The laboratory core unit will be divided into two major subdivisions: 1) Virology/Toxicology/Pharmacology/Immunology Laboratory Core Unit. This Core will be involved with all the virological, immunological, toxicological and pharmacological studies conducted in all programs. This central core will thus provide several sophisticated in vitro cell systems to evaluate the anti-retroviral effects of drugs conceived and synthesized in programs I through IV as well as materials submitted by industrial collaboration. Tests on viral latency as well as toxic effects to uninfected cells with particular emphasis on human bone marrow progenitor cells will be investigated with the active drugs. As part of the in vitro screening, immunotoxicology studies will also be assessed with potentially selective anti-retroviral drugs. Then biochemical pharmacological studies, with evaluation of drug uptake, intracellular metabolism and RNA, DNA and protein synthesis and/or key sites of interactions (enzymes, cell membrane, glycoproteins etc...) in HIV-infected and noninfected cell systems will be carried out. Metabolic studies will be further evaluated with human liver systems and potential identified metabolites will be evaluated for their anti-retroviral properties. Assays to resolve and quantitate anti-retroviral entities and metabolites will be developed for the biochemical pharmacological studies (see above) as well as for the in vivo pharmacokinetic studies. Lastly, in vivo virological, pharmacological and toxicological studies with active and selective anti-retroviral compounds will be carried out to examine their disposition, metabolism, elimination, acute and chronic toxicity as well as anti-retroviral effects in experimental animals. 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 programs I through IV. 2) X-Ray Crystallography Core Unit. This core facilities for all programs i through IV will perform x-ray crystallographic studies of HIV related proteins. This approach is of particular importance for rational anti-retroviral drug design.
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