红树林烟曲霉菌中新颖免疫抑制活性成分筛选与作用机制研究

Microbes are receiving increasing attention by natural product chemists due to their diverse and structurally unprecedented compounds which make them interesting candidates for drug discovery. Since the discovery of the potential immunosuppressive agent fumigaclavine C from Aspergillus fumigatus, interest to find bioactive compounds from the genus has increased considerably. Substantial advances in biotechnologically assisted chemistry have surmounted the barriers of limited methodology and sparked a resurgence in the discovery of interesting compounds with novel structures. Our previous investigation for chemically new and biologically potent metabolites from plant endophytes, we recently isolated and identified a series of new fumigaclavine C analogues from endophytic fungus A. fumigatus. Application of 1H-NMR-based metabonomics guided rapid discrimination provides a means to our further studies of immunosuppressive agents from mangrove associated endophytic fungus A. fumigatus. The isolation and purification of natural products was performed by using some chromatography techniques. The structures of all these will be unequivocally determined by one- and two-dimensional NMR spectroscopy, UV spectroscopy, IR spectroscopy. Their immunosuppressive activities will be evaluated using a Con A induced proliferation of mouse splenic lymphocytes (T cells) assay. The objective of this research is to lead the rapid discovery of new natural products from mangrove associated endophytic fungus A. fumigatus, which have established a strengthened immunosuppressive function and lessened side effects. It is hoped that the more efficient and effective application of 1H-NMR-based metabonomics would direct a rapid discrimination and isolation of the fungal metabolites and these FC derivatives will available to promote the rapid microbial immunosuppressive drug discovery process in prospect.

微生物是新先导化合物的重要来源，结构的新颖性是新单体药物发现的充要条件。烟曲霉菌可高效产出重要免疫抑制活性药物烟曲霉文丙，使这属菌的药用开发潜力得到了证实，而从中寻找新型活性物质也成微生物学和天然药物化学的研究新热点。在前期工作从烟曲霉菌Aspergillus fumigatus中系统分离获得系列新颖烟曲霉文丙类似物的基础上，本项目拟以红树林共生真菌烟曲霉菌为素材，基于微生物代谢组学概念的混合物氢谱导向代谢物快速识别追踪技术为依托，采用先进的色谱分离技术，快速获得结构新颖的代谢产物，采用T细胞增殖实验，对分离获得单体成分进行体外免疫抑制活性初筛，进一步采用钙调蛋白磷酸酶开展靶酶活性筛选和机制研究，配合整体动物模型，提供给药途径的依据进行药理学以及毒理学验证，该研究不仅建立一种基于微生物代谢组学混合物氢谱测定指导下的实用高效分离方法，又可望为研制新型高效低毒的免疫抑制活性药物奠定重要基础。

微生物是新先导化合物的重要来源，结构的新颖性是新单体药物发现的充要条件。烟曲霉菌可高效产出重要免疫抑制活性药物烟曲霉文丙，使这属菌的药用开发潜力得到了证实，而从中寻找新型活性物质也成微生物学和天然药物化学的研究新热点。在前期工作从烟曲霉菌Aspergillus fumigatus中系统分离获得系列新颖烟曲霉文丙类似物的基础上，从红树林内生烟曲霉等红树林内生菌种分离得到化合物70个，其中新骨架化合物1个，新化合物10个，生物碱类成分18个，高效免疫抑制剂4个，课题计划立项4年内完成在国内外重要期刊上发表5-8篇论文，其中至少1篇为影响因子IF≥3.0的论文，完成发明专利1-2件，实际成功出版“十三五规划”教材1部（主编）、出版中文专著1册、参编英文专著1册，论文22篇（其中11篇为SCI收录、5篇影响因子≥3.0、1篇EI），申报专利4项，参加国际、国内学术大会21次，做大会报告9次，入选海南省515人才工程第二层次、入选海南省高层次拔尖人才，入选海南省南海名家，获第三届全国高校青年教师教学竞赛三等奖、海南省第二十三届青年五四奖章，超额高质量完成计划。