以FtsZ为靶点的抗结核药物筛选模型的建立及应用

发布时间：2019-03-28 07:33

【摘要】：目的发现结核分枝杆菌Fts Z的特异性抑制剂,为开发针对该靶点的新型抗结核化合物奠定基础。方法克隆和表达结核分枝杆菌Fts Z蛋白并优化其酶活测活方法,构建Fts Z抑制剂的高通量筛选模型;对化合物库中2万个化合物进行筛选,将筛选得到的抑制剂212H进行IC50以及分子水平活性测定;用菌液稀释法评价212H对结核标准株、临床分离株以及耐药株的抗结核活性。结果得到了较纯的结核分枝杆菌Fts Z蛋白,建立并优化了Fts Z酶活测定体系以及其抑制剂的高通量筛选模型,筛选得到1个具有较高抑制率的抑制剂212H,该抑制剂具有显著的体外抗结核活性。结论建立了稳定的结核分枝杆菌Fts Z抑制剂的高通量筛选模型,应用该模型筛选得到的抑制剂具有抗结核活性。
[Abstract]:Aim to identify specific inhibitors of Mycobacterium tuberculosis Fts Z, and to lay a foundation for the development of new antituberculosis compounds targeting the target. Methods the Fts Z protein of Mycobacterium tuberculosis was cloned and expressed, and the enzyme activity assay was optimized. The high throughput screening model of Fts Z inhibitor was constructed. A total of 20 000 compounds in the compound library were screened. The IC50 and molecular level activity of the selected inhibitor 212H were determined, and the antituberculous activity of 212H against tuberculosis standard strains, clinical isolates and drug-resistant strains was evaluated by bacterial dilution method. Results the purified Fts Z protein of Mycobacterium tuberculosis was obtained. The enzyme activity assay system of Fts Z and the high throughput screening model of its inhibitors were established and optimized, and a inhibitor with high inhibition rate of 212H was obtained. The inhibitor has significant anti-tuberculosis activity in vitro. Conclusion A high throughput screening model for stable Fts Z inhibitors of Mycobacterium tuberculosis was established, and the inhibitors obtained by this model had antituberculous activity. [WT5 "HZ] conclusion [WT5" BZ]
【作者单位】：中国医学科学院药物研究所天然药物活性物质与功能国家重点实验室;中国医学科学院医药生物技术研究所国家新药(微生物)筛选实验室;
【基金】：国家自然科学基金项目(81302816,81321004)
【分类号】：R52

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