珊瑚共附生微生物具有丰富的物种多样性，能够产生结构新颖、活性显著的次级代谢产物，已成为活性海洋天然产物和药物先导化合物发现的新的热点资源。表观遗传修饰能激活真菌沉默基因，调控真菌代谢，提高次级代谢产物结构多样性和新颖性，是新颖结构活性次级代谢产物发现的有效手段。在前期工作中，我们从西沙珊瑚共附生真菌中发现了一系列结构新颖的生物碱、大环内酯、萜类等化合物，具有抑制乙酰胆碱酯酶(Acetylcholinesterase, AchE)等活性。本项目拟在已有工作基础上，对3株西沙珊瑚共附生真菌进行表观遗传修饰，以激活真菌独特的代谢途径，增加真菌次级代谢产物的化学多样性和生物活性；在集成筛选和发酵条件优化基础上，以添加最佳表观遗传修饰剂的最优发酵条件进行发酵，重点从发酵提取物中追踪分离鉴定结构新颖的具有AchE抑制活性的化合物，系统分析构效关系，为新颖AchE抑制剂先导结构的发现提供基础资料。

The symbiotic fungi of the corals have proven to be a rich source for searching for secondary metabolites with novel structures and potential bioactivities. In recent year, the coral-derived fungi have been considered as a new hot resource for the discovery of bioactive marine natural products and lead compounds. Epigenetic modification could activate the silent genes of fungi and regulate the fungal metabolism, resulting in the improvement of structure diversity and novelty of their secondary metabolites. Therefore, epigenetic modification has been used as a feasible approach to find novel secondary metabolites. In our previous work, a series of bioactive new compounds have been isolated from the fingi derived from the corals collected from the coral reef in Xisha Islands, including alkaloids, macrolides, and terpenoids with such as acetylcholinesterase (AchE) inhibitory activity. In this research proposal, epigenetic modification will be applied to three coral-derived fungal strains to activate their unique metabolic pathways. The chemical diversity and high bioactivities should be prospected for the culture of the treated fungal strains with chemical genetic modification agents. The large scale culture of the treated strains should be conducted under the optimal fermentation conditions with the selected genetic modification agents. The bioactive secondary metabolites will be isolated and identified from the fermentation broth under bioassay guidance, especially the novel compounds with AchE inhibitory activity. The structure-activity relationship will be discussed for the acitive compounds to find the lead structures of AchE inhibitors.