A Structural Approach for Treating Drug Resistant Fungal Pathogens

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DESCRIPTION (provided by applicant): There is an urgent need to discover more effective therapeutic regimens for fungal infections. Nosocomial infections caused by Candida albicans have a 50% mortality rate. Aspergillosis is a leading cause of death in organ transplant recipients, as well as patients suffering from cancer and auto-immune disorders. The annual cost of treating fungal infections is about $2.6 billion in the United States and is increasing due to the larger number of immunocompromised patients who suffer from these illnesses. The emergence of fungal drug resistance to widely used antifungals including triazoles and echinocandins further compromises the efficacy of the limited armamentarium of antifungal therapeutics. A number of in vitro and in vivo studies have established that molecules which inhibit the fungal protein, calcineurin, are highly synergistic with several important classes of antifungal therapeutics including triazoles and echinocandins. However, a great challenge with exploiting fungal calcineurin as a therapeutic target is the structural similarity to human calcineurin, and that inhibition of human calcineurin causes severe immunosuppression and toxicity. By solving the X-ray crystal structure of calcineurin from C. albicans, we hope to gain insight into the structure activity relationships of non- immunosuppressive cyclosporin A analogues. We hope to develop these cyclosporin A analogues as potent antifungals employing the following steps: 1. Homology model the known x-ray crystal structure of the ternary complex of H. sapiens calcineurin/cyclosporin A/cyclophilin A to create a model of the ternary structure of C. albicans calcineurin/cyclopsorin A/cyclophilin A. 2. Determine the x-ray crystal structure of the ternary complex of C. albicans calcineurin, cyclosporin A, cyclophilin A. 3. Design and synthesize cyclosporin A analogues by comparing the human ternary structure with the fungal ternary structures generated by the homology model and/or x-ray model and employing molecular modeling tools to assist with library design. 4. Screen and select compounds against both C. albicans and non-albicans Candida strains. PUBLIC HEALTH RELEVANCE: Fungal infections represent a significant challenge due to the limited armamentarium available to treat diseases caused by fungi. Nosocomial infections caused by Candida albicans have a 50% mortality rate. Amplyx proposes a new combination therapy approach to treating drug resistant fungal infections via the design and synthesis of non-immunosuppressive molecules to inhibit fungal calcineurin that can be co- administered with existing antifungals.