(65d) Development of Target-Specific Antifungal Beta-Peptides

Our project is focused on the design and characterization of engineered materials with intrinsic antifungal activity. We have chosen beta-peptides as a platform for the synthesis of target-specific antifungal agents. The already studied molecular interactions of antimicrobial synthesis peptides with cell membranes of pathogenic fungi and bacteria provide an excellent start point from which to optimize our designs. We propose the utilization of chitin-binding domains (CBDs) as models to create target-specific beta-peptides. CBDs are short amino acid sequences that bind specifically to the N-acetyl glucosamine subunits of the structural biopolymer chitin. We hypothesize that since chitin is a specific structural component of fungal cell walls, a CBD-based beta-peptide will exhibit an enhanced antifungal activity and decrease cytotoxicity particularly in mammalian cells, which lack chitin as a structural component. We will synthesize and characterize CBD-based beta-peptides and assess their activity against fungal cells in vitro using Candida albicans and Cryptococcus neoformans, important human pathogens. Furthermore, we will characterize the in vivo activity of CBD-based beta-peptides using murine pathogenesis models.