(4cs) Engineering Proteins and Peptides for the Investigation and Treatment of Infectious Disease

My research interests are focused on engineering proteins and peptides that can be used to better understand fungal infections and study potential antifungal compounds. I plan to use two approaches to design and synthesize proteins and peptides for studying antifungal properties of the compounds and for studying the interactions of fungal pathogens with host cells. The first approach is to use organic synthesis to produce compounds that mimic and improve on the activity of naturally occurring antifungal peptides. Organic synthesis provides the ability to tightly control the peptide sequence and to easily incorporate non-natural amino acid building blocks into the peptides. During my PhD research, I used this approach to synthesize antifungal peptides composed of non-natural, β-amino acids that mimicked the structure of natural antimicrobial peptides. The designed peptides had both improved antifungal activity and improved specificity for fungal cells compared to natural antimicrobial peptides. The second approach to peptide and protein design and synthesis that I will apply to my research is directed evolution. The protein production machinery in bacteria can be harnessed to perform protein synthesis, and the proteins can be evolved to improve on their natural functions or to have novel functions. Directed evolution can be used without any knowledge of the mechanism of action of a protein or peptide and offers the ability to create large numbers of potentially improved sequences that can be screened for desired functions. My postdoctoral research utilizes directed evolution to engineer high-affinity antibodies that fold in the intracellular environment, providing the opportunity to study the effects of antibody binding to intracellular targets. My experience with both organic synthesis and directed evolution provides a complementary set of techniques that can be used to tailor a protein or peptide engineering approach based on what is known about a particular fungal pathogen. Thus, my future plans are to make use of this molecular toolkit to create proteins and peptides that can be used to address basic questions underlying fungal pathogenesis or that can inhibit key mechanisms in fungal disease.