DRUG DISCOVERY FOR TREATMENT OF CRYPTOCOCCAL DISEASE

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The long term objective of this NCDDG proposal is to address the critical need for new therapeutic strategies to treat Cryptococcus neoformans infections in AIDS patients. Cryptococcosis is the most common life-threatening fungal infection in AIDS. Infection in these patients is usually manifested as acute meningoencephalitis, often presenting with relatively mils neurologic symptoms. The clinical presentation, however, belies the severity of the disease. Prior to the advent of amphotericin B therapy, cryptococcal meningitis in AIDS cryptococcosis. However, the need for new therapeutic approaches is underscored by the high rate of relapse following cessation of therapy, requirements for lifelong maintenance therapy, and problems of serious drug toxicity. In response to the urgent need for new treatment modalities for cryptococcosis, we have assembled a team of investigators whose expertise will be directed toward innovative approaches of "drug discovery". The collaborative nature of the scientific and organizational infrastructure will facilitate the attainment of project specific aims and program objectives. The specific aims of the five projects of this NCDDG program are: 1)to test the in vivo utility of leukocyte-derived antifungal peptides for treating experimental cryptococcosis. Solid phase synthetic production of selected, highly characterized peptides will provide adequate material for full evaluation of these molecules; 2) to test new strategies for enhancing host clearance mechanisms using in vitro assays systems and an in vivo model of cryptococcosis. This will entail evaluation of selected cytokines, as well as synthetic and immunologic reagents generated by other NCDDG projects; 4) to exploit the pheromone-controlled mating response of C. neoformans as a mechanism for arresting cryptococcal growth; 5) to evaluate the therapeutic of cryptococcosis: 6) to develop strategies for delivering new anticryptococcal agents.