稀土杂多化合物抗乙型肝炎病毒的研究

发布时间：2018-04-29 23:38

本文选题：乙型肝炎病毒 + 杂多化合物　；参考：《吉林大学》2014年博士论文

【摘要】：慢性乙型肝炎属于重大传染性疾病，其传染性强，患病率高，对人体健康危害严重。我国是乙肝高发区之一，约有乙肝病毒携带者近1.3亿人。目前临床使用的抗病毒药物主要为核苷类似物，但其缺点是易产生耐药性，毒副作用大，因此开发高效低毒的抗病毒药物十分重要。本研究首次选用杂多化合物为主要研究体系，利用其分子可设计性的特点，设计、合成了系列稀土杂多化合物。在此基础上，按照临床前新药研发标准的要求，全面系统地开展了稀土杂多化合物抗HBV的药学、药效学、毒理学和药代动力学研究。同时，首次应用先进的同步辐射成像技术，探讨了杂多化合物抗病毒作用机制。药学研究中，采用红外光谱、紫外光谱、X射线单晶衍射及核磁共振光谱等检测方法，对受试化合物进行结构确证性和稳定性研究。多种检测方法共同表明，，受试化合物化学结构明确，稳定性良好。药效学研究中，分别以HepG2.2.15细胞和HBV转基因鼠为研究模型，检测受试化合物对HBeAg、HBsAg和HBV DNA的抑制作用，结果表明，受试化合物对抗原分泌和病毒DNA合成有较强的抑制作用。经药效学筛选，选取受试化合物9开展急性毒性、长期毒性和遗传毒性等安全性评价研究。毒性评价结果表明，受试化合物9属于基本无毒化合物，长期毒性实验未发现毒性作用，无致畸、致突变作用。采用ICP-MS技术评价受试化合物9经口途径给药的药代动力学特征，结果表明，受试化合物9在大鼠体内的动力学过程符合二室模型，其吸收过程迅速，肝脏靶向性好，无组织蓄积，与血浆蛋白呈中度结合。X射线纳米CT细胞成像结果表明，杂多化合物的抗病毒机理是通过抑制病毒侵入宿主细胞过程发挥作用。本研究首次系统的研究稀土杂多化合物抗HBV的活性，课题研究成果已获得国家发明专利。本实验研究为开发具有自主知识产权的新型非核苷类抗HBV药物奠定了坚实的基础。
[Abstract]:Chronic hepatitis B (CHB) is a major infectious disease, which is highly infectious and harmful to human health. China is one of the high incidence of hepatitis B, about 130 million people with hepatitis B virus carriers. At present, the main antiviral drugs used in clinic are nucleoside analogues, but their disadvantages are that they are easy to produce drug resistance and have large side effects, so it is very important to develop high efficiency and low toxicity antiviral drugs. For the first time, a series of rare-earth heteropoly compounds were designed and synthesized by using heteropoly compounds as the main research system. On the basis of this, the pharmacological, pharmacodynamic, toxicological and pharmacokinetic studies of rare earth heteropoly compounds against HBV were carried out comprehensively and systematically according to the requirements of pre-clinical new drug research and development standards. At the same time, the antiviral mechanism of heteropoly compounds is discussed for the first time by using advanced synchrotron radiation imaging technology. In pharmaceutical research, the structure and stability of the tested compounds were studied by means of IR, UV X-ray single crystal diffraction and nuclear magnetic resonance spectroscopy. The chemical structure of the tested compounds is clear and the stability is good. In the pharmacodynamics study, HepG2.2.15 cells and HBV transgenic mice were used as the study models to detect the inhibitory effects of the tested compounds on HBeAgN HBsAg and HBV DNA. The results showed that the tested compounds had strong inhibitory effects on antigen secretion and viral DNA synthesis. The safety evaluation of acute toxicity, long term toxicity and genetic toxicity was carried out by pharmacodynamics screening. The toxicity evaluation showed that the tested compound 9 was a basic nontoxic compound, and no toxic effect, teratogenicity and mutagenicity were found in the long-term toxicity test. The pharmacokinetic characteristics of tested compound 9 were evaluated by ICP-MS technique. The results showed that the kinetic process of compound 9 in rats was in accordance with the two-compartment model, and its absorption process was rapid and liver targeting was good. The results showed that the antiviral mechanism of heteropoly compounds was mediated by inhibiting virus invasion into host cells. In this study, the activity of rare earth heteropoly compounds against HBV was studied systematically for the first time. This study has laid a solid foundation for the development of new non-nucleoside anti-HBV drugs with independent intellectual property rights.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R512.62

【参考文献】