针对阿尔茨海默症（AD）发病机制复杂等特点，多靶点策略已成为抗AD药物研发的新趋势，但目前有针对性地从天然产物中寻找多靶点抗AD活性成分的研究较少。申请人前期发现了8个真菌来源的多节孢绿胶霉素类新化合物，它们能显著提高AD果蝇的记忆能力，显示抗AD活性。申请人采用靶点预测结合体外靶点验证发现该类化合物都具有抑制Aβ聚集和抑制AChE活性，部分化合物还作用于AD的另外两个靶点GSK-3β和CDK5，呈现多靶点抗AD的特点。本项目基于上述工作基础，拟通过OSMAC策略和微生物转化方法丰富该类化合物的结构多样性，构建化合物库；采用“五边形”综合评价体系，以果蝇药效、细胞水平活性、靶点预测结果、虚拟ADME预测、稳定性为考量指标，优选出最具研究前景的多靶点抗AD活性化合物；并开展优选化合物作用机制研究，为多靶点抗AD药物研发提供新的候选分子，并从中探索出高效发现多靶点抗AD活性天然产物的新模式。

Due to the multifactorial aetiology of this disease, the multi-target-directed ligand (MTDL) approach is a promising method in search for new drugs for AD. However, purposefully searching multi-target-directed anti-AD reagents from natural products is still seldom reported. In applicant’s previous research, 8 new nodulisporiviridins, which were isolated from the extract of a fungal strain Nodulisporium sp., showed improving the short-term memory capacity in Aβ transgenic AD drosophila model, which indicated that nodulisporiviridins had anti-AD activity. After in silico target fishing approach and in vitro testing, these compounds displayed anti-Aβ42 aggregation and anti-acetylcholinesterase (AChE) activities, and some of them also showed inhibitions against other two AD targets (glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinase 5 (CDK5), which indicated that nodulisporiviridins were multi-target-directed anti-AD reagents. Based on the above research, the OSMAC (one strain many compounds) approach and microbial transformation method will be carried out to enrich the structural diversity of nodulisporiviridins to build the chemical library. Then, “pentagon” evaluation system will be applied to evaluate the compounds of the chemical library based on the date from AD drosophila assay, PC12 cell assay, in silico target fishing approach, in silico ADME prediction, and stability experiments. Through this system, the promising molecules will be obtained, and their anti-AD targets and anti-AD mechanism will be investigated. This project intends to provide new candidate molecules for the development of multi-target-directed anti-AD reagent, and to explore a new screening system for efficiently searching multi-target-directed anti-AD reagent from natural products.