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The Washington Research Foundation Fellowship

Matthew Sonnett, Biochemistry, 2012-13 WRFF

Matthew SonnettI originally came to UW with the long-term goal of pursuing a Ph.D. in neuroscience, but for reasons I don't really understand, I figured chemistry was close enough, and I began doing research in Dr. Michael Gelb's lab during my freshman year that consisted mostly of organic synthesis. Since then, I have remained in the Gelb lab, and I have continued to make small molecule inhibitors that can be used to better understand the role of several proteins intimately involved in a number of inflammatory events. I had not taken organic chemistry when I began working in lab, so my appreciation and understanding of my research, and chemistry in general, grew exponentially over my sophomore year, and continued to blossom last year as I took the graduate organic chemistry series. I cannot overstate how phenomenal of an experience I have had with undergraduate research. It has defined my career ambitions, and it has taught me how to think critically. I am incredibly grateful for the experience that I have had in Dr. Gelb's lab here at UW, and I would like to thank the Washington Research Foundation for their generous support.

I am applying to Ph.D. programs this fall and I hope to join a lab that is working at the interface of chemistry and biology. I am interested in both enzymology and protein engineering, and I am hoping that my graduate work will be centered in those areas.

Mentor: Michael Gelb, Chemistry

Project Title: Design and Synthesis of Specific Inhibitors for Cytosolic Phospholipase A2 alpha and zeta

Abstract: It is well known that mammals contain several types of phospholipase A2. The cytosolic phospholipases A2 (cPLA2s) are one type, and are composed of six enzymes. There has been significant interest in the cPLA2alpha isoform because of the enzyme's ten-fold preference for the hydrolysis at the sn-2 position of the glycerol backbone in phospholipids, resulting in the liberation of arachidonic acid (AA). AA serves as a precursor for several highly regulated inflammatory mediators that play an important role in asthma, atherosclerosis, arthritis, and other inflammatory diseases. To address these problems, inhibitors that target cPLA2alpha have been developed by Wyeth pharmaceuticals to serve as anti-inflammatory therapeutics. However, a recent study has shown that in cPLA2 -/- stimulated lung fibroblasts AA production is lessened but still present. cPLA2zeta has been identified as the other enzyme involved in the release of AA. Consequently, our aim is to develop a selective and potent inhibitor that can distinguish between the cPLA2alpha and cPLA2zeta isoforms. Our synthetic strategy is to modify the scaffold of Wyeth's cPLA2alpha inhibitor. After analyzing structure-activity relationships, we have generated and assayed over two dozen inhibitors, with many more in progress. Our main focus is to increase the selectivity of our inhibitors in order to regulate and better understand the roles of cPLA2alpha and cPLA2zeta in eicosanoid generation.