Therapeutic promises of leukocyte elastase and macrophage metalloelastase inhibitors for the treatment of pulmonary emphysema

The fibrous protein elastin, which comprises an appreciable percentage of a ll protein content in some tissues, such as arteries, some ligaments, and t he lungs, can be hydrolysed or otherwise destroyed by a select group of enz ymes classified as elastases. To date four elastases are known, three of wh ich are human: human leukocyte elastase (HLE), pancreatic elastase II (PE-I I) and macrophage metalloelastase (MME, MMP-12). Human leukocyte and pancre atic elastases are both serine proteinases (i.e., having a catalytic triad corresponding to Ser(195), Asp(102) and His(57) of chymotrypsin). However, macrophage metalloelastase is a member of the matrix metalloproteinase fami ly (MMPs, matrixins), which contain a zinc atom at the catalytic site. Imba lances in the levels or regulation of tissue or cellular proteases are thou ght to manifest themselves in various disease states. In order to prevent s elf-inflicted tissue damage due to over expression of enzymes, numerous end ogenous inhibitors directed against proteolytic enzymes exist. In the case of human leukocyte elastase the primary endogenous inhibitor is alpha(1)-pr oteinase inhibitor (alpha(1)-PI). In the case of the MMPs the endogenous in hibitors are the tissue inhibitors of metalloproteinases (TIMPs). Both of t hese natural inhibitors are proteins. Because of the liabilities of protein s as drugs, low molecular weight inhibitors may be useful as therapeutic ag ents as a replacement to alpha(1)-PI and TIMPs. Since HLE and MME have been implicated in the pathogenesis of pulmonary emphysema, inhibitors of these enzymes should have beneficial effects for the treatment of this chronic d isease. This report reviews inhibitors of HLE that have appeared in the pat ent literature since 1997 as well as patents that specifically claim MME in hibition.