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Infect Immun. 1973 April; 7(4): 655-665
Copyright © 1973 American Society for Microbiology. All Rights Reserved.

Inhibition of the Cathepsin D-Type Proteinase of Macrophages by Pepstatin, a Specific Pepsin Inhibitor, and Other Substances

^a Department of Radiological Sciences, School of Hygiene and Public Health, and the Department of Pathology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland 21205

ABSTRACT

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 -NH linkages, two ß-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.

¹ Affiliation: Searle Laboratories, G. D. Searle and Co., Chicago, Ill. 60680.

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