抗幽门螺杆菌新化学实体NE-2001的发现及药效学研究

发布时间：2018-05-25 14:19

本文选题：幽门螺杆菌 + NE-2001　；参考：《中国科学院研究生院（上海生命科学研究院）》2006年硕士论文

【摘要】：幽门螺杆菌是一种生长于胃粘膜层的革兰氏阴性细菌,据报道全世界约有一半人群感染了此病原菌。根除幽门螺杆菌对于治疗胃炎、胃溃疡以及减少胃癌发生的积极作用已经得到了广泛的共识。 NE-2001是由我国研究开发的一个具有自主知识产权的新化学实体。本论文的主要内容包括:(1)系统考察NE-2001对幽门螺杆菌标准菌株以及不同来源的临床菌株,特别是临床常见耐药菌株的抗菌活性。(2)针对NE-2001水溶性差的缺点,开发基于2-羟丙基-β-环糊精包合的制剂技术,并通过动物实验研究包合物的体内抗幽门螺杆菌作用。(3)以幽门螺杆菌体特异性亮氨酸氨肽酶为靶点,建立相应的高通量筛选模型并完成对国家新药筛选中心化合物库的大规模筛选。结论:(1)通过对江苏省人民医院及上海仁济医院随机采集的24株幽门螺杆菌临床菌株,以及从50株临床菌株中筛选得到的13株对甲硝唑和克拉霉素耐药菌株所进行的两组独立的体外药敏实验表明, NE-2001对临床随机样本及耐药菌株均有明显的抑制作用,提示其良好的抗菌活性并具有深入研究开发的价值。(2)建立了一套基于2-羟丙基-β-环糊精包合技术的制剂工艺流程,显著地改善了NE-2001的水溶性,包合效果通过X射线衍射和差示扫描量热分析得以证实。引建了C57BL/6小鼠感染幽门螺杆菌SS1菌株的动物模型,初步实验显示感染小鼠单独口服NE-2001即具有一定的幽门螺杆菌根除效果,NE-2001与其它两种药物联用的药效学实验正在进行之中。(3)建立了基于亮氨酸氨肽酶的高通量筛选模型并完成了对国家新药筛选中心化合物库32000个样品的大规模筛选,发现多个对该酶具有抑制活性的化合物,其中一个具有一定的抗幽门螺杆菌活性,相关的构效关系研究已经展开。
[Abstract]:Helicobacter pylori is a gram-negative bacterium that grows in the gastric mucosa and is reported to infect about half of the world's population. Eradication of Helicobacter pylori has been widely recognized as a positive role in the treatment of gastritis, gastric ulcers and the reduction of gastric cancer. NE-2001 is a new chemical entity with independent intellectual property rights developed by our country. The main contents of this thesis include: (1) to investigate the antibacterial activity of NE-2001 against standard strains of Helicobacter pylori and clinical strains from different sources, especially the common clinical resistant strains. To develop a preparation technology based on 2-hydroxypropyl- 尾 -cyclodextrin inclusion, and to study the anti-Helicobacter pylori effect of inclusion complex in vivo by animal experiments.) to target helicobacter pylori specific leucine aminopeptidase, A high-throughput screening model was established and a large-scale screening of the compound library of the National Center for New Drug screening was completed. Conclusion Twenty four clinical strains of Helicobacter pylori were randomly collected from Jiangsu Provincial people's Hospital and Shanghai Renji Hospital. Two independent in vitro drug sensitivity tests of 13 strains of metronidazole and clarithromycin resistant strains screened from 50 clinical strains showed that NE-2001 had obvious inhibitory effects on clinical random samples and drug-resistant strains. It was suggested that the preparation process based on 2-hydroxypropyl- 尾 -cyclodextrin inclusion technology was established, and the water solubility of NE-2001 was significantly improved, which indicated that it had good antibacterial activity and had the value of further research and development, and established a set of preparation process based on 2-hydroxypropyl- 尾 -cyclodextrin inclusion technology. The inclusion effect was confirmed by X-ray diffraction and differential scanning calorimetry. An animal model of C57BL/6 mice infected with Helicobacter pylori SS1 strain was established. Preliminary experiments showed that NE-2001 alone in infected mice had a certain eradication effect of Helicobacter pylori. The pharmacodynamics experiment of NE-2001 combined with two other drugs was under way.) High throughput screening based on leucine aminopeptidase was established. The model also completed the large-scale screening of 32000 samples from the compound library of the National Center for New Drug screening. A number of compounds with inhibitory activity to the enzyme were found, one of which had a certain activity against Helicobacter pylori, and the studies on the structure-activity relationship have been carried out.
【学位授予单位】：中国科学院研究生院（上海生命科学研究院）
【学位级别】：硕士
【学位授予年份】：2006
【分类号】：R378;R96

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