基于结构的耐药流感病毒抑制剂的设计、合成及生物活性研究

项目名称： 基于结构的耐药流感病毒抑制剂的设计、合成及生物活性研究

项目编号： No.31470801

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 李学兵

作者单位： 中国科学院微生物研究所

项目金额： 85万元

中文摘要： 近年来，新型流感的爆发率呈上升趋势（如2009年甲型H1N1和2013年H7N9禽流感），同时针对传统抗流感药物（扎那米韦和奥司米韦）的耐药病毒已大量出现，如何快速地发现新一代抗流感药物已成为流感防控中的一个重要问题。在前期研究中，根据流感病毒表面囊膜蛋白Neuraminidase（NA）四聚体的构象以及药物结合位点的空间分布特征，设计并合成了一种以NA为靶标、含有四个扎那米韦药效团的四价流感病毒抑制剂。初步活性评价表明该化合物对耐药毒株NA的抑制强度约为扎那米韦的30倍。本课题拟对该化合物进行更加深入、广泛的药效学评价，选择不同亚型的耐药与非耐药NA及病毒分别在分子水平、细胞水平以及动物（小鼠）水平上研究其活性和作用机制，并通过构效关系优化其结构，旨在获得可高效抑制流感病毒（包括耐药毒株在内）的抑制剂，为发现创新型抗流感药物提供基础。

中文关键词： 流感病毒；神经氨酸酶；唾液酸；扎那米韦；抑制剂

英文摘要： Recent outbreaks of new influenza viruses, such as 2009 A/H1N1 and 2013 avian H7N9, have caused public panic and economic losses. The emergence of resistant strains to currently available drugs (zanamivir and oseltamivir) further necessitates effective means to prevent and treat these contagious pathogens. Previously, based on the 3D structure of target protein, the viral surface tetrameric neuraminidase (NA), we have developed a novel anti-influenza agent, which has four terminal zanamivir pharmacophores covalently linked on a small core molecule. This compound has showed 30-fold higher inhibitory activity against a NA derived from a drug-resistant viral strain than monovalent zanamivir. Here we propose the more comprehensive studies on the biochemical and physiological effects of this compound. These include both the in vitro and in vivo evaluations of the inhibitory effect against both drug-resistant and -nonresistant strains and their NAs, as well as the mechanism-of-action studies. The optimization of structure and activity of the compound is also incorporated in the research program to obtain potential anti-influenza drug candidate that is effective to both resistant and nonresistant strains. This research project may provide a valuable example of the application of structure-based drug design.

英文关键词： influenza virus;neuraminidase;sialic acid;zanamivir;inhibitor