STRUCTUAL BIOLOGY AND TARGETED DRUG DESIGN FOR AIDS

这项提案将侧重于使用结构生物学来帮助 开发可以以特定方式干扰的药物 人类免疫缺陷病毒(HIV)基因组的蛋白质产物。自.以来 HIV是导致获得性免疫缺陷的病原体 综合症(艾滋病)，人们希望这些药物能治愈或至少 遏制艾滋病的症状。找到一种治疗艾滋病的方法是一个极端的 世界卫生事业的当务之急。然而，可以预见的是， 在这个以艾滋病为目标的项目中开发的方法可以 开发其他抗病毒药物的基础是 在未来将不可避免地演变成困扰人类的疾病。 针对几种HIV-1蛋白的抑制剂将被开发：相反 转录酶、蛋白酶、整合酶和核糖核酸酶H 逆转录酶的活性。病毒的重组方法 蛋白质生产正在发展中。这些蛋白质，以及 从外部来源获得的病毒蛋白将酌情 高纯度、晶化、X射线衍射仪 分析。新出现的结构将使用计算机建模 图形和潜在的抑制因素将依次被建模为 应用分子动力学、分子力学和量子力学的结构 机械师。 候选抑制剂将被合成，用酶系统进行测试， 有时与酶共结晶以获得更多的结构 分析。我们将对它们的有效性与 细胞酶以及相应的从 HIV-2和猿猴免疫缺陷病毒(SIV)。更多的想法 然后，应该会出现有效的、有选择性的抑制剂。现场定向- 突变将被用来改进关于 酶参与了抑制过程。无论是体外还是体内 抗病毒测试将与一些更有希望的 化合物。

This proposal will focus on the use of structural biology to aid in the development of drugs that can interfere in a specific manner with protein products of the human immunodeficiency virus (HIV) genome. Since HIV is the etiological agent implicated in Acquired Immunodeficiency Syndrome (AIDS), it is hoped that these drugs will cure or at least arrest the symptoms of AIDS. Finding a cure for AIDS is an extremely urgent health priority for the world. However, it can be anticipated that the methodologies developed in this AIDS-targeted project could lay the foundations for the development of other anti-viral agents that inevitably will evolve in the future to plague mankind. Inhibitors will be developed toward several HIV-1 proteins: the reverse transcriptase, the protease, the integrase and the ribonuclease H activity of the reverse transcriptase. Recombinant methods for viral protein production are being developed. These proteins, as well as viral proteins obtained from external sources, as appropriate, will be highly purified, crystallized and subjected to X-ray diffraction analysis. The emerging structures will be modeled using computer graphics, and potential inhibitors will in turn be modeled into the structures using molecular dynamics, molecular mechanics and quantum mechanics. Candidate inhibitors will be synthesized, tested with enzyme systems, and sometimes co-crystallized with the enzyme for further structural analysis. Comparisons will be made with regard to their efficacy with cellular enzymes as well as with corresponding enzymes obtained from HIV-2 and simian immunodeficiency virus (SIV). Ideas for even more potent and selective inhibitors should then emerge. Site-directed- mutagenesis will be used to refine notions about which groups on the enzyme are involved in the inhibitor process. Both ex vivo and in vivo anti-viral testing will be performed with some of the more promising compounds.