(627g) Engineering Antimicrobial Peptides to Target Fungal Pathogens

Candida albicans and other Candida species are human commensal organisms but can cause disease when patients are immunocompromised. Increasing drug resistance and the limited number of available antifungal agents necessitate the search for new therapeutic strategies. To address current therapeutic challenges, we are engineering peptides for improved interactions with fungal cells. One of these peptides is histatin 5, is an antimicrobial peptide found in human saliva that has potent and specific activity against C. albicans. Although histatin 5 has promise as a therapeutic agent, the fungus produces secreted aspartic proteases that degrade the peptide and reduce its antifungal activity. We have designed analogs of histatin 5 that offer strong resistance to the fungal proteases without reducing antifungal activity. We are investigating the use of these analogs for treating and preventing disease, while also improving understanding of how the secreted aspartic proteases recognize and cleave peptide substrates. In addition to exploring peptides as potential therapeutics, we are also using peptides to target and deliver bioactive molecules to Candida pathogens. We are examining how properties of these cell-penetrating peptides affect their translocation across the cell wall and cell membrane of Candida cells and are defining the types of cargo that can be delivered into fungal cells. By applying protein engineering strategies to designing peptides for targeted interactions with fungal cells, we are gaining information on structure-function relationships that will enable more efficient design of biomolecules for specific interactions with biological systems.