Design and Synthesis of HIV Integrase as Potential Anti-AIDS Drugs

HIV整合酶抑制剂正在与NCI分子药理学实验室合作开发，作为潜在的抗艾滋病药物。铅抑制剂结构最初是从几个来源获得的，包括对NCI化学储存库中超过25万种化合物的三维药效团搜索。通过化学合成类似物系统地探索了有前途的化合物，以确定整合酶抑制的结构-活性关系（SAR）。以这种方式产生的信息已应用于设计和制备新的类似物，这些类似物在感染艾滋病毒的细胞中具有更高的效力、更低的附带细胞毒性和更强的抗病毒保护作用。在这些研究中，一类铅结构是一系列含硫双石蜡酰肼，它们在细胞外检测中都显示出对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。合作研究正在进行中，以检查HIV整合酶在整个细胞系统中的抑制作用。在单独的研究中，正在进行合作努力，以获得与HIV整合酶结合的抑制剂的x射线结构。从这种x射线结构中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。一种方法是对强效抑制剂进行合成修饰，使其可溶于水，更适合与HIV整合酶共结晶。在另一种方法中，有希望的抑制剂正在被合成修饰，使它们能够不可逆地与酶活性位点结合。这就要求开发新的合成化学，以潜在的、非反应性的形式引入高度反应性的功能，这可以在与酶孵育之前的最后一步揭开活性物质的面纱。最后，对含有1,3-二酮酮的抑制剂进行了合成结构-活性研究，这些抑制剂可能适合与HIV整合酶结合的x射线晶体测定。这类药物也可能在hiv感染细胞中潜在地表现出抗病毒活性。

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.