 口袋中的天然口袋因子，而衣壳结构没有发生任何可检测到的重排。此外，我们还表明，该化合物稳定了肠道病毒 71 病毒粒子并限制了其感染性，可能是通过限制衣壳释放基因组所需的动力学。因此，我们的结果为开发抗肠道病毒 71 衣壳结合药物提供了结构基础。
