STRUCTURAL BIOLOGY AND TARGETED DRUG DESIGN FOR AIDS

血管紧张素转换酶关键蛋白抑制剂的结构研究进展 人类免疫缺陷病毒(HIV)和引起 与艾滋病毒相关的机会性感染被提出。尽管少校 获得性免疫缺陷的治疗进展 艾滋病仍是对公众健康的主要威胁。 此外，抗药性的广泛发展 抗菌和抗病毒药物，新疾病的出现，以及 不断攀升的药物发现和医疗保健成本使 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艾滋病毒靶点 整合、修订和以前未开发的地点是否处于相反位置 转录酶。一种主要的消极方法来抑制艾滋病毒 蛋白水解酶也将受到追捧。此外，两项发现工作将 重点关注艾滋病毒相关机会性感染的蛋白质靶标：(A) Kaposi肉瘤病毒HHV8的蛋白水解酶和(B) 结核分枝杆菌烷基过氧化氢酶。这个 烷基过氧化氢酶补偿细胞中katG过氧化物酶的丢失 对异烟肼耐药菌株是一个新的令人兴奋的目标 耐药结核病的治疗。 这些研究所需的蛋白质目前是由 重组方法和将被提纯、结晶和 进行了X射线衍射分析。较少人的机械论研究 将进行充分表征的酶靶标以获得 可逆和不可逆设计所需的信息 抑制剂。结构和机械信息将用于 结合计算方法确定潜在的抑制剂 酶的作用。将合成候选缓蚀剂，并对其进行检测 与分离的酶，在某些情况下与 用于结构分析的酶。将协助进行抑制剂优化 通过计算方法，以及对这样的改进 发现和优化候选药物的方法是 这项提案的目标之一。有希望的候选药物将是 在细胞培养和体内评估。这种广泛的、基于结构的攻击 关于艾滋病毒和两大机会性感染不应产生 不仅有可能有用的药物线索，而且还有基础知识 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.