基于三环苦参骨架衍生物的设计、合成及其广谱抗流感病毒活性研究

项目名称： 基于三环苦参骨架衍生物的设计、合成及其广谱抗流感病毒活性研究

项目编号： No.81502934

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 唐胜

作者单位： 中国医学科学院医药生物技术研究所

项目金额： 17.9万元

中文摘要： 流感病毒引起的突发传染性疾病时有发生。我们自主创新的苦参烷类化合物DB-1对A、B多个流感病毒亚型均显示较好活性，尤其对达菲/金刚烷胺耐药株也有效。提示，DB-1具有广谱抗流感活性，化学骨架与生物机制目前临床用药完全不同。.本项目拟在一系列原创性工作基础上，以DB-1为先导物，以抗A型流感病毒为活性导向，保留三环苦参骨架，主要在其11-和12-位侧链开展丰富的结构修饰与优化，累计合成不少于80个苦参骨架衍生物，阐明其抗流感构效关系。通过对多株耐药流感病毒、初步毒性、药代参数以及体内药效等综合性评价，优选出成药性高、治疗窗口宽的候选物，为发展一类全新骨架抗流感药物提供科学数据。.本项目产生的候选物，为流感治疗及耐药克服提供一个全新组分；为突发性流感的应急与防控提供重要的物质储备，尤其在病原来不及鉴定的应急情况下使用。提升我国药物研究源头创新能力，将我国抗病毒原创药物研究推向世界前沿。

中文关键词： 苦参骨架；构效关系；抗流感病毒；广谱；耐药

英文摘要： Outbreak epidemics caused by influenza occurs all the time. Our innovative matrinane derivative (DB-1) was active against several subtypes of type A and B influenza, especially active against those showing resistance to oseltamivir and amantadine, which hinted that DB-1 diaplayed a broad-spectrum influenza antiviral activity with the chemical skeleton and mechanism different from that of clinical medication..Based on theses original work, taking DB-1 as the lead, directed by the activity against type A influenza viruses, systematic structural modifications and optimizations mainly focusing on the 11- and 12- side chain will be carried out in the titled project, while the three-ring matrine skeleton was remained, at least 80 novel matrine butane derivatives with novel structures will be synthesized to illustrate their anti-influenza structure-activity relationships (SAR). By the following comprehensive druaggable evaluation studies, including assay towards multi-drug resistant influenza strains, primary toxicity, ppharmacokinetics and pharmacodynamics in vivo, several novel candidates characterized by high druggablity and high therapeutic window will be selected out. The research will provide scientific data for the development of them into a new class of anti-influenza candidates..The candidates generated from this project will provide a novel component for the treatment of influenza and especially drug-resistant influenza, offer an important prevention and control material reservoir for the outbreak epidemic of influenza, especially in case of emergencies when the pathogen was unable or too late to be determined, improve China’s original innovative ability in drug research, and prompt China’s innovative antiviral drug research to enter the frontier of the world.

英文关键词： matrinanin scaffold;structure-activity relationship ; anti-influenza virus;broad-spectrum;drug resistance