SYNTHESIS AND ANALYSIS OF HIV INTEGRASE INHIBITORS

人类免疫缺陷病毒(HIV)是与 患有获得性免疫缺陷综合症(艾滋病)。像所有人一样 逆转录病毒，整合病毒的互补DNA拷贝 RNA基因组进入宿主染色体是绝对必要的 艾滋病毒对细胞的高效而稳定的感染。整合 功能是由一种名为整合酶的病毒酶执行的，整合酶是一种 成为开发新的抗艾滋病毒疗法的有吸引力的目标。至 到目前为止，对HIV整合酶抑制剂的搜索在某种程度上 令人失望：大多数化合物被描述为抑制艾滋病毒 生化反应中的整合酶未能干扰HIV 组织培养中的复制。二咖啡酰奎宁酸和L- 菊苣酸是第一个小分子整合酶抑制剂 在组织培养中具有抗艾滋病毒的活性。这些化合物阻碍了 HIV在浓度从2微米到10微米的范围内复制，而 抑制细胞生长的剂量(毒性浓度)是完全 大50-100倍。它们的抗HIV整合酶活性 生化反应的范围从100 nm到大约800 nm， 使其成为迄今为止最有效的小分子整合酶抑制剂 据报道。随着这些抑制物的确定，现在是 有可能进行深入的结构活性关系研究 从而合成功能更强、选择性更强的整合酶 抑制因素不仅是一个目标，而且是一种可能的可能性。这个项目将 通过以下具体目标实现这一目标：1)综合 更有效、毒性更低的艾滋病毒整合酶抑制剂。2)执行 现有整合酶和新型整合酶的生化和机理分析 抑制剂。3)优化联合用药中的整合酶抑制剂 心理治疗。4)开发更灵敏、更定量的病毒检测方法 细胞内的整合。 至少，这些研究应该提供关于 HIV整合酶的功能及三联靶向治疗的作用 对三种不同的HIV酶：逆转录酶，整合酶， 和蛋白酶。这些具体目标的成功实现可能会 结果产生了一类新的抗艾滋病毒药物，可以进行评估 在HIV感染者中单独和联合使用 其他抗艾滋病毒药物。

The human immunodeficiency virus (HIV) is the retrovirus associated with the acquired immune deficiency syndrome (AIDS). Like all retroviruses, integration of a complementary DNA copy of the viral RNA genome into a host chromosome is absolutely required for productive and stable infection of cells by HIV. The integration function is carried out by a viral enzyme, integrase, which is an attractive target for the development of novel anti-HIV therapies. To date, the search for HIV integrase inhibitors has been somewhat disappointing: the majority of compounds described that inhibit HIV integrase in biochemical reactions fail to interfere with HIV replication in tissue culture. The dicaffeoylquinic acids and L- chicoric acid represent the first small molecule integrase inhibitors with activity against HIV in tissue culture. These compounds block HIV replication at concentrations ranging from 2 uM to 10uM while the doses that inhibit cellular growth (toxic concentrations) are fully 50-100 times greater. Their activity against HIV integrase in biochemical reactions range from 100nM to approximately 800nM, making them the most potent small molecule integrase inhibitors yet reported. With the identification of these inhibitors, it is now possible to perform in-depth structure activity relationship studies thus making synthesis of more potent and more selective integrase inhibitors not just a goal but a likely possibility. This project would achieve that goal through the following specific aims: 1) Synthesize more potent and less toxic HIV integrase inhibitors. 2) Perform biochemical and mechanistic analyses of existing and new integrase inhibitors. 3) Optimize integrase inhibitors in combination drug therapy. 4) Develop more sensitive and quantitative measures of viral integration within cells. At the least, these studies should offer significant information about the function of HIV integrase and the role of triple therapy targeted against three different HIV enzymes: reverse transcriptase, integrase, and protease. The successful completion of these specific aims may result in a new class of anti-HIV agents that could be evaluated for use in HIV infected individuals both alone and in combination with other anti HIV agents.