Characterization of three small molecule inhibitors of enterovirus 71 identified from screening of a library of natural products
Characterization of three small molecule inhibitors of enterovirus 71 identified from screening of a library of natural products
复制标题
通过筛选天然产物库鉴定出三种肠道病毒 71 型小分子抑制剂的表征
DOI：
10.1016/j.antiviral.2017.04.006
复制
发表时间：
2017-07-01
影响因子：
7.6
通讯作者：
Zou, Gang
中科院分区：
文献类型：
--
作者：
Li, Guiming;Gao, Qianqian;Zou, Gang
肠道病毒71（EV-A71）是手足口病（HFMD）的主要病因。EV-A71感染通常与儿童的神经系统并发症有关，并且是大多数死亡的原因，但目前还没有批准的抗病毒治疗。在这里，我们确定了auraptene，芒柄花素，和yangonin作为有效的抑制剂EV-A71感染的低微摩尔范围内筛选的天然产物库。其中芒柄花素和羊黄素选择性抑制EV-A71，而金萝卜素可抑制肠道病毒A种内的病毒。添加时间的研究表明，所有三种抑制剂抑制附着和附着后进入步骤。我们在VP 1和VP 4衣壳蛋白中发现了赋予对这些抑制剂的抗性的突变，并使用反向遗传方法确认了靶残基。有趣的是，auraptene和芒柄花素耐药病毒表现出对其他抑制剂的交叉耐药性，而yangonin耐药病毒仍然对auraptene和芒柄花素敏感。此外，auraptene和芒柄花素，但不是yangonin保护EV-A71对热灭活，表明两种化合物对病毒粒子衣壳构象的直接稳定作用。最后，鹰嘴豆芽素A（芒柄花黄素的类似物）和DL-Kavain（羊黄素的类似物）都没有表现出抗EV-A71活性，表明抗EV-A71活性所需的结构元件。总之，这些化合物可能成为抗EV-A71药物开发的潜在先导化合物，也可作为研究病毒进入的工具化合物。(C)2017爱思唯尔B. V.保留所有权利。
Enterovirus 71 (EV-A71) is a major cause of hand, foot, and mouth disease (HFMD). Infection with EV-A71 is more often associated with neurological complications in children and is responsible for the majority of fatalities, but currently there is no approved antiviral therapy for treatment. Here, we identified auraptene, formononetin, and yangonin as effective inhibitors of EV-A71 infection in the low-micromolar range from screening of a natural product library. Among them, formononetin and yangonin selectively inhibited EV-A71 while auraptene could inhibit viruses within the enterovirus species A. Time of addition studies showed that all the three inhibitors inhibit both attachment and postattachment step of entry. We found mutations conferring the resistance to these inhibitors in the VP1 and VP4 capsid proteins and confirmed the target residues using a reverse genetic approach. Interestingly, auraptene and formononetin-resistant viruses exhibit cross-resistance to other inhibitors while yangonin-resistant virus still remains susceptible to auraptene and formononetin. Moreover, auraptene and formononetin, but not yangonin protected EV-A71 against thermal inactivation, indicating a direct stabilizing effect of both compounds on virion capsid conformation. Finally, neither biochanin A (an analog of formononetin) nor DL-Kavain (an analog of yangonin) exhibited anti-EV-A71 activity, suggesting the structural elements required for anti-EV-A71 activity. Taken together, these compounds could become potential lead compounds for anti-EV-A71 drug development and also serve as tool compounds for studying virus entry. (C) 2017 Elsevier B.V. All rights reserved.