阿尔茨海默病(AD)的发病机制涉及多个环节，单一靶点的药物疗效十分有限，临床上缺乏理想的抗 AD 药物。从植物内生真菌中寻找新的先导化合物，已成为国内外研究的热点。石蒜（Lycoris radiata）中的加兰他敏(galantamine)为抗AD的乙酰胆碱酯酶抑制剂，申请人前期从石蒜中获得了2株抗AD的活性内生真菌（Aspergillus sclerotiorum和Trichoderma atroviride）。本项目拟以AChE和BACE1为双靶点，采用添加“化学表观遗传试剂”、“皮氏酶激活剂”等OSMAC的策略，综合运用多样性评价和生物活性评价相结合的筛选模式，以寻找与发现石蒜内生真菌中结构新颖、作用显著、多靶点起作用的抗AD先导化合物。本项目的实施，可为进一步开发药用植物资源和研发抗AD候选药物提供新的思路。

The single-target drugs are limited in the treatment of complex disease Alzheimer’s disease (AD), which has multiple pathogenic mechanisms. Prevention and treatment of AD has attracted the widespread concern of the society. The discovery of new anti-AD lead compounds is becoming an important topic for the scientists. Since galantamine from Lycoris radiata was used as acetylcholinesterase inhibitors (AChEI) against AD, 2 anti-AD active endophytic fungi from L. radiata were obtained in our early research, which were Aspergillus sclerotiorum and Trichoderma atroviride. In this project, the secondary metabolite diversity of the 2 fungi will be studed on the basis of OSMAC method. The epigenetic chemical reagent and fungi Pictet–Spenglerase activator will be added for activating the fungi secondary metabolite diversity. The metabolites will be seperated and identified by modern chromatographic and spectral techniques. The investigation of active principle will be directed by biossays of AChE and BACE1 model. The final purpose is to develop new multi-target leading compounds with strong against AD bioactivities from the 2 fungi secondary metabolites. This project will provide a new idea for the utilization of medicinal plant and explore new mothods for anti-AD drug research.