DESIGN AND SYNTHESIS OF HIV INTEGRASE AS POTENTIAL ANTI-AIDS DRUGS

HIV整合酶抑制剂正在与分子药理学实验室、DBS、NCI合作开发，作为潜在的抗艾滋病药物。铅抑制剂结构最初来自几个来源，包括三维药效团搜索超过250，000化合物内所包含的NCI化学库。有前途的化合物已被系统地探索，通过化学合成的类似物，以确定负责整合酶抑制的结构-活性关系（SAR）。以这种方式产生的信息已被应用于设计和制备新的类似物，具有更高的效力，减少附带的细胞毒性和更大的抗病毒保护作用，在HIV感染的细胞。这些研究中的一种先导结构是菊苣酸，菊苣酸是一种天然产物，先前报道在HIV感染细胞中表现出有效的HIV整合酶抑制作用和保护作用。通过大量的合成类似物，我们建立了这类整合酶抑制剂的重要SAR参数。在进一步的工作中，我们已经制备了一系列含硫的双芳酰肼，其在细胞外测定中均显示出对HIV整合酶的有效抑制，并且能够在微摩尔浓度下表现出对HIV感染细胞的100%保护。正在进行合作研究，以检查在全细胞系统中的HIV整合酶抑制。在不同的研究中，合作的努力正在进行中，以获得X-射线结构的抑制剂结合到艾滋病毒整合酶。从这种X-射线结构获得的信息应该提供一个起点，为计算机辅助设计的有效的新抑制剂。在一种方法中，已经进行了有效抑制剂的合成修饰，以使它们可溶于水，并且更适合于与HIV整合酶共结晶。在另一种方法中，有前途的抑制剂正在以允许它们不可逆地结合到酶活性位点的方式进行合成修饰。这需要开发新的合成化学，其允许以潜在的非反应性形式引入高反应性官能团，其可以在与酶孵育之前的最后步骤中暴露于活性物质。 - 艾滋病，设计，HIV，抑制剂，整合酶，合成，

Inhibitors of HIV integrase are being developed as potential anti-AIDS drugs in collaboration with the Laboratory of Molecular Pharmacology, DBS, NCI. Lead inhibitor structures have initially been derived from several sources, including three-dimensional pharmacophore searching of the more than 250,000 compounds contained within the NCIs chemical repository. Promising compounds have been systematically explored through chemical synthesis of analogues to determine structure-activity relationships (SAR) responsible for integrase inhibition. Information generated in this fashion has been applied to the design and preparation of new analogues having higher potency, reduced collateral cytotoxicity and greater antiviral protective effects in HIV infected cells. One lead structure in these studies has been provided by chicoric acid, which is a natural product previously reported to exhibit potent HIV integrase inhibition as well as protective effects in HIV-infected cells. Through a large number of synthetic analogues, we established important SAR parameters for this class of integrase inhibitor. In further work, we have prepared a series of sulfur- containing bisaroyl hydrazines which both show potent inhibition of HIV integrase both in extracellular assays, and are capable of exhibiting 100% protection of HIV-infected cells at micromolar concentrations. Collaborative studies are underway to examine HIV integrase inhibition in whole cell systems. In separate studies, collaborative efforts are underway to obtain X-ray structures of inhibitors bound to the HIV integrase enzyme.Information obtained from such X-ray structures should provide a starting point for the computer assisted design of potent new inhibitors. In one approach, synthetic modification of potent inhibitors has been undertaken to render them water soluble and more suitable for co-crystallization with HIV integrase. In an alternate approach, promising inhibitors are being synthetically modified in ways which will allow them to bind irreversibly to the enzyme active site. This has required the development of new synthetic chemistry which allows the introduction of highly reactive functionality in latent, non reactive form, which can be unmasked to the active species in a final step prior to incubation with the enzyme. - AIDS, design, HIV, inhibitor, integrase, synthesis,