THERAPIES FOR AIDS-RELATED OPPORTUNISTIC INFECTIONS

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The overall goal of this group effort is to identify promising drug candidates for the therapy of Pneumoycstis carinii pneumonia and disseminated fungal infections in AIDS patients. We propose to accomplish this goal by investigating the mechanism(s) of action and structure activity relationships of new lead compounds already shown to be effective against the target Ol pathogens. These prototype compounds have demonstrated desirable biological activitaies, but virtually no SAR and/or mechanism of action information is available to direct future development efforts. Thus, we propose to investigate the mechanism(s) of action of selected novel fungicidal agents and pursue structure-activity relationship studies for three classes of agents with anti-Pneumocystis and/or antifungal activity. The research objectives of the Group are; . Investigate the mechanism(s) of action (MOA) of selected prototype fungicidal natural products. . Investigate the utility of in vitro assays to search for novel agents that act at potential new targets. . Investigate the role of primaquine-binding proteins in the MOA and clinical utility of 8-aminoquinolines and other antiPneumocystis drugs. . Explore the SAR of 8-aminoquinolines as anti-Pneumocystis agents. . Explore the SAR of two prototype fungicidal antibiotics. Thus, the Group will couple knowledge of the molecular basis of action with synthetic efforts to prepare improved analogs. Additionally, as a consequence of the investigation of the MOA of selected antifungal agents, it is likely that new molecular targets will be identified. As part of this effort, we also propose to develop rapid, reliable and convenient in vitro assays designed to detect novel selective antifungal activity based on specific mechanism(s) of action. Successful completion of the project should provide; . specific drug candidates for development as new therapies for treatment of AIDS related PCP and disseminated mycoses . identification of potential new targets . novel means of searching for new selective therapies in the future.