乌拉尔甘草中NO合酶（NOSs）小分子抑制剂的发现

一氧化氮合酶(NOSs)有三种同工酶。eNOS被公认为是有益的，而iNOS和nNOS的过表达，产生过量NO可引起炎症性和慢性神经退行性病变。甘草对炎症性疾病，特别是肺炎有一定的疗效。部分甘草中的小分子化合物显示有抑制LPS诱导细胞生成NO和抑制细胞内iNOS表达的作用，含量较低化合物的抑制作用，及化合物对NOSs三种同工酶的选择性抑制作用未见报道。我们将系统的分离乌拉尔甘草中的次生代谢物，对含量丰富的化合物进行结构修饰，测试所得化合物抑制NO生成及其抑制iNOS表达的作用，以及对NOSs三种同工酶的选择性，结合作用机理和构效关系的研究，获得高活性、高选择性的NOSs小分子抑制剂，特别是iNOS小分子抑制剂。揭示乌拉尔甘草抗炎作用的药效成分及其作用靶点和机理，建立甘草源次生代谢物及其衍生物的化合物库，为新型疾病的治疗和甘草中次生代谢物生物功能的活性筛选进行化合物储备。

There are three isoenzymes of nitric oxide synthetase (NOS). eNOS is recognized as a beneficial NOS for disease. Overexpression of iNOS promotes the occurrence and development of inflammatory diseases. Overexpression of nNOS can cause chronic neurodegenerative diseases. It has been reported that several secondary metabolites obtained from G. uralensis Fisch. have the inhibitory effect on NO production induced by LPS in RAW264.7 macrophages, and few compounds with higher content have been tested to the inhibition against iNOS. A systematic phytochemical investigation will be carried out on G. uralensis, and the rich compounds will be modified. All compounds will be evaluated for the inhibitory effect on NO production induced by LPS in RAW264.7 macrophages, followed by the test of inhibition against three isoenzymes of NOSs to discover selective small molecular inhibitors of NOSs. Combined with the study of structure-activity relationship, we can obtain high activity and high selectivity of small molecular inhibitors of iNOS and nNOS. At the same time, a compound library from G. uralensis will be established, and these compounds can be screened for the treatment of new diseases.