Coxsackievirus A10 atomic structure facilitating the discovery of a broad-spectrum inhibitor against human enteroviruses
Coxsackievirus A10 atomic structure facilitating the discovery of a broad-spectrum inhibitor against human enteroviruses
复制标题
柯萨奇病毒 A10 原子结构促进人类肠道病毒广谱抑制剂的发现
DOI：
10.1038/s41421-018-0073-7
复制
发表时间：
2019-01-15
期刊：
影响因子：
33.5
通讯作者：
Huang, Zhong
中科院分区：
文献类型：
--
作者：
Chen, Jinhuan;Ye, Xiaohua;Huang, Zhong
柯萨奇病毒A10（CV-A10）属于肠道病毒A种，是手足口病的病原体。在这里，我们提出了CV-A10成熟病毒粒子和天然空颗粒（NEP）的冷冻电镜结构，分别在2.84和3.12埃。我们的CV-A10成熟病毒粒子结构揭示了对应于在病毒蛋白1内形成的疏水口袋中的18个碳原子的疏水口袋因子的密度。通过结构导向的高通量药物筛选和随后的基于细胞的感染抑制试验的验证，我们鉴定了四种体外抑制CV-A10感染的化合物。这些化合物代表了一类新的抗肠道病毒药物先导。值得注意的是，化合物之一ICA 135也对来自所有四种人类肠道病毒（A-D）的许多代表性病毒发挥广谱抑制作用。我们的研究结果将有助于开发广泛有效的肠道病毒感染药物和疫苗。
Coxsackievirus A10 (CV-A10) belongs to the Enterovirus species A and is a causative agent of hand, foot, and mouth disease. Here we present cryo-EM structures of CV-A10 mature virion and native empty particle (NEP) at 2.84 and 3.12 angstrom, respectively. Our CV-A10 mature virion structure reveals a density corresponding to a lipidic pocket factor of 18 carbon atoms in the hydrophobic pocket formed within viral protein 1. By structure-guided high-throughput drug screening and subsequent verification in cell-based infection-inhibition assays, we identified four compounds that inhibited CV-A10 infection in vitro. These compounds represent a new class of anti-enteroviral drug leads. Notably, one of the compounds, ICA135, also exerted broad-spectrum inhibitory effects on a number of representative viruses from all four species (A-D) of human enteroviruses. Our findings should facilitate the development of broadly effective drugs and vaccines for enterovirus infections.