ABSTRACT
The phospholipase A2 enzymes are important components of the cellular machinery that responds to inflammatory stimuli and maintains cell homeostasis by membrane remodelling. Their role as the rate-limiting step in the production of pro-inflammatory lipid mediators makes these enzymes an important therapeutic target for the treatment of inflammatory disorders. Keith Glaser and colleagues explain how the two major groups of phospholipase A2, the secretory and cytosolic forms, are very different both structurally and enzymatically. Understanding the relative contributions of these different forms of phospholipase A2 to physiological and pathological conditions requires greater insight into their cellular regulation and the development of selective inhibitors.
Subject(s)
Phospholipases A/physiology , Animals , GTP-Binding Proteins/physiology , Humans , Models, Molecular , Phospholipases A/antagonists & inhibitors , Phospholipases A/metabolism , Phospholipases A2 , Stereoisomerism , Synovial Fluid/enzymologyABSTRACT
Modified heterocyclic phenylalanine analogues designed as replacements for the P3-P4 region were synthesized and incorporated into renin inhibitors. These inhibitors were found to have significant activity versus human recombinant renin, as well as in vivo activity. The compounds proved to be very resistant to chymotrypsin degradation, as exemplified by compound 8, which remained greater than 60% intact after a 24-h exposure to chymotrypsin. In contrast, the Boc-Phe analogue was nearly completely degraded after 1 h. Compound 6 proved to be the most potent renin inhibitor with an IC50 = 8.9 nM. These stable cyclized phenylalanines should prove to be generally useful as a substitute for Boc-Phe in protease inhibitors.
