This contract supports the National Institute of Allergy and Infectious Diseases (NIAID) in its mission to stimulate the discovery of improved therapies of AIDS-associated opportunistic infections. While a few drugs are available to treat some of these infections, more efficacious and less toxic therapies are needed. Additionally, accepted therapies do not exist for certain opportunistic infections (OIs). In vitro assays and biochemical prescreening have been used effectively to identify structure-activity relationships (SAR) of potential new therapies. Biochemically based screening tests may be particularly useful in discovery of anti-OI drugs because: l) certain AIDS-related opportunistic pathogens cannot be cultured in vitro, 2) such assays are rapid, and more efficient for pathogens that replicate poorly in vitro, 3) enzymes critical in the replication of certain pathogens have been identified and may be exploitable therapeutically, 4) analogous host enzymes may be identified that could be used to simultaneously evaluate selectivity, and 5) development of high volume assays permits detailed SAR evaluations of compounds. Such a biochemical prescreening project has been operational at NIAID since 1988 and several promising compounds have been identified. Specifically, compounds were rationally selected from an automated data base and evaluated for inhibition of enzymes of folic acid metabolism isolated from Pneumocystis carinii, Toxoplasma gondii and host mammalian tissues. The purpose of this contract is to continue efforts to screen agents in enzymatic assays of metabolic pathways essential to the replication of AIDS-related opportunistic pathogens. Pathogens to be addressed include P. carinii, T.gondii. and Mycobacterium avium.
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