靶向HCV IRES和NS3蛋白抑制剂筛选及评价小鼠模型的建立

发布时间：2018-05-10 11:19

本文选题：丙型病毒性肝炎 + NS3　；参考：《中国人民解放军军事医学科学院》2006年博士论文

【摘要】：丙型病毒性肝炎是一种严重危害人类健康的常见病和多发病。全球大约有1.7亿的人口感染丙型肝炎病毒(Hepatitis C Virus，HCV)。我国HCV感染者已达6000万。HCV急性感染后50-80％转变为慢性感染，其中的10-20％发展成肝硬化，并与肝细胞癌的发生密切相关。迄今α-干扰素和病毒唑联合治疗是唯一的治疗方法，但这种治疗方法只对不到50％的患者显效，且具有费用高、易复发和副作用多等缺陷；尤其是我国流行的HCV 1b型，对α干扰素的治疗应答最低，因此，加强对HCV防治的研究至关重要。 HCV为单股正链RNA病毒，属黄病毒科，全长约9600个核苷酸，ORF区编码3010个氨基酸的多聚蛋白前体，经过宿主和病毒本身基因编码的蛋白酶裂解为十个功能性片段，包括4个结构蛋白(核心蛋白C、包膜蛋白E1、E2以及P7)及6个非结构蛋白(NS2、NS3、NS4A、NS4B、NS5A和NS5B)。HCV RNA 5’端没有帽子结构，由5’非编码区(NCR)内的内部核糖体进入位点(IRES)介导启动并控制着整个HCV基因组的翻译过程，而HCV NS3蛋白具有丝氨酸蛋白酶和解旋酶活性，，参与病毒蛋白翻译后加工，为病毒复制所必须。因此IRES及HCV NS3／4A丝氨酸蛋白酶是目前抗病毒治疗研究的主要靶位。多年来针对HCV NS3／4A及HCV IRES抑制剂的研究取得可喜的进展，但由于缺乏理想的小动物模型，这些药物在体内抗HCV的作用效果，以及对其毒性、安全性等难以作出评估，极大地延缓了这些药物进入临床，因而建立适用于HCV IRES和NS3蛋白抑制剂筛选及评价小鼠模型迫在眉睫。
[Abstract]:Hepatitis C is a common and frequent disease that seriously endangers human health. About 170 million people worldwide are infected with hepatitis C virus. In China, 50-80% of patients infected with HCV have been transformed into chronic infection after acute infection, of which 10-20% have developed into cirrhosis, which is closely related to the occurrence of hepatocellular carcinoma (HCC). Up to now, interferon 伪 combined with ribavirin is the only treatment method, but it is effective only for less than 50% of the patients, and has many defects, such as high cost, easy to relapse and many side effects, especially the prevalent HCV 1b type in our country. Interferon alpha has the lowest therapeutic response, so it is very important to strengthen the research on the prevention and treatment of HCV. HCV is a single-stranded positive strand RNA virus, belonging to the family flaviridae. It encodes a polypeptide precursor of 3010 amino acids with a total length of 9600 nucleotides. The protease encoded by the host gene and the virus itself cleavage into ten functional fragments. There are four structural proteins (core protein C, envelope protein E1, E2, and P7) and six nonstructural proteins, NS2NS2NS3, NS4AN4NS4BN5A and NS5B).HCV RNA 5', which have no cap structure. IRES, an internal ribosomal entry site in the 5'noncoding region, initiates and controls the translation process of the entire HCV genome. The HCV NS3 protein has the activities of serine protease and helicase, and participates in the post-translation processing of virus proteins. Necessary for virus replication. Therefore, IRES and HCV NS3/4A serine protease are the main targets of antiviral therapy. Over the years, great progress has been made in the study of HCV NS3/4A and HCV IRES inhibitors. However, due to the lack of ideal small animal models, it is difficult to evaluate the effect of these drugs on HCV in vivo, as well as their toxicity and safety. Therefore, it is urgent to establish a mouse model suitable for screening and evaluating HCV IRES and NS3 protein inhibitors.
【学位授予单位】：中国人民解放军军事医学科学院
【学位级别】：博士
【学位授予年份】：2006
【分类号】：R-332

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