Although significant advances have been made recently in the chemotherapy of AIDS, the presently available, clinically useful anti-AIDS agents target only two biological macromolecules, reverse transcriptase and protease. Therefore, new anti-AIDS agents are needed which will interact with additional viral targets important in the replication cycle of the virus. These new agents with novel mechanisms of action can be expected to enhance the prospects for successful treatment of AIDS by combination chemotherapy. Recent work by this Principal Investigator and his associates has involved the design and synthesis of cosalane, a novel anti-HIV agent which inhibits the binding of CD4 to gp120 and inhibits the cytopathic effects of HIV-1 and HIV-2 in cell cultures. Although enthusiasm surrounding the antiviral activity of cosalane is high, the potential therapeutic use of cosalane is restricted by low oral bioavailability and unoptimized potency. The present application is for support to design and synthesize certain cosalane analogs which will broach these remaining problems. In order to address the problem of low oral bioavailability, a series of cosalane analogs and prodrugs is proposed in which the compounds are designed to have enhanced oral absorption and increased metabolic stability. The metabolism of these compounds will be studied in rat intestinal and hepatic microsomal systems as well as by mesenteric and systemic blood sampling in whole animals. The pharmacokinetics will be defined, the structures of the metabolites will be determined, and the metabolites will be synthesized. The design and synthesis of more potent cosalane analogs is also being carried out. These efforts are being assisted by computer graphics molecular modeling of hypothetical ligand-protein complexes, as well as by analysis of the available information concerning the structural parameters associated with the biological activities of the cosalane analogs synthesized to date. The cosalane congeners will be examined for a number of biological activities, including: (1) prevention of HIV-1 cytopathicity in cell culture; (2) cytotoxicity; (3) inhibition of syncytium formation; (4) inhibition of virion binding to cells; (5) CD4 binding; (6) gp120 binding; (7) inhibition of gp120-CD4 binding; (8) HIV-1 RT inhibition; (9) inhibition of integrase; (10) inhibition of protease; (11) effect of time of addition, limited treatment, and preincubation on activity; (12) effects on virus production; (13) stability in serum and serum protein binding; and (14) activity in an in vivo hollow fiber animal model.
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