Inhibition of cathepsin D-type proteinase of macrophages by pepstatin, a specific pepsin inhibitor, and other substances.
The macrophage is the main cell participating in chronic inflammation. It contains an acid-acting, cathepsin D-type proteinase with the specificity of pepsin, which may release mediators of the inflammatory process. To find new pharmaceutical inhibitors of this proteinase, we tested a variety of chemical compounds in vitro. For this survey, the possible inhibitor (at a concentration of 0.4 mg/ml) was assayed with partially purified cathepsin D-type proteinase from beef lung (a macrophage-rich tissue) and hemoglobin as the substrate. Diazophenylbutanone, three acetophenones, two barbiturates, a gold salt, a copper chelate of a substituted nicotinic acid, a hexapeptide containing a d-amino acid, and Pepstatin inhibited this enzyme; over 200 other potential inhibitors did not. By far the most active and specific inhibitor found to date is Pepstatin, a pentapeptide with two gamma-NH linkages, two beta-OH groups, and five branched aliphatic side chains. Banyu Pharmaceutical Co., Tokyo, Japan, produces this nontoxic compound for the treatment of peptic ulcers. In vitro, as little as 4 ng of Pepstatin inhibits the acid-acting cathepsin D-type proteinase purified from beef and rabbit lung as well as the similar proteinase of rabbit peritoneal and pulmonary macrophages.
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001202:Ascitic Fluid / Q000166:cytology; D001463:Barbiturates / Q000494:pharmacology; D002074:Butanones / Q000494:pharmacology; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D002417:Cattle; D002614:Chelating Agents; D003300:Copper / Q000494:pharmacology; D006046:Gold / Q000494:pharmacology; D006454:Hemoglobins; D006851:Hydrochloric Acid; D006863:Hydrogen-Ion Concentration; D007249:Inflammation / Q000188:drug therapy; D008168:Lung / Q000166:cytology / Q000201:enzymology; D008264:Macrophages / Q000201:enzymology*; D010434:Pepsin A / Q000037:antagonists & inhibitors; D010455:Peptides / Q000494:pharmacology*; D011817:Rabbits; D014508:Urea
D000098:Acetophenones; D001463:Barbiturates; D002074:Butanones; D002614:Chelating Agents; D006454:Hemoglobins; D010455:Peptides; D006046:Gold; D003300:Copper; D014508:Urea; D002403:Cathepsins; D010434:Pepsin A; D006851:Hydrochloric Acid