Abstract
There has recently been a major revival of interest in serine protease structure, mechanism and inhibition. Recognition that this class of enzymes plays an essential role in such diverse and important processes as cellular regulation, viral infection, blood coagulation, and diseases like emphysema has led to new efforts to control their reactivites. Because serine proteases are ubquitous, but highly specific, they pose special problems as targets for inhibitor design. A “generic” protease inhibitor that bases its reactivity solely on the nucleophilicity of the active site serine hydroxyl will inactivate too many essential proteases as well as the target enzyme; phenylmethanesulfonyl fluoride is such a compound, and is highly toxic. Consequently, the most fruitful approach would be to use the natural specificity of the protease to direct the inhibitor to only the desired target. This specificity resides in a set of specificity sub-sites, some distance from the reactive serine and extending away from it in two opposite directions. Naturally occurring protein protease inhibitors derive their specificity from a number of interactions between inhibitor and enzyme, which are not restricted to the catalytic site or primary specificity site.