靶向蓝藻FBP/SBPase 的新型选择性杀藻剂的设计合成及作用机制研究

Cyanobacterial FBP/SBPase is an important regulatory enzyme during cyanobacteria photosynthesis, which was reported to be as a novel target of algicide. We have gotten several thioacetamide compounds in our previous research, which can effectively and selectively inhibit cyanobacterial FBP/SBPase and cyanobacteria. In this project, by using computer-aided drug design and organic synthesis and protein crystallography combined with spectrum analysis and so on, we will firstly synthesize several series of thioacetamide derivatives (TADs) with different structure characteristics. Then using TADs as molecular probes, we will explore TADs’ structure-function relationship and the differences of interaction amongst the TADs and FBPases from different species, including cyanobacterial FBP/SBPase and animal FBPase and plant FBPase and bacterial FBPase, then analyze interaction mechanism between the TADs and target enzyme cyanobacterial FBP/SBPase, systematically and deeply explore the principles of selective inhibition of TADs against cyanobacterial FBP/SBPase, and further build their reasonable design and synthesis mode of novel selective algicides targeted on cynobacterial FBP/SBPase . Based on the research, we will comprehensively do more deep research on design and optimization and synthesis of lead compounds of cyanobacterial FBP/SBPase inhibitors, with the hope of gaining the lead compounds of algicides with high selectivity and effectivity and less toxic. This work will provide reasonable design guidance and necessary research base for the creation of green algicide with proprietary intellectual property rights to solve the cyanobacterial bloom problem.

蓝藻FBP/SBPase 是蓝藻光合作用中重要的调控酶，是可作为杀藻剂研究的新靶标。前期研究中我们获得了几个可选择性地抑制蓝藻FBP/SBPase及蓝藻的硫代乙酰胺类化合物。本项目拟综合运用计算机辅助药物设计、有机合成、蛋白晶体学及光谱表征等技术，合成不同类型的硫代乙酰胺类化合物（TADs），并以TADs为分子探针，探讨TADs对Cy-FBP/SBPase及其他物种的FBPases选择性抑制的作用特点，揭示TADs对蓝藻FBP/SBPase选择性抑制的作用机制，分析 TADs对蓝藻及动植物等选择性抑制的规律，建立合理有效的设计和筛选高选择性高活性的杀藻剂先导化合物的模型。在此基础上，展开靶向蓝藻FBP/SBPase的新型杀藻剂先导化合物的设计、优化及合成，以期获得具有应用前景的新型高选择性高活性的杀藻剂先导化合物，为我国开发具有自主知识产权的新型杀藻剂的创制工作提供设计指导和研发基础。

本项目以蓝藻光合作用中重要的调控酶FBP/SBPase为杀藻剂研究的新靶标。基于前期研究中获得了可高选择性地抑制蓝藻FBP/SBPase及蓝藻的硫代乙酰胺类化合物，本项目综合运用计算机辅助药物设计、有机合成、蛋白表达纯化、光谱表征等技术，合成了I-V类不同类型的硫代乙酰胺类化合物（TADs），并以TADs为分子探针，探讨了TADs的构效关系、TADs与不同物种FBPases相互作用的差异特点，揭示了TADs与蓝藻FBP/SBPase相互作用机理及其选择性作用机制，建立了TADs与蓝藻FBP/SBPase合理的相互作用模型。系统分析研究了TADs对Cy-FBP/SBPase相互作用的差异特点，揭示TADs对Cy-FBP/SBPase选择性抑制的作用机制；开展TADs对人源细胞及斑马鱼、杂草和水生植物、铜绿微囊藻及小球藻等生物选择性作用规律的分析；建立了合理有效的设计和筛选高选择性高活性的杀藻剂先导化合物的模型。在此基础上，进行蓝藻FBP/SBPase抑制剂的设计、合成及筛选的研究，获得6个以蓝藻FBP/SBPase 为靶酶的具有应用前景的高效高选择性杀藻剂先导化合物，申请发明专利8项，获得授权发明专利7项，发表研究论文9篇，为我国开发具有自主知识产权的新型杀藻剂的创制工作提供设计指导和前期研发基础。