申请者主要研究领域是在天然产物发现的基础上，对活性分子核心骨架的生源途径进行生物学改造，构建衍生物库，为新药创制服务。我们从海洋生物及微生物中发现了84个新化合物，其中6个新骨架，3个分子被评为热点化合物，初步筛选发现6个有显著抗菌和抗肿瘤活性。利用计算机反向虚拟筛选技术，发现了1个活性成分的靶点并在体外验证。在新化合物发现中，利用关键中间体预测分子骨架合成的生源途径，并在两类复杂多环抗生素的体内合成途径研究中首次发现了新型螺环合成酶和[4+2]D-A环化酶，证实了其具有广谱催化活性。进一步研究这些酶的编码基因，利用基因重组和代谢途径改造制备衍生物，重组菌株实现产业转化。在此基础上，申请者拟选择前期发现的有显著抗菌和抗肿瘤活性的乙酰乙酸内酯/内酰胺家族为对象，研究成环关键酶的催化机制，进而利用基因重组和代谢改造的方法实现这类极难化学合成的天然产物衍生物库的生物合成，以期发现新药先导化合物。

My research focuses on the discovery of natural products and on the structure modification of bioactive molecules using genomic and biosynthetic methods. On the basis of the biosynthetic study of new skeletons we try to construct a library of derivatives by using genomic engineering and combinatorial biosynthesis. From marine invertebrates and microorganisms, we have isolated and identified 84 new compounds, in which 6 skeletons are new and 3 new skeletons were selected in the hot off the press by Natural Products Report. With a biological screening we have discovered 6 bioactive molecules which may serve as antitumor or antibacterial leads. With the utilization of inverse virtual screening we have discovered that swinhoeisterol A, a trace amounts of metabolite from marine sponge, is the inhibitor of protein h(P300). This has been confirmed by a in vitro test. Triggered by the discovery of key intermediates, we uncovered the novel biosynthetic mechanisms and key enzymes involved in the biosynthesis of two complex polycyclic antibiotics. In avermectin’s biosynthesis, we found a dual function of AveC by correlating its activity with spiroketal formation and dehydration modification, which was kept secret since the discovery of 20 years ago. We reported an unprecedented enzymatic [4+2] cyclization cascade that has a central role in the biosynthesis of pyrroindomycins. Our finding provides a solid evidence for the existence of Diels-Alder cyclase. With metabolic engineering of avermectin biosynthetic pathway we created unnatural derivatives. A mutant strain is constructed that greatly simplifies the metabolite profile and can be used in industry. The new project will continue to work on the tetramic acids or tetronic acids family which shows strong antitumor and antibiotic activities. On the basis of the previous discovery of Diels-Alder cyclases in pyrroindomycin’s biosynthesis, we will further investigate the generality and specificity in enzymatic mechanism by comparison of the enzymatic activity of spirocyclases derived from different molecules. By metabolic engineering and combinatorial biosynthesis we try to create some unnatural derivatives. With the above endeavor we will build a compound library of spiro-lactone or spiro-lactam derivatives to enrich the skeleton novelty and chemical diversity of natural products. This will be helpful to further investigate the structure-activity relationship and to serve new drug development.

天然产物由于具有结构多样性和生物活性多样性的特点，是创新药物研究中发现先导分子的重要来源。本项目以天然产物基础和应用研究为研究目标，建立了结合天然产物化学、计算生物学、分子生物学、药理学多学科交叉研究团队、技术平台和人才队伍，围绕天然药物资源中新类型、新结构的天然产物的发现和活性研究，取得了以下成绩：（1）对马鞭草科、车前科、益母草属以及五味子科等10余种药用植物的化学成分进行了研究，分离得到了500余个天然产物，包括100余个新的结构；（2）通过活性筛选，发现了系列具有抗HIV、精神性疾病、肿瘤以及在抗炎免疫等方面的系列天然产物活性分子，结构类型涉及到二萜、三萜以及生物碱等类型，为进一步的新药研发提供科学依据和研究基础；（3）初步完成了抗HIV活性分子“二苯胺酯”成药性评价，研究表明该目标分子是很有开发前景的抗HIV候选药物，作用机理研究表明化合物“二苯胺酯”抑制病毒（＋）链DNA的合成，为新的作用机制，相关研究已经申请了专利进行保护，拥有自主知识产权；（4）共发表SCI论文16篇，其中13篇为通讯作者，2项专利获得授权。（5）培养博士生1名、硕士生3名，另外1名博士研究生和2名硕士研究生已经完成了研究工作，将于2018年夏季申请毕业答辩；项目五味子化学于2015年获得了云南省自然科学科学技术奖特等奖（排名第4）；项目负责人获得了中国科学院王宽诚西部学者突出贡献奖（2015年）、中国药学会赛诺菲生物药物奖（2015）以及入选了中国科学院首批青年创新促进会优秀会员等奖项和荣誉。