Cyclooxygenase Structure, Function, and Inhibition

Cyclooxygenase (COX) enzymes catalyze the double dioxygenation of arachidonic acid to prostaglandin endoperoxides, the immediate precursors to prostaglandins and thromboxane. These lipid mediators act through multiple G-protein-coupled receptors to trigger a broad range of physiological and pathophysiological responses. Their biosynthesis is inhibited by non-steroidal anti-inflammatory drugs (NSAIDs) which block the binding of arachidonic acid to the COX enzymes. NSAIDs – e.g., aspirin, ibuprofen, naproxen, celecoxib – are among the most widely prescribed drugs in the world and alleviate a great deal of human suffering.

Our laboratory is interested in how COX enzymes carry out their biochemical function. We use X-ray crystallography, site-directed mutagenesis, kinetics, and computational modeling to investigate the molecular determinants that COX enzymes use to bind both substrates and inhibitors. We use this information to design novel inhibitors with enhanced binding or novel functions. Among our recent accomplishments are (1) the design of a novel class of COX-2-selective inhibitors, (2) elimination of COX inhibitory activity of several classes of NSAIDs, which enables them to bind to other molecular targets in vivo, and (3) synthesis and validation of COX-2 targeted imaging agents and therapeutics. The latter class of compounds offer great promise for the diagnosis and treatment of cancer because COX-2 is expressed at high levels in many solid tumors but not in surrounding normal tissues. This provides a strategy for directing imaging or therapeutic agents selectivity to tumors.

Article Links:

L.J. Marnett “The COXIB Experience: A Look in the Rear-View Mirror,” Ann.Rev.Pharmacol.Toxicol., 49, 265-290 (2009)

A.S. Felts, B.S. Siegel, S.M. Young, C.W. Moth, T.P. Lybrand, A.J. Dannenberg, and K. Subbaramaiah “Sulindac Derivatives That Activate the Peroxisome Proliferator-Activated Receptor g but Lack Cyclooxygenase Inhibition,” J.Med.Chem. 51, 4911-4919 (2008)

A.L. Blobaum and L.J. Marnett “The Structural and Functional Basis of Cyclooxygenase Inhibition,” J.Med.Chem., 50, 1425-1441 (2007)