新型神经炎症保护剂先导化合物的快速发现及构效关系研究

项目名称： 新型神经炎症保护剂先导化合物的快速发现及构效关系研究

项目编号： No.81502951

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 王海峰

作者单位： 沈阳药科大学

项目金额： 17.9万元

中文摘要： 现代医学研究表明寻找抑制神经退行性疾病中过度炎症反应、抑制其炎症因子的过表达的抑制剂，可能成为神经退行性疾病的有效治疗手段。发现具有高效低毒的神经炎症保护剂对预防和治疗神经退行性疾病具有重要的作用。申请人在前期研究工作中发现Butyrolactone类丁内酯衍生物对LPS激活的BV2小胶质细胞具有显著的抗炎作用，且对LPS激活的小胶质细胞的存活率没有太大影响，表明该类化合物极有可能发展成为一类高效低毒的神经炎症保护剂。目前在天然界发现的该类化合物仅10余个，且因含量低，难于获得足量样品，无法对其进行深入研究。本项目拟通过基因筛选-色谱学-波谱学-生物学相结合的方法快速寻找能产该类化合物的菌株，并快速定向的从中分离获得化学结构多样的该类化合物，对活性较好的化合物进行结构修饰；通过活性测试和与生物大分子反相对接等方法探讨该类化合物的构效关系，推测其作用机理和靶点，进而发现理想的对神经炎症具有保护作用的先导化合物。

中文关键词： 神经炎症；神经退行性疾病；快速发现；构效关系；P38；MAPKs/IΚB/；iNOS；通路

英文摘要： Modern medical research shows that looking for suppressing excessive inflammation in neurodegenerative disease and inhibiting inflammatory cytokines expression may be effective treatments for neurodegenerative diseases. Found with high effect and low toxicity of nerve inflammation of protective agents for the prevention and treatment of neurodegenerative diseases play an important role. In preliminary studies, the applicant found butyrolactone derivatives has significant anti-inflammatory on LPS-activated microglia and LPS-activated BV2 microglia survival rates do not have much impact, indicating that the compound is likely to develop into a high efficacy and low toxicity of neuroinflammation protectant. At present, the compounds in nature are only no more than 10. The content is low, and it is difficult to get enough samples. Therefore, it can not be further academic study. The project aims to use genetic screening-chromatography-spectroscopy-method combining biological rapid looking for strains producing the compounds. And rapid directional isolated from diverse chemical structures of these compounds, structural modification for activity compounds. By activity tests and with biological molecules docking method of this class of compounds, we would discuss the compounds of structure-activity relationships, and hypothesize mechanism of action and targets, and look for the ideal lead compounds with nerve inflammation protection.

英文关键词： Nerve inflammation ;Neurodegenerative disease;fast finding;structure-activity relationship;P38 MAPKs/IΚB/ iNOS pathway