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,
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