靶向DNA聚合酶α的海洋来源新型aphidicolin类二萜结构多样性挖掘及其抗肿瘤作用机制研究

DNA聚合酶α是抗肿瘤药物研究的重要靶点，其抑制剂aphidicolin曾进入I期临床试验，由于生物利用度低限制了其临床应用。申请人前期从深海真菌bf494中发现新型aphidicolin A8活性优于aphidicolin，有成药潜力，已转让给药企推进抗肿瘤药物研发。对bf494全基因组测序和生物信息学分析发现该菌中含有大量二萜类化合物。为了寻找发现较好成药潜力的aphidicolin类二萜，本项目以bf494为研究菌株，拟采用OSMAC、化学表观遗传调控、物理化学复合诱变、二萜环化酶体外催化策略开展aphidicolin类二萜结构多样性挖掘，对其进行抗肿瘤活性评价，研究活性化合物靶向DNA聚合酶α诱导肿瘤细胞凋亡的作用机制，富集目标活性化合物开展体内活性及生物利用度评价。通过本项目的实施，以期获得活性更优及生物利用度较好的aphidicolin类二萜，为抗肿瘤药物研发提供先导化合物。

DNA polymerase α is an important target for antitumor drug research. Its inhibitor aphidicolin had been entered phase I clinical trial, but its low bioavailability limits the clinical application. Previously, the applicant discovered that the undescribed aphidicolin A8 derived from the deep-sea-derived fungus bf494 showed more potent activity than aphidicolin. Since it has potential to be developed as an antitumor drug, it has been transferred to a pharmaceutical company to promote the development of antitumor drug. The genomic sequencing and bioinformatics analysis of the bf494 showed that it contains a large number of diterpenoids. In order to discover aphidicolin diterpenoids with the potential for antitumor drug, bf494 will be used as the studying strain to further mine the structural diversity of the aphidicolin diterpenoids by the means of one strain many compounds (OSMAC), chemical epigenetic modification, physical and chemical mutagenesis, and diterpenoid cyclase catalysis. Then, the antitumor activities of the isolated aphidicolin diterpenoids will be evaluated and the mechanism of the active compounds inducing tumor cell apoptosis by targeting DNA polymerase α will be studied. The targeted active compounds will be further enriched to evaluate the antitumor activities and bioavailability in vivo. Through the implementation of this project, the aphidicolin diterpenoids with novel structures, better activities and preferable bioavailability could be obtained as the lead compounds for the development of antitumor drugs.