抗高尿酸血症药物筛选平台建立与应用

发布时间：2018-06-12 22:07

本文选题：黄嘌呤氧化还原酶抑制剂筛选模型 + 急性高尿酸血症小鼠模型　；参考：《北京协和医学院》2017年硕士论文

【摘要】：高尿酸血症(hyperuricemia,HUA)是一种代谢性疾病,由嘌呤代谢紊乱所致,不但是痛风的直接致病因素,而且还与代谢综合征、慢性肾病、心血管疾病密切联系。临床上在对上述疾病的防治中,越来越关注对血尿酸的控制。高尿酸血症患者人群庞大,但用于治疗痛风和控制血尿酸的药物还相对缺乏,传统的降尿酸药物已不能满足临床实际需要,药物研发需求迫切。现有的筛选方法中,体外黄嘌呤氧化还原酶(Xanthine oxidoreductase,XOD)来源多样,其抑制剂筛选容易出现假阴性和假阳性结果;整体水平的模型动物种属多样,存在血尿酸维持不稳定等问题,限制了抗高尿酸血症药物的研发。本研究首先利用牛奶来源黄嘌呤氧化还原酶XOD1(PDBID:3AMZ),建立了 XOD抑制剂体外筛选模型;并应用该模型筛选样品1566个,发现活性较好的样品20个。其次,利用氧嗪酸钾(Potassium Oxonate,OXO)合并次黄嘌呤(Hypoxanthine,HA)单次刺激形成血尿酸一过性升高的急性高尿酸血症小鼠模型,探讨了其XOD活性、肝肾功能等一般特征;并应用该模型评价了9个样品的抗急性高尿酸血症的药效。最后,利用OXO多次给药形成慢性高尿酸血症小鼠模型,探讨了其XOD活性、肝肾功能等一般特征;并应用该模型评价了 4个样品治疗小鼠慢性高尿酸血症的药效。综上,本研究建立了基于靶点XOD的抗高尿酸血症药物体外和体内药物筛选实验体系,并应用该实验体系开展药物筛选和药效评价,为抗高尿酸血症药物研发奠定了实验基础。
[Abstract]:Hyperuricemia (HUAA) is a metabolic disease caused by metabolic disorder of purine, which is not only a direct pathogenic factor of gout, but also closely related to metabolic syndrome, chronic nephropathy and cardiovascular disease. More and more attention has been paid to the control of serum uric acid in the prevention and treatment of these diseases. There is a large population of patients with hyperuricemia, but the drugs used to treat gout and control uric acid are relatively scarce. The traditional anti-uric acid drugs can not meet the actual clinical needs, and the need for drug development is urgent. Among the existing screening methods, Xanthine oxidoreductase XODs in vitro come from a variety of sources, and the screening of Xanthine oxidoreductase XODs is prone to false negative and false positive results. It limits the development of anti-hyperuricemia drugs. In this study, an in vitro screening model of XOD inhibitor was established by using xanthine redox enzyme XOD1: PDBID: 3AMZN, and 1566 samples were screened by the model, and 20 samples with good activity were found. Secondly, an acute hyperuricemia mouse model was established by single stimulation of Potassium OxonateOXO combined with Hypoxanthine Hypoxanthine (HAH), and its XOD activity, liver and kidney function were studied. The model was used to evaluate the antihyperuricemia effect of 9 samples. Finally, the mice model of chronic hyperuricemia was established by using OXO for many times, and the general characteristics of XOD activity, liver and kidney function were discussed, and the pharmacodynamics of 4 samples in treating chronic hyperuricemia in mice was evaluated. In conclusion, a drug screening system for anti-hyperuricemia drugs in vitro and in vivo was established based on the target XOD, and the experimental system was used to screen drugs and evaluate their efficacy, which laid an experimental foundation for the research and development of anti-hyperuricemia drugs.
【学位授予单位】：北京协和医学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R589.7

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