The increase in opportunistic fungal infections such as candidiasis, zygomycosis, cryptococcosis, histoplasmosis, and Aspergillus and Fusarium infections in immunocompromised individuals, including AJDS patients, the elderly, surgical patients. and burn victims, has demonstrated that these infections are often fatal even with present day therapies. The two accepted therapies, amphotericin B and the azoies, have limited effectiveness and toxic side-effects. Hence, there is a clear need for more effective antifungal agents. To address this need, we plan to discover antifungal therapeutics with novel mechanisms of action by targeting drug discovery efforts on a group of actin-binding proteins essential for cell and membrane integrity in pathogenic fungi. Using a high-throughput screen developed by Cytokinetics, we will isolate inhibitors of these molecules' activities from chemical libraries totaling 225,000 compounds. We will test hits for activity against a panel of fungi and determine mammalian toxicity. In an effort to develop broad-spectrum antifungal compounds, we will use in our high-throughput screen homologs of these targets that we have isolated from multiple fungal pathogens. PROPOSED COMMERCIAL APPLICATION: The increase in patients suffering from opportunistic fungal infections, including AIDS patients, the elderly, transplant patients, and burn victims, has demonstrated these infections are frequently fatal if untreated. The accepted therapies have limited effectiveness and toxic side effects. There is a compelling need to find a new molecular targets and inhibitors of these targets. Current antifungals have potential market sales of $6.5 billion annually. Clearly, a novel, broad-spectrum antifungal will have significant commercial value, and will increase the quality of life for infected individuals
