水稻白叶枯病菌潜在分子靶标二氢硫辛酸琥珀酰转移酶的结构、功能及其新抑制剂发现

Target identification is among the most important basic research in agrochemical innovation. It is also the important research trend in pesticide discovery in China. Xanthomonas oryzae pv. oryza, (X. oryzae) is a kind of worldwide important rice bacterial disease and is very difficult to control. It was found in our previous study that 1,3,4-oxadiazole sulfone compound displayed good inhibition activity against X. oryzae. Then dihydrolipoyl succinyltransferase (DLST) was found to be the molecular target of 1,3,4-oxadiazole sulfone compound against X. oryzae through activity-based protein profiling (ABPP) strategy, which is the first report of DLST as a potential target of agrochemicals. However, the structure and biological function of DLST remains unclear. Thus, this proposal aims to carry out the research of structural biology as well as biological function of DLST. Investigations will also be carried out to elucidate the binding site of DLST and oxadiazole sulfone compounds. A new screening method is expected to be established based on competitive ABPP strategy. And a series of new compounds will be designed and synthesized and their interaction with DLST will be evaluated, among which potent new compounds are expected to be found. The research will provide very important scientific basis for new lead structure as well as new mode of action discovery against plant pathogenic bacterial disease.

新靶标的发现是新农药创制的重要基础研究，也是我国当前新农药创制研究的重要方向。水稻白叶枯病是一种世界性水稻细菌病害，防治困难。申请者课题组前期工作中发现二氢硫辛酸琥珀酰转移酶（DLST）是高效抗菌活性噁二唑砜类化合物对水稻白叶枯病菌的作用靶标，而DLST作为新的潜在分子靶标在农药领域还未见报道。本申请拟系统地开展DLST的结构生物学研究、DLST与砜类化合物结合位点研究、DLST功能研究，并将基于竞争性的活性蛋白质组分析（ABPP）策略构建新型筛选方法，设计和合成新型砜类化合物，期望从中发现新型DLST抑制剂。研究结果可为新型抗植物病原细菌新先导和新作用机制发现提供重要的科学基础。

新靶标的发现是新农药创制的重要基础研究，也是我国当前新农药创制研究的重要方向。水稻白叶枯病是一种世界性水稻细菌病害，防治困难。本研究基于前期工作中发现的噁唑砜类化合物潜在靶标二氢硫辛酸琥珀酰转移酶（DLST），系统地开展DLST的结构生物学研究，成功解析了DLST的晶体结构。同时，探究了DLST与砜类化合物结合位点，并结合计算机辅助药物设计进行辅助验证。进而，通过琥珀酰化蛋白质组学的定量研究发现，甲磺酰菌唑能抑制DLST的活性，进而抑制细胞内赖氨酸琥珀酰修饰水平，从而干扰其能量代谢过程。通过设计并合成了多个系列的噁二唑类目标化合物，从中发现了具有研究价值的新型DLST抑制剂1个。此外，在工作的开展中，探索并发现了以香豆素、紫檀芪为先导结构的新型群体感应抑制剂，探索了基于ROS诱发的细菌凋亡机制的1,2,3,4-四氢-β-咔啉衍生物、含异丙醇胺亚结构的咔唑衍生物和18β-甘草次酸衍生物。上述的研究工作为新农药的创制提供了扎实的基础数据。