SUMMARY OF RESEARCH PROJECTS

Amino acids

We have recently discovered a general method for the synthesis of optically active alpha-amino acids. The method is based on the utilization of an ortho ester as a blocking group on the carboxylic acid function of serine. The hydroxyl function can then be oxidized to the corresponding aldehyde or substituted without racemization. This approach allows for the synthesis of several uncommon amino acids that are found in many natural products. We have used this approach to prepare amino acid analogs as selective receptor agonists for the glutamate receptors or as enzyme inhibitors for important enzymes such as nitric oxide synthase(NOS) (in collaboration with Prof. Guy Guillemette, University of Waterloo).

Antimicrobial Peptides

Histatins are a class of antimicrobial peptides found in the saliva of man and of other primates. They have a broad range of antimicrobial activity and are believed to be an important in the non-immune response to invading organisms. We have synthesized many members of the histatins family and analogs. We are studying their conformational properties by various biophysical techniques such as CD and NMR in different environments in order to gain insight in their mode of action. Based on NMR studies, we have designed analogs that are 100 times more potent than the natural sequence as antifungal agent.

Inhibitors proteins of serine proteases

Many physiological processes are controlled by inhibitory proteins. An imbalance in the protease-antiprotease can result in severe disease states. The study the binding region of the inhibitory proteins is important to understand these interactions and could lead to novel therapeutic agents. We are studying a small inibitory protein eglin c, isolated from the leech Hirudo medicinalis. The goal is to develop highly selective and non-immunogenic proteins as inhibitors of physiologically relevant proteases. With the appropriate mutation in the binding domain of eglin c, we have obtained extremely potent inhibitors (Ki ~10-14 M) which are ~10,000 times more potent for human leukocyte elastase (HLE) than for chymotrypsin and cathepsin G. These enzymes have been implicated in the development of emphysema and rheumatoid arthritis.

Biological Mass Spectrometry and Proteomics

We are using modern mass spectrometry based on both MALDI or electrospray ionization to characterize a wide range of biomolecules as well as their complexes. In the context of proteomics we are using these techniques to discover the function of new proteins and their modifications in various biological systems. These studies will provide fundamental knowledge on how cells work and, in the biomedical context, how diseases evolve. These latter studies could lead to new diagnostics and to new drug targets. We collaborate with numerous scientists from UWO, the Robarts Research Institute, the Child Health Research Institute and from elsewhere in Canada. In parallel, we are developing alternative approaches for protein isolation and purification. In addition, in collaboration with colleagues from the Department of Computer Science, we are developing new software tools to handle the large number of complex data generated by mass spectrometry.