苯并二氢吡喃类化合物抗HIV-1药效学及作用机理的研究

发布时间：2018-12-05 18:03

【摘要】：人类免疫缺陷病毒（human immunodeficiency virus，HIV）能够引起人类致死性疾病艾滋病（Acquired Immunodeficiency Syndrome，AIDS）。HIV-1是目前主要流行的亚型，病毒在其复制周期中存在多个药物作用靶点与潜在靶点。整合酶是病毒复制所必需的三个基本酶之一，能够催化病毒将自己的遗传物质整合到宿主细胞中。据联合国艾滋病规划署统计，全球艾滋病患者数量达到3000多万。而目前针对该病毒的药物治疗存在严重的抗药性问题，因此迫切需要研发能够有效对抗新靶点的安全药物。本课题通过BIAcore技术对几类化合物筛选出针对整合酶与逆转录酶靶点的药物，然后应用假病毒单轮侵染实验对效果较好的KA104和其同类化合物KA103进行药效学研究，并进一步探讨其作用靶点与机理，结合计算机模拟技术对药物作用方式与药代动力学性质进行模拟和计算。结果显示，KA103与KA104具有良好的抗病毒活性，IC50分别为4.86μg/ml（17.48μM）和1.03μg/ml（17.82μM），TI指数分别为19.88和40.87。通过对药物作用靶点和机理的研究发现，KA103与KA104不能作用于Vif靶点。KA104对整合酶具有较强的结合能力，在假病毒整合时段加药能够明显抑制病毒数量。对KA103和KA104的协同能力进行研究发现二者呈相加关系，具有联合用药潜力。通过计算机的对接方法对KA104作用于整合酶的方式进行分析，其作用方式与阳性对照药物相比具有很多共同点。此外还通过软件对药物的ADMET药代动力学性质进行分析，，预测其临床实验中的各项指标，为进一步的研究和开发提供数据基础。
[Abstract]:Human immunodeficiency virus (human immunodeficiency virus,HIV) can cause human fatal disease (Acquired Immunodeficiency Syndrome,AIDS). HIV-1 is a major subtype of HIV. There are many drug targets and potential targets in its replication cycle. Integrase is one of the three basic enzymes necessary for virus replication. It can catalyze the virus to integrate its genetic material into host cells. According to UNAIDS statistics, the number of AIDS patients worldwide reached more than 30 million. However, there is a serious problem of drug resistance in the current drug treatment of the virus, so there is an urgent need to develop safe drugs that can effectively combat new targets. Drugs targeting integrase and reverse transcriptase were screened by BIAcore technique, and the pharmacodynamics of KA104 and its similar compound KA103 were studied by pseudovirus single wheel infection experiment. Furthermore, the target and mechanism of the drug were discussed, and the pharmacokinetic properties of the drug were simulated and calculated by computer simulation. The results showed that KA103 and KA104 had good antiviral activity, IC50 was 4.86 渭 g/ml (17.48 渭 M) and 1.03 渭 g/ml (17.82 渭 M), TI index) was 19.88 and 40.87, respectively. It was found that KA103 and KA104 could not act on the target of Vif, and that KA104 had strong binding ability to integrase, and the amount of virus could be inhibited obviously by adding drugs in the period of pseudovirus integration. The synergistic ability of KA103 and KA104 was studied. The way of KA104 acting on integrase was analyzed by computer docking method. In addition, the pharmacokinetic properties of ADMET were analyzed by software, and the indexes in clinical trials were predicted, which provided the data basis for further research and development.
【学位授予单位】：北京工业大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R512.91

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