Invasive aspergillosis (IA), caused by the fungus Aspergillus fumigatus, is associated with mortality rates of 40- 50%. In response to the lack of effective treatments, the Infectious Diseases Society of America highlighted A. fumigatus as one of only six pathogens for which it mandated that a "substantive breakthrough is urgently needed". IA accounts for the largest financial burden of all invasive fungal infections, with an annual economic cost in the United States of over $1.1 billion. Driven by the growing immunosuppressed patient population, both the incidence and mortality due to A. fumigatus have risen three-fold in the last decade. While much is known regarding the cellular processes required for fungal pathogenesis, translating understanding into tangible clinical benefit has been difficult due to the fact that these fungal pathogens and their hosts have similar physiology. As a result, current antifungal agents have limited clinical efficacy, are poorly fungicidal in the host, are occasionally toxic, and are increasingly ineffective due to emerging resistance. Thus, innovative antifungal targeting agents and strategies are critically needed. It has been well established that molecules targeting fungal calcineurin (FC) have extremely potent antifungal activity against a broad range of fungi. Over the past decade, our collaborator has established that calcineurin is required for A. fumigatus hyphal growth and virulence. Moreover, calcineurin is required for fungal stress response and small molecule or genetic inhibition of calcineurin thwarts drug resistance. The challenge of exploiting FC as an antifungal agent is due to structural and sequence homology with human calcineurin (HC). Knowledge of the HC pathway and the immunosuppressive capacity of calcineurin inhibition has been one of the greatest contributions to our current solid organ and bone marrow transplantation abilities. However, inhibition of HC causes severe immunosuppression and toxicity. Recent chemical innovations have enabled Amplyx to rapidly create libraries of analogues of FK506 and FK520 that were previously synthetically intractable. These new chemistries have resulted in promising analogs with substantially lower immunosuppression than the parent compounds yet maintain a high-degree of antifungal activity. Based on these preliminary results, our goals in this proposal are to (1) Use existing structural data and perform computational modeling to design non-immunosuppressive calcineurin inhibitors of A. fumigatus; (2) Synthesize and purify a library of these calcineurin inhibitors for initial testing; and (3) Screen and select these compounds for low immunosuppression, potent antifungal activity, and favorable pharmacokinetics. The impact of this work will be to utilize a structural biologic approach to design, synthesize, and test fungal-specific calcineurin inhibitors with minimal immunosuppressive action and robust antifungal activity against both A. fumigatus wild-type and antifungal resistant strains, potentially transforming the treatment paradigm for IA.
Public Health Relevance Statement: Public Health Relevance: Mortality rates due to infections caused by the pathogenic fungus, Aspergillus fumigatus, are 40-50% and there is an urgent need for more effective therapeutics. The estimated annual healthcare cost due to these infections is over $1.1 billion in the United States. Amplyx proposes to create a new class of antifungal drugs to improve treatment outcomes.
Project Terms: Accounting; Acute; Affinity; Americas; analog; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; base; Binding (Molecular Function); biological adaptation to stress; Bone Marrow Transplantation; Calcineurin; Calcineurin inhibitor; Calcineurin Pathway; calcineurin phosphatase; Candidiasis; Caspofungin; Cause of Death; Cell physiology; Cell Wall; Chemicals; Chemistry; Clinical; clinical efficacy; clinically relevant; Communicable Diseases; Computer Simulation; cost; Cyclosporine; Cytochrome P450; Data; data modeling; design; Development; Disease; Drug Kinetics; Drug resistance; economic cost; effective therapy; Eukaryota; FDA approved; FK506; Fungal Drug Resistance; fungus; Genetic; Goals; Growth; Health Care Costs; Homology Modeling; Human; Immunocompromised Host; Immunosuppressive Agents; improved; In Vitro; in vitro activity; Incidence; Industrial fungicide; Infection; innovation; insight; Investigation; Knowledge; Libraries; Michigan; model design; Molds; Mortality Vital Statistics; Mycoses; Natural immunosuppression; next generation; novel; novel therapeutics; Organ; Outcome; Parents; pathogen; Pathogenesis; patient population; Patients; Permeability; Physiology; preclinical study; prevent; Process; professor; Proteins; public health relevance; Publishing; Relative (related person); Resistance; resistant strain; response; Roentgen Rays; Saccharomyces cerevisiae; Sales; screening; Sequence Homology; small molecule; Societies; Solid; Specificity; Structure; Structure-Activity Relationship; Tacrolimus Binding Protein 1A; Testing; Therapeutic; Therapeutic Index; Toxic effect; Translating; Transplant Recipients; Treatment outcome; United States; Universities; Virulence; Voriconazole; Work
