TRICIRIBINE AND NOVEL ANALOGS AS INHIBITORS OF HIV

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Triciribine (TCN) and its water soluble prodrug (TCN-5'-monophosphate, TCN-P) have been studied as anticancer drugs; phase II clinical trials are in progress with TCN-P. Neither compound is metabolized to the di- or triphosphate and is not incorporated into nucleic acids. Recently we discovered that TCN and TCN-P are active against human immunodeficiency virus (HIV) in acutely infected and chronically infected T-cells and monocyte/macrophages at nanomolar concentrations. These concentrations are at least a thousand-fold lower than those which are cytotoxic in uninfected human cells. Activity also was demonstrated against a panel of HIV-1 and HIV-2 clinical isolates. HIV resistant to zidovudine (AZT) was not cross-resistant to TCN or TCN-P and isolated reverse transcriptase (RT) was not inhibited by TCN nor its nucleotides demonstrating that the compound does not act via this mechanism. Based upon these new discoveries, the broad objective of this proposal is to use TCN as a lead compound and invent new agents having greater activity and selectivity for HIV. A systematic program of chemical synthesis of new TCN analogs has been designed to develop novel compounds which will be evaluated for activity against HIV and for cytotoxicity in human cells. Coupled with an examination of the mode of action of TCN against HIV, these studies should permit the design and synthesis of compounds which are more active and/or less toxic than the parent compounds. The specific aims involve the synthesis of new congeners of TCN including but not limited to the following: (i) heterocycle-substituted analogs, (ii) sugar analogs, (iii) ring-modified compounds, and (iv) C-- nucleosides. Direction for the chemical synthesis will be provided by antiviral and cytotoxicity evaluation of the new compounds. Evaluations will include a syncytial plaque assay in acutely infected cells and one or more of the following methods using acutely and chronically infected T-cells, monocyte/macrophages, or peripheral blood leukocytes (PBL): infectious virus yield reduction, p24 core antigen, or RT assays. TCN and active analogs will be studied in combination with existing antiviral drugs to determine if potentiation of activity against HIV- 1 occurs without a concomitant potentiation of cytotoxicity. Data will be analyzed using three-dimensional dose-response methodology developed by us and areas of statistically significant synergy (or antagonism) will be identified and quantitated.