孙鹏 教授
硕士招生类型：
硕士招生专业：
博士招生类型：学术型
博士招生专业：生物医学方向
所在院系：医学院
联系方式：sunpeng78@126.com
课题组链接：
研究方向
主要任职
科研业绩

海洋天然产物发现和生物合成
Marine natural products discovery and biosynthesis

1、 中国药学会海洋药物专业委员会委员 (Member of Marine Drugs Committee of theChinese Pharmaceutical Association)
2、《药学学报》青年编委 (Editorial Board of ActaPharmaceutica Sinica B)


天然药物在新药发现中具有重要地位，结构新颖性与化学多样性是天然产物的首要因素，实现这一目的需要不断引入新资源和新技术。海洋生物的多样性远超过陆地，是21世纪新药发现的资源宝库。生物合成通过对代谢途径的遗传修饰进行天然产物的结构改造，在复杂化合物的药物研发方面有独特优势。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，通过生物合成路径建立衍生物库，为新药创制服务。我们从20余种海洋生物及其共附生菌中发现了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。在活性研究中利用计算机反向虚拟筛选技术，成功发现了1个活性成分的靶点为(h)P300，并经过体外生物学验证。在构型确定中，采用量子计算化学建立了大环柔性分子的模式图谱，使微量成分的绝对构型通过简单比对即可确定。在新化合物发现过程中，利用关键中间体建立了两类复杂多环抗生素分子骨架合成的生源途径，并发现了新颖的环化酶。在阿维菌素生物合成中，从一个极不稳定中间体的表征入手，首次揭示AveC蛋白是一种新型螺环合成酶，能够催化6,6-螺缩酮的手性合成及可选择性脱水修饰，解开了20年来AveC功能未知之谜，推翻了螺环自发形成的猜想。在螺乙酰乙酸内酯/内酰胺抗感染抗生素的生物合成中，首次发现两种不同的酶可以极大地催化[4+2]环化D-A反应生成6,6-萘烯和6,5-螺内酯/内酰胺，以串联方式构建刚性多环骨架，该发现为D-A反应酶的天然存在提供了有力证据。进一步研究证实了这些酶具有广谱催化活性，对这些酶的编码基因进行研究，利用基因重组和代谢途径改造的方法，成功创造了阿维菌素的 “非天然”螺环异构体，获得的重组菌株实现了单一活性成分制备并完成产业转化。研究结果共发表SCI论文47篇，他引498次，其中以第一/共同第一或通讯作者在自然-化学生物学Nat. Chem. Biol.、美国化学会会刊J. Am. Chem. Soc.和有机化学快报Org. Lett.等本领域高影响力期刊发表SCI论文15篇，总影响因子65.46。参编海洋药物学专著4部，研究成果获海洋科学技术一等奖在内的3项科技奖励。
Naturalproducts play an important role in the discovery of new drugs. The key factors fornatural products are structural novelty and chemical diversity. To achieve thisgoal, new resources and new technologies need to be introduced continuouslyinto this research area. The marine organisms are treasure trove of resources fornew drugs discovery in the 21st century. Biosynthesis The structuralmodification through genetic engineering of metabolic pathways has specialadvantages in new drug development of complex natural products. My research focusedon the discovery of new skeletons, biological evaluation, and establishment ofa derivative library of natural products. I have discovered more than 80 newcompounds from 20 marine organisms and the related bacteria, including 6 newskeletons. Three new compounds were selected as Hot of the Press. Six compoundsshowed significant antibacterial and antitumor activities. Using a reversevirtual screening technology, the protein target of swinehesterol was found tobe (h)P300. In the discovery process of new compounds, the biosyntheticpathways of complex polycyclic antibiotics were established and novel cyclaseswere discovered. In the biosynthesis of avermectin, starting from thecharacterization of a unstable intermediate, the function of AveC protein thatcan catalyze the chiral synthesis and modification of 6,6-spiroketal was firstrevealed. The results uncover the mystery of AveC since 20 years ago. In thebiosynthesis of tetramic/tetronic acids, we have discovered two new enzymes thatcan greatly catalyze the [4+2] cyclization of D-A reaction in tandem to form6,6-naphthene and 6,5-spiro-lactone/lactam, which provides strong evidence forthe natural presence of D-A enzymes. The "non-natural" avermectinderivatives were successfully prepared by metabolic pathway modification. Atotal of 18 SCI papers were published in journals of natural products field,such as Nat. Chem. Biol., J. Am. Chem. Soc., and Org. Lett.