Chapter 20. Human Leukocyte Elastase Inhibitors

Publisher Summary Human leukocyte elastase (HLE) is a serine protease and a basic glycoprotein, with isoforms of 25-30 kD. The active site of HLE is a channel on the protein surface that has extended substrate binding sites. The catalytic triad of Serlg5, Hisr7, and Asplo2 that resides in the active site channel catalyzes amide bond hydrolysis of various proteins, including elastin, the connective tissue of the lung. The S1 specificity pocket of serine proteases is largely responsible for the selectivity of the class of enzymes to cleave proteins at specific sites. HLE has a relatively small S1 pocket that is lined, with hydrophobic residues, thus HLE preferentially cleaves proteins at sites, with small lipophilic residues, such as alanine and valine. The specificity has been exploited in the design of HLE inhibitors. The isoforms of HLE have identical amino acid sequences and catalytic properties, but differ based on the nature of the carbohydrate content. The different carbohydrate content of the E-1 and E-3 isoforms of elastase is proposed to direct these isoforms to secretory and lysosomal functions, respectively. Human elastase, from polymorphonuclear neutrophils (PMN) and from purulent sputum, display identical kinetics, with various substrates and inhibitors, suggesting that elastase, from sputum, is from polymorphonuclear leukocytes (PMNs). In the chapter, the term HLE will be used to indicate elastase, from either PMNs or purulent sputum.