STRUCTURAL BIOLOGY AND TARGETED DRUG DESIGN FOR AIDS

关键蛋白抑制剂的结构基础开发 人体免疫机能丧失病毒（艾滋病毒）和 提出了与艾滋病毒有关的机会性感染。尽管少校 获得性免疫缺陷治疗的最新进展 综合症（艾滋病）仍然是对公共卫生的主要威胁。 此外，广泛发展的耐药性， 抗菌和抗病毒药物，新疾病的出现， 药物研发和医疗保健的成本不断上升， 开发更快速、更有效的药物发现方法 势在必行 用于开发抑制剂的主要HIV靶标 是整合酶，Rev，和以前未探索的网站上的反向 录酶显性负性抑制HIV的方法 蛋白酶也将被追求。此外，两项发现工作将 重点关注与艾滋病毒有关的机会性感染的蛋白质靶点：（a） HHV 8的蛋白酶，卡波西肉瘤病毒，和（B） 结核分枝杆菌烷基氢过氧化物酶。的 烷基氢过氧化物酶补偿了katG过氧化物酶的损失， 异烟肼耐药菌株，是一个新的和令人兴奋的目标， 治疗耐药结核病。 这些研究所需的蛋白质目前由 重组方法，并将其纯化，结晶， 进行X射线衍射分析。少的机械学研究 将进行充分表征的酶靶，以获得 可逆和不可逆设计所需的信息 抑制剂的结构和机械信息将用于 结合计算方法来识别潜在的抑制剂 的酶。候选抑制剂将被合成，分析 与分离的酶，并在某些情况下，共结晶与 用于结构分析的酶。将协助抑制剂优化 通过计算方法，以及这种改进， 用于发现和优化候选药物的方法是 这是该提案的目标之一。有前途的候选药物将是 在细胞培养物和体内评价。这种广泛的、基于结构的攻击 艾滋病毒和两种主要的机会性感染不应产生 只有潜在有用的药物线索， 与感染性病原体药物的设计有关。

The structure-based development of inhibitors of key proteins of the human immunodeficiency virus (HIV) and of organisms responsible for HIV-related opportunistic infections is proposed. Despite the major advances made recently in the treatment of acquired immunodeficiency syndrome (AIDS) it remains a major threat to the public health. Furthermore, the widespread development of resistance to antibacterial and antiviral drugs, the emergence of new diseases, and the escalating costs of drug discovery and health care make the development of more rapid and efficient drug discovery methods imperative. The primary HIV targets to be used for the development of inhibitors are integrase, Rev, and previously unexplored sites on reverse transcriptase. A dominant negative approach to inhibition of the HIV protease will also be pursued. In addition, two discovery efforts will focus on protein targets of HIV-related opportunistic infections: (a) the protease of HHV8, the Kaposi's sarcoma virus, and (b) the Mycobacterium tuberculosis alkylhydroperoxidase. The alkylhydroperoxidase compensates for loss of the katG peroxidase in isoniazid resistant strains and is a new and exciting target for the treatment of drug resistant tuberculosis. The proteins required for these studies are currently produced by recombinant methods and are to be purified, crystallized, and subjected to X-ray diffraction analysis. Mechanistic studies of the less well characterized enzyme targets will be carried out to obtain the information required for the design of reversible and irreversible inhibitors. Structural and mechanistic information will be used in conjunction with computational methods to identify potential inhibitors of the enzymes. The inhibitor candidates will be synthesized, assayed with isolated enzymes, and in some cases co-crystallized with the enzymes for structural analysis. Inhibitor optimization will be assisted by computational approaches, and the improvement of such approaches for the discovery and optimization of drug candidates is one of the goals of this proposal. Promising drug candidates will be evaluated in cell culture and in vivo. This broad, structure-based attack on HIV and two major opportunistic infections should produce not only potentially useful drug leads but also fundamental knowledge relevant to the design of drugs for infectious agents.