胡椒属植物中抗真菌天然先导化合物及其作用机制研究

Antifungal Drugs face a serious challenge caused by toxicity, resistance and limited chemical scaffolds. An important research strategy in antifungal discovery is to investigate the diverse antifungal natural products. Previously, we tested the herbs used for the treatment of fungal diseases by local peoples and the crude extracts of 132 plants showed antifungal activity. Among them, we studied the active compounds of 10 plants from the genus Piper and Liliaceae family, which led to the isolation of more than 40 active compounds, including the cyclopentenedione derivative coruscanone A that exhibited significant antifungal activity against Candida albicans better than the positive control drug. The proposed research in this project will continue our investigation on the selected eight plants from genus Piper that have shown antifungal activity. Guided by LC-MS analysis, the active compounds will be isolated efficiently.Using drug-resistant and genetically-modified fungal strains, as well as a variety of target enzymes, the possible antifungal mechanisms of the active compounds will be investigated. Our goal is to identify a couple of antifungal lead compounds, laying a foundation for developing new and safer antifungal drugs.

临床抗深部真菌感染药物结构类型(Scaffolds)单一，面临毒性强、耐药性明显的问题。高效识别，快速寻找结构多样化的天然抗真菌活性分子，是抗真菌药物研究的重要方向之一。我们前期对民间有抗真菌药用记载的植物粗提物进行活性评价，共筛选出132种植物，并对胡椒属、百合科等10多种目标植物开展研究，发现40多个抗深部真菌活性天然产物，其中包括从胡椒属植物得到的具有显著抗白色念珠菌活性的天然环戊二烯酮类先导化合物coruscanone A。在此基础上，本项研究拟继续对粗提物显示抗真菌活性的8种胡椒属目标植物进行研究。主要通过基因突变的耐药株系及靶向机制相结合的方法，采用LC-MS分析，锁定目标分子量，在分子量追踪下，进一步挖掘和丰富抗真菌活性分子，并从酶抑制活性等多方面探讨其作用机制，以期发现新的抗深部系统真菌活性Scaffolds，为抗真菌药物的开发提供科学依据。

临床抗深部真菌感染药物结构类型(Scaffolds)单一，面临毒性强、耐药性明显的问题。高效识别，快速寻找结构多样化的天然抗真菌活性分子，是抗真菌药物研究的重要方向之一。本项目完成了8种胡椒属植物抗真菌性成分研究，从中共分离鉴定217个化合物，新化合物有16个。抗真菌活性测试，发现11个化合物显示抗真菌活性，其中具有进一步研究前景的活性化合物1个。基于前期的研究基础，探讨活性分子的可能的作用机理，发现了耐药泵的作用靶点，为进一步深入研发抗真菌新药奠定较好的药效学基础。基于上述研究，已发表研究论文6篇，5篇为SCI论文，已投搞SCI研究论文1篇，正在撰写SCI研究论文2篇，申报专利1项。已辅助培养毕业研究生3名，其中博士研究生1名，硕士研究生2名，正在培养硕士研究生2名。