STRUCTUAL BIOLOGY AND TARGETED DRUG DESIGN FOR AIDS

该提案将重点关注结构生物学的使用，以帮助 开发药物，可以以特定的方式干扰 人类免疫缺陷病毒（HIV）基因组的蛋白质产物。以来 HIV是获得性免疫缺陷的病原体 综合症（艾滋病），人们希望这些药物将治愈或至少 阻止艾滋病的症状。找到治愈艾滋病的方法是一个极其困难的问题。 世界卫生的当务之急。然而，可以预见， 在这个针对艾滋病的项目中开发的方法可以 为开发其他抗病毒药物奠定了基础， 不可避免地会在未来演变为人类的瘟疫。 将针对几种HIV-1蛋白开发抑制剂： 转录酶、蛋白酶、整合酶和核糖核酸酶H 逆转录酶的活性。用于病毒的重组方法 蛋白质生产正在发展。这些蛋白质，以及 从外部来源获得的病毒蛋白，如适用， 高度纯化、结晶并进行X射线衍射 分析.新出现的结构将用计算机模拟 图形和潜在的抑制剂将反过来建模到 利用分子动力学、分子力学和量子力学 力学 候选抑制剂将被合成，用酶系统测试， 有时与酶共结晶， 分析.将比较其功效， 细胞酶以及从 HIV-2和猿猴免疫缺陷病毒（SIV）。更多创意 然后，应该会出现有效的和选择性的抑制剂。现场指导- 诱变将被用来完善的概念，哪些集团对 酶参与抑制剂过程。离体和体内 抗病毒测试将与一些更有前途的 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.