Current Research Interests:
Research Projects:

Development of High-Throughput Screens for Vasoactive Intestinal Peptide Analogs Vasoactive intestinal peptide (VIP) is a neuropeptide that signals in tissues local to nerve tissue. VIP shows potential beneficial bioactivity regarding the treatment of a number of disease states. Among the most notable are asthma, Parkinson’s disease, and Alzheimer’s disease. However, most peptides are easily degraded in the body by constituitively expressed proteases. Perhaps the easiest way to curtail proteolytic digestion is to incorporate unnatural amino acids into the VIP sequence which allow the now modified peptide to retain its signaling function, while thwarting proteolytic degradation. However, there is no systematic approach toward making substitutions of unnatural amino acids. My lab is working on a method that can select VIP analogs based on structure and charge homology to the native VIP.

Correlating Structure with Activity in Bioactive Peptides Small peptides are typically unlike natively folded proteins. Peptides are more appropriately described as having a configurational ensemble rather than a native fold. However, one of the basic tenets of drug design is that the structure of bioactive agents correlate with their activity. My lab is testing the hypothesis that a small subset of the ensemble of VIP structures are responsible for biological activity, and that the activity of a given alanine substitution mutant of VIP is proportional to the contribution of these active structures to the configurational ensemble. The structures of all 26 Ala substitution mutants are being determined using TOCSY and NOESY NMR studies.

Complete Mechanistic Analyses of Stereoselective Reactions Nature’s catalysts, enzymes, often catalyze reactions with nearly complete stereospecificity. Man-made catalysts have been developed that can achieve similar stereospecificity. My lab is performing complete mechanistic analyses on reactions of high stereoselectivity in order to determine the fundamental physical reasons for high stereoselectivity. Some of these reactions utilize chiral natural product-derived reagents, small chiral organocatalysts, and enzymes. Kinetic analyses and kinetic isotope effects are the main tools used in this research.

Systematic Methods for the Development of Lipoxygenase Inhibitors Understanding how a substrate binds to an enzyme is crucial to rational drug design. While many drugs are structurally dissimilar from the natural substrate of the enzyme they inhibit, potential side effects and cross-reactivity could be diminished if inhibitors were developed based on the natural substrate structural motifs. My lab is measuring binding kinetic isotope effects on the oxidation of linoleic acid catalyzed by soybean lipoxygenase 1 and 15 human lipoxygenase. This process is, in effect, like being able to determine how the vibrational frequencies of individual C-H bonds on the substrate change upon binding to the enzyme. Using this method, we can determine where the enzyme is making close contact with the substrate and where there is room to optimize substrate-enzyme complementarity in the transition state. This information is crucial, since most enzyme inhibitors are transition state analogs. From this information, we seek to construct viable inhibitors that are selective for soybean lipoxygenase 1 and 15 human lipoxygenase.