Molecular Biology & Biochemistry
My research interest is in understanding the molecular basis for antigen recognition by antibodies using peptide as probes of these interactions. My postdoctoral work involved the initial development of phage-displayed, peptide libraries for this purpose. A peptide library comprises tens of millions of short, variable, amino acid sequences that have been engineered into a viral coat protein, thereby displaying the fusion products on the surface of filamentous bacteriophage. The phage-displayed peptide is linked to an amplifiable readout, encoded on the viral genome. This allows a library to be searched with binding molecules such as antibodies, receptors and enzymes, using affinity-selection to find the rare phage displaying binding peptides. The sequences of binding peptides can be easily determined from clones isolated from affinity-enriched phage pools, by sequencing the region of phage DNA encoding the variable peptides.
We have constructed a panel of peptide libraries, with emphasis on designing frameworks around the variegated residues that mimic structures on folded proteins. Such constrained peptides will give us more information about the types of structures that are required for binding (and thus for successful mimicry), as well as the chemistry of the selected amino acids. By screening the panel of peptide libraries with polyclonal antibodies against proteins of known structure, we can compare the structures of the peptide mimics we find with their corresponding protein epitopes. This gives us a good starting point for understanding the molecular basis of peptide mimicry. Moreover, to understand how peptides may rationally be used as immunogens, we are investigating select peptide mimics for their ability to induce antibody responses that recognize a target antigen.
As a molecular immunologist and physician, I have a strong interest in understanding how the peptide recognition profile of an antibody response may be applied to the development of vaccines and autoimmune diagnostics. One of our most interesting projects involves our search for peptides will bind to human monoclonal antibodies that kill HIV-1. We hope to create a vaccine that will elicit these same antibodies in uninfected people, and thus protect them from AIDS.