POTENTIAL SYNERGISTIC INHIBITORS OF HIV INFECTIVITY

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The long term goals of this research program are to contribute tot he discovery of new generation nucleosides and heterocyclic systems with useful therapeutic potential against the infectivity of HIV-1, HIV-2 and drug-resistant HIV variants. The specific aims of this proposal are the synthesis and anti-HIV studies of novel compounds that are designed to be inhibitors of two phases of the life cycle of HIV, an early phase involving reverse transcription (HIV RT inhibitors) and a later phase involving transcriptional HIV gene expression (Tat inhibitors). Compounds chosen for investigation as pro-drugs for HIV RT inhibition are stereochemically defined, novel deoxygenated nucleosides that carry hypermodification in the carbohydrate moiety and those designed as Tat inhibitors are chiral heterocyclic systems belonging to the aminobenzodiazepine family. There is documentation for potent anti-HIV activity for both families of inhibitors. In addition, the rationale for the selection of these compounds for study includes, where relevant, considerations of phosphorylation, cellular stability, bioavailability and host cell toxicity. The synthetic work will involved the development of approaches to both families of compounds so that they could be produced in stereochemically defined, optically pure forms. Characterization including stereochemistry of the final target molecules will be performed by multinuclear NMR spectroscopy, high resolution FAB mass spectrometry, UV and optical activity data, elemental analysis and single crystal X-ray data. Stability studies including the behavior toward selected nucleoside and nucleotide metabolizing enzymes will be investigated. Collaborative antiviral studies of highly purified forms of the target compounds, their derivatives and pro-drug forms will be carried out against HIV-1, HIV-2 and drug-resistant HIV isolates. A number of cell lines will be used in toxicity, on inhibition of HIV-1 p24 Gag protein, on inhibition of HIV RT, on inhibition of proviral DNA synthesis, on inhibition of Tat, and on therapeutic indexes will be determined and analyzed. Cellular combination drug therapeutic studies particularly those involving synergistic inhibition of HIV with antivirally active chiral aminobenzodiazepines (Tat inhibitors) and new or known active nucleosides and nucleotides (HIV RT inhibitors) ar planned. The proposed compounds have a high probability of being antivirally useful and the investigation will contribute to filling some of the gaps in knowledge in this area.