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NCI化学库中包含的超过250，000种化合物的三维药效团搜索。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。这些研究中的一类先导结构是一系列含硫的双芳酰肼，它们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保护HIV感染的细胞。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。在单独的研究中，正在进行合作，以获得与HIV整合酶结合的抑制剂的X射线结构。从这种X射线结构获得的信息应该为计算机辅助设计有效的新抑制剂提供一个起点。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。最后，合成的结构-活性研究已经进行了1，3-二酮含有抑制剂，这可能是服从X-射线晶体测定结合到HIV整合酶。这类药物也可能在HIV感染的细胞中表现出抗病毒活性。

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 NCI's 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 class of lead structure in these studies has been a series of sulfur-containing bisaroyl hydrazines which both show potent inhibition of HIV integrase both in extracellular assays, and are capable of protectng 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. Finally, synthetic structure-activity studies have been conducted on 1,3-diketo-containing inhibitors, which may be amenable to X-ray crystal determination bound to HIV integrase. This class of agent may also potentially exhibit antiviral activity in HIV-infected cells.