The design, synthesis, and evaluation of new therapeutic agents for the treatment of the acquired immunodeficiency syndrome (AIDS) is a significant challenge now facing the scientific community. Recent work by this research group has resulted in the synthesis of a novel agent against the human immunodeficiency virus, Type 1 (HIV) agent called cosalane. Enthusiasm about the anti-HIV activity of cosalane has been high, as evidenced by the fact that it has reached the Decision Network (DN) Stage II developmental stage at the National Cancer Institute, and that considerable resources have already been invested in its scaled-up synthesis in order to obtain sufficient material for clinical studies. Cosalane is active against all strains of HIV tested, including those resistant to zidovudine (AZT) and non-nucleoside reverse transcriptase (RT) inhibitors. Initial studies have indicated that cosalane inhibits both the binding of the virus to the cell membrane as well as postbindlng fusion events. The research proposed in this application is for the synthesis of cosalane derivatives and analogues that have been designed to address a number of important issues related to the preclinical development of cosalane. In particular, one of the main goals of this research is to improve the oral bioavailability of cosalane through the utilization of a prodrug approach. In addition, attempts will be made to synthesize more lipophilic cosalane analogues which retain the antiviral activity of cosalane and would presumably be more readily absorbed after oral administration. Lead optimization through the study of cosalane analogs will also receive high priority. An array of cosalane analogs will be synthesized and evaluated in order to probe the structural parameters associated with the anti-HIV activity of cosalane and also to obtain additional compounds having increased potencies and decreased toxicities. The structural parameters to be examined include the point of attachment of the linker chain from the disalicylmethane moiety to the steroid nucleus, the length of the linker chain, the replacement of the dichlorodisalicylmethane moiety with a trisalicylmethane unit, and the replacement of the steroid with other membrane-targeting structural fragments, including simple phospholipids, ether lipids, and zwitterionic alkylglycerol derivatives. In this work, present collaborations for evaluation of cosalane analogs as anti-HIV agents will continue. The assays presently being performed on a collaborative basis include the prevention of HIV cytopathicity, the cytotoxicity in uninfected cells, the inhibition of syncytium formation, the inhibition of virion binding to cells, CD4 binding, gp120 binding, the inhibition of gp120- CD4 binding, the inhibition of RT, the inhibition of integrase, and the inhibition of protease. In addition, experiments will be done on time of addition, limited treatment, preincubation, the inhibition of virus production, plasma protein binding, and stability in the presence of serum and under acidic conditions, oral bioavailability, pharmacokinetics, and prodrug metabolism. The effectiveness of the proposed prodrug strategies will also be evaluated.
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