协同氟康唑抗耐药真菌的小分子探针设计合成及其靶点研究

项目名称： 协同氟康唑抗耐药真菌的小分子探针设计合成及其靶点研究

项目编号： No.21272270

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 数理科学和化学

项目作者： 张大志

作者单位： 中国人民解放军第二军医大学

项目金额： 80万元

中文摘要： 真菌耐药日益严重，尚无良策。我们前期发现连翘酯苷A、小檗碱、黄芩素、芒果苷等化合物具有协同氟康唑抗耐药真菌作用。化合物之间具有相近的体内外药效、作用机制存相同之处；构效关系研究表明了它们有相似的药效基团。但我们对其作用靶点研究一直未获明确结果并严重制约研究的深入。本课题拟设计合成光亲和探针，探索上述化合物的作用靶点及其共同作用靶点的可能性，为抗耐药真菌药物研究提供新靶点。该类探针由药物或配体、三氟甲基苯基diazirine（光亲和部分）、生物素（作为标签）三部分组成。探针合成过程中，配合体外抗耐药真菌的活性跟踪，筛选30-50个探针，期望获得有效探针5-10个，用于光亲和结合靶点试验，获得相关蛋白的生物学信息。对获得的蛋白信息通过探针的类间比较、类内比较，最终获得靶点蛋白的生物学信息。

中文关键词： 协同；耐药；真菌；探针；靶点

英文摘要： Fungi become progressively resistant to conventional antifungal drugs and no better strategy is used to fight against it so far. In our previous work, we found that forsythiaside A, berberine, baicalein, and mangiferin could synergistically inhibit the resistant fungi with antifungal drugs, which might be a progressive method to fight against resistant fungi. Further research indicated they have same action mechanism,similar pharmacophore in SAR reaserch,besides their same efficacy. However, their action target remains unknown, which delay the further research for drug development. In this project, photoaffinity labeling probes will be employed to investigate their action targets, which might be the same target useful to overcome drug-resistance in fungi. The designed probes were consisted of three parts: drugs or ligands, triflouromethyl phenyl diazirine(for photoaffinity),and biotin(as a tag), which will be assembled by linkers. 30-50 probes will be designed and synthesized following by antifungal screening. 5-10 effective probes are expected to be obtained for the following photoaffinity labeling tests. The bioinformation of target proteins are expected to be obtained by inter or intra comparision of different kinds of probes.

英文关键词： synergism；drug-resistance；fungi；probe；taget