The aims of this interdisciplinary project are to develop clinically useful non-toxic drugs for patients infected with AIDS,which can penetrate the central nervous system and exert potent and selective antiviral activities against human immunodeficiency viruses (HIV). The Biological Core Laboratory, which is an integral part of this project, will interact closely with the Chemists in the group in developing the new porphyrins, phthalocyanines, unfused heterocycles, and other heterocycles. The Core will continue to perform all the virological, immunological, toxicological, and pharmacological studies conducted in all programs. This central core will provide several sophisticated in vitro cell systems to evaluate the antiretroviral effects of drugs conceived and synthesized in Project 1-3. Toxic effects to uninfected cells, with particular emphasis on human lymphocytes and macrophages, will be conducted with the active drugs. Compounds that are found to be selective antiviral drugs will be further evaluated in order to determine the primary mechanism of action. Cross-resistance studies with the newly discovered compounds will be performed. Biochemical pharmacological studies, with evaluation of drug uptake, intracellular metabolism, and RNA, DNA, and protein synthesis and/or key sites of interactions (e.g., viral and cellular enzymes, cell membrane, glycoproteins) in HIV-infected cell systems, will be conducted. The immunotoxicity and effect on binding/fusion of chronically infected to uninfected lymphocytes will also be examined. Assays to resolve and quantitate antiretroviral entities and metabolites will be developed for the biochemical pharmacological studies as well as for the in vivo pharmacokinetic studies. In vivo virological, pharmacological, and toxicological studies with the selective antiretroviral agents will be performed to examine their disposition, metabolism, elimination, and toxicity. Toxicity studies in mice and evaluation of the in vitro effect of the drugs against simian immunodeficiency virus (SIV) prior to testing in monkeys will be essential. Lastly, the antiretroviral effects of the drugs will also be evaluated in mouse cultures infected with Friend virus and in an experimental retroviral murine model. In summary, a rational progression from in vitro screening tests with biochemical pharmacologic and/or toxicologic approaches to the in vivo research will be conducted by this core program which will closely work in collaboration with Projects 1 through 4.
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