發(fā)布時(shí)間：2018-04-29 23:38

  本文選題：乙型肝炎病毒 + 雜多化合物　； 參考：《吉林大學(xué)》2014年博士論文

【摘要】：慢性乙型肝炎屬于重大傳染性疾病，其傳染性強(qiáng)，患病率高，對人體健康危害嚴(yán)重。我國是乙肝高發(fā)區(qū)之一，約有乙肝病毒攜帶者近1.3億人。目前臨床使用的抗病毒藥物主要為核苷類似物，但其缺點(diǎn)是易產(chǎn)生耐藥性，毒副作用大，因此開發(fā)高效低毒的抗病毒藥物十分重要。本研究首次選用雜多化合物為主要研究體系，利用其分子可設(shè)計(jì)性的特點(diǎn)，設(shè)計(jì)、合成了系列稀土雜多化合物。在此基礎(chǔ)上，按照臨床前新藥研發(fā)標(biāo)準(zhǔn)的要求，全面系統(tǒng)地開展了稀土雜多化合物抗HBV的藥學(xué)、藥效學(xué)、毒理學(xué)和藥代動(dòng)力學(xué)研究。同時(shí)，首次應(yīng)用先進(jìn)的同步輻射成像技術(shù)，探討了雜多化合物抗病毒作用機(jī)制。 藥學(xué)研究中，采用紅外光譜、紫外光譜、X射線單晶衍射及核磁共振光譜等檢測方法，對受試化合物進(jìn)行結(jié)構(gòu)確證性和穩(wěn)定性研究。多種檢測方法共同表明，，受試化合物化學(xué)結(jié)構(gòu)明確，穩(wěn)定性良好。藥效學(xué)研究中，分別以HepG2.2.15細(xì)胞和HBV轉(zhuǎn)基因鼠為研究模型，檢測受試化合物對HBeAg、HBsAg和HBV DNA的抑制作用，結(jié)果表明，受試化合物對抗原分泌和病毒DNA合成有較強(qiáng)的抑制作用。經(jīng)藥效學(xué)篩選，選取受試化合物9開展急性毒性、長期毒性和遺傳毒性等安全性評價(jià)研究。毒性評價(jià)結(jié)果表明，受試化合物9屬于基本無毒化合物，長期毒性實(shí)驗(yàn)未發(fā)現(xiàn)毒性作用，無致畸、致突變作用。采用ICP-MS技術(shù)評價(jià)受試化合物9經(jīng)口途徑給藥的藥代動(dòng)力學(xué)特征，結(jié)果表明，受試化合物9在大鼠體內(nèi)的動(dòng)力學(xué)過程符合二室模型，其吸收過程迅速，肝臟靶向性好，無組織蓄積，與血漿蛋白呈中度結(jié)合。X射線納米CT細(xì)胞成像結(jié)果表明，雜多化合物的抗病毒機(jī)理是通過抑制病毒侵入宿主細(xì)胞過程發(fā)揮作用。 本研究首次系統(tǒng)的研究稀土雜多化合物抗HBV的活性，課題研究成果已獲得國家發(fā)明專利。本實(shí)驗(yàn)研究為開發(fā)具有自主知識(shí)產(chǎn)權(quán)的新型非核苷類抗HBV藥物奠定了堅(jiān)實(shí)的基礎(chǔ)。
[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.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R512.62

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