炭皮属真菌来源杂萜抗阿尔茨海默症活性成分及作用机制研究

The pathogenesis of Alzheimer's disease (AD) is complicated, and there are no curative therapies currently available for this disease, which resulted in tremendous threat to global public health. In applicant’s previous work, a type of new meroterpenoids, which were obtained from the secondary metabolites of a endolichenic fungi of Biscogniauxia sp. was discovered, showed improving the short-term study and memory capacity in transgenic AD drosophila model, which indicated that they had anti-AD activities. However, there have been only few reports on this kind of meroterpenoids until now, and their structure-anti-AD relationships and mechanism of anti-AD are not clear. The applicant’s previous work showed that a large number of un-revealed same types of meroterpenoids were existed in Biscogniauxia sp. Based on our previous research, we plan to carry out further investigations on the meroterpenoids from Biscogniauxia sp. though expanding fermentation scale to Biscogniauxia sp. 71-10-1-1, OSMAC strategy, and studying the same genus strain to enrich the structural diversity of meroterpenoids and build the compounds library of meroterpenoids. The structure-anti-AD relationships of the meroterpenoids from Biscogniauxia sp. will be researched by the Thioflavin T model, hippocampal neuron cell model, and transgenic AD drosophila model. Considering the structure-anti-AD relationships, content, and druggability of compounds, the anti-AD activity candidate compounds of the meroterpenoids from Biscogniauxia sp. will be optimized. The anti-AD activities of candidate compounds will be assessed by the transgenic mice AD model. In addition, ligand-receptor capture technology will be carried out to illuminate the target and mechanism of the candidate compounds. In conclusion, this project intends to obtain the new anti-AD candidate compounds of the meroterpenoids from Biscogniauxia sp. with strong effects and definite mechanism.

阿尔茨海默症（AD）发病机制复杂且尚无药物能逆转其病情，危害巨大。申请人一直以地衣内生真菌为研究对象，从一株炭皮属真菌中发现一类结构新颖的杂萜，并发现它们能显著提高AD果蝇学习记忆能力，具有抗AD活性。该类杂萜研究较少，其抗AD活性的构效关系和作用机制并不清楚。前期工作提示该菌及其同属菌株仍存在大量同型杂萜未被发现。基于此，本项目拟通过对该菌株扩大发酵规模及OSMAC策略发现更多同类成分，并拟从同属优质菌株中寻找更多类似结构，丰富炭皮属真菌来源杂萜结构多样性，构建化合物库；基于Thioflavin T、海马神经元细胞及转基因AD果蝇模型综合评价其抗AD活性，探讨其构效关系；综合考虑药效、生物量及成药性，优选出抗AD候选分子，采用转基因AD小鼠模型对候选分子进行药效评价；利用小分子垂钓技术阐明其抗AD活性作用靶标和机制，以期获得药效显著、机制明确的新型抗AD候选药物。

阿尔茨海默病（AD）危害巨大，发病机制复杂，目前尚无有效治疗药物。特殊生境真菌是发现药物先导化合物和创新药物研究的重要源泉和宝贵资源，项目负责人前期从一株地衣内生真菌炭皮属71-10-1-1中发现一类结构新颖的杂萜类成分，具有抗AD活性，显示良好研究前景，值得深入研究。本项目基于前期工作基础，分别通过对炭皮属真菌71-10-1-1扩大大米固体发酵规模、OSMAC策略及对同属优质菌株炭皮属真菌69-8-7-1进行研究，来增加炭皮属来源杂萜及萜类化学多样性，通过各种色谱分离手段及广泛的波谱学方法，从中分离并鉴定59个化合物，其中37个为新化合物，包括炭皮属真菌来源杂萜及萜类化合物共34个。同时围绕AD发病的多种假说，采用转基因AD果蝇模式动物模型、LPS诱导的炎症细胞模型、乙酰胆碱酯酶抑制模型对炭皮属真菌来源的化合物进行活性评价，结果显示有5个化合物具有明显的提高AD果蝇学习记忆能力，7个化合物能明显的抗炎活性（IL-6与TNF-α），4个化合物具有显著的乙酰胆碱酯酶抑制活性。通过以上活性筛选，优选出炭皮属真菌来源的抗AD候选分子，且首次发现炭皮属真菌来源杂萜的抗炎活性。进一步地，项目还扩展研究内容，开展了炭皮属真菌来源杂萜的生物合成研究，阐明了炭皮属真菌来源杂萜biscognienyne B的生物合成途径，为后续优选的炭皮属真菌来源杂萜抗AD候选分子的生物量的富集打下坚实基础。本项目部分研究成果已发表SCI论文4篇，其中A1类论文3篇，申请国家发明专利2项，培养研究生2名。

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