Structure-Guided Synthesis of FK506 and FK520 Analogs with Increased Selectivity Exhibit <i>In Vivo</i> Therapeutic Efficacy against Cryptococcus
Michael J. Hoy, Eunchong Park, Hyunji Lee, Won Young Lim, Deborah Cole, Nicholas D. DeBouver, Benjamin G. Bobay, Phillip G. Pierce, David Fox, Maria Ciofani, Praveen R. Juvvadi, William J. Steinbach, Jiyong Hong, Joseph Heitman
Abstract
Due to rising rates of antifungal drug resistance and a limited armamentarium of antifungal treatments, there is a paramount need for novel antifungal drugs to treat systemic fungal infections. Calcineurin has been established as an essential and conserved virulence factor in several fungi, making it an attractive antifungal target. However, due to the immunosuppressive action of calcineurin inhibitors, they have not been successfully utilized clinically for antifungal treatment in humans. Recent availability of crystal structures of fungal calcineurin-bound inhibitor complexes has enabled the structure-guided design of FK506 analogs and led to a breakthrough in the development of a compound with increased fungal specificity. The development of a calcineurin inhibitor with reduced immunosuppressive activity and maintained therapeutic antifungal activity would add a significant tool to the treatment options for these invasive fungal infections with exceedingly high rates of mortality.