More-powerful virus inhibitors from structure-based analysis of HEV71 capsid-binding molecules.
More-powerful virus inhibitors from structure-based analysis of HEV71 capsid-binding molecules.
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DOI：
10.1038/nsmb.2769
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发表时间：
2014-03
影响因子：
16.8
通讯作者：
Stuart DI
中科院分区：
文献类型：
--
作者：
De Colibus L;Wang X;Spyrou JAB;Kelly J;Ren J;Grimes J;Puerstinger G;Stonehouse N;Walter TS;Hu Z;Wang J;Li X;Peng W;Rowlands D;Fry EE;Rao Z;Stuart DI
肠病毒71型（HEV71）在儿童和婴儿中的流行主要导致轻微症状，然而，特别是在亚太地区，感染可能是致命的。目前尚无治疗方法。我们利用完整病毒的结构分析来指导HEV71抑制剂的设计。分析了4个具有不同抗hev71活性的3-（-4-吡啶基）-2-咪唑烷酮衍生物的配合物，确定了关键的结构-活性相关关系。然后，我们确定了其他潜在的有益取代，开发了通过量子力学增强配体对接可靠地分类化合物的方法，并合成了两个候选化合物。结构分析和体外实验证实了预测的结合模式及其阻断病毒感染的能力。一个配体（IC50 = 25 pM）比以前报道的最好的抑制剂更有效，也更容易溶解。我们的方法可能有助于设计有效的肠病毒感染药物。
Enterovirus 71 (HEV71) epidemics amongst children and infants result mainly in mild symptoms, however, especially in the Asia-Pacific region, infection can be fatal. At present no therapies are available. We have used structural analysis of the complete virus to guide the design of HEV71 inhibitors. Analysis of complexes with four 3-(-4-pyridyl)-2-imidazolidinone derivatives with varying anti-HEV71 activities, pinpointed key structure-activity correlates. We then identified additional potentially beneficial substitutions, developed methods to reliably triage compounds by quantum mechanics-enhanced ligand docking, and synthesized two candidates. Structural analysis and in vitro assays confirmed the predicted binding modes and their ability to block viral infection. One ligand (IC50 = 25 pM) is an order of magnitude more potent than the best previously reported inhibitor, and is also more soluble. Our approach may be useful in the design of effective drugs for enterovirus infections.