The Smith lab is primarily focused on understanding the role of defensins in antiviral immunity. Defensins are a class of antimicrobial peptides with broadly acting antibacterialactivity; however, their role in antiviral immunity, particularly for nonenveloped viruses, is less well understood. Using a variety of approaches from virology, cell biology, biochemistry, structural biology, and genetics, our work is focused on understanding the interaction of defensins with human adenovirus in molecular detail. We are also interested in using animal models of viral diseases to understand the role of defensins in antiviral immunity in vivo. Finally, through comparative studies with other nonenveloped viruses such as human papillomavirus and adeno-associated virus, we will determine general principals of defensin-mediated neutralization of nonenveloped virus infection.
A second focus of the Smith lab is the development of antivirals against influenza virus based on a novel cyclic D,L-alpha-peptide scaffold. In collaboration with M. Reza Ghadiri at the Scripps Research Institute, we have identified a number of peptides that broadly neutralize influenza virus infection at low micromolar concentrations. Ongoing research is focused on understanding the mechanisms by which these compounds neutralize infection, optimization of initial hits through structure-activity relationship studies, identification of additional peptides with novel modes of action, and efficacy and toxicity studies in animal models.