五环三萜类手足口病病毒抑制剂的作用机制与结构优化研究

项目名称： 五环三萜类手足口病病毒抑制剂的作用机制与结构优化研究

项目编号： No.81473080

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 温小安

作者单位： 中国药科大学

项目金额： 73万元

中文摘要： 手足口病是多发于学龄前儿童的急性传染病，重症患儿易出现脑炎、脑膜炎等神经系统伤害，其危害已超过流行性乙型脑炎和流行性脑脊髓膜炎。肠道病毒EV71型是手足口病的主要致病原，然而目前在临床上尚无有效的抗EV71病毒药物可用于手足口病的治疗。前期研究发现，一系列五环三萜化合物具有显著的抗EV71病毒活性，其中活性最好的化合物IC50值达41nM。初步的机制研究表明，五环三萜极可能结合于EV71病毒衣壳蛋白VP1上的疏水口袋，取代其中的口袋因子，使衣壳蛋白更稳定，病毒基因不易被释放感染宿主细胞。本课题研究五环三萜类EV71病毒抑制剂的作用机制，确定其抗EV71病毒的作用靶标和作用模式。并基于上述研究结果，以五环三萜为骨架进行EV71病毒抑制剂的合理药物设计、合成及生物活性研究。期望通过本项目研究为开发抗EV71病毒药物提供新方向，并发现具有成药性的候选化合物，为开发手足口病治疗药物奠定基础。

中文关键词： 手足口病；肠道病毒71型；抑制剂；作用机制；结构优化

英文摘要： Hand,foot, and mouth disease (HFMD) is an acute infectious disease often broken out among the preschoolers. The seriously sick children are easily suffered from severe encephalitis, meningitis and other neurological damage.The HFMD harm has exceeded Japanese encephalitis and meningococcal meningitis. Entrovirus 71 (EV71)is the main causative pathogen of hand, foot and mouth disease. However, currently there is no clinically effective anti-viral drugs available for the treatment of EV71 HFMD. Our previous studies have found that a series of pentacyclic triterpenes have significant anti-EV71 viral activity, among which the best active compound has an IC50 value of 41 nM. Preliminary mechanism studies indicate that the pentacyclic triterpenes likely bind to the hydrophobic pocket on the EV71 capsid protein VP1, replacing the pocket factor so that the capsid protein is more stable and less susceptible to the release of viral genes to infect host cells. This application project is to study the mechanism of pentacyclic triterpenes as EV71 virus inhibitors, including to determine their anti- EV71 virus targets and modes of action. Based on the resulting findings, rational drug design, synthesis and biological evaluation of EV71 virus inhibitors will also be conducted with pentacyclic triterpenes as the skeletons. This research is expected to find a new direction for the development of anti- EV71 viral drugs and identify candidate compounds with drug likability to pave the way to drug discovery for treatment of hand foot and mouth disease.

英文关键词： Hand-foot-mouth disease;Enterovirus 71;Inhibitor;Mechanism;Structural optimization