Journal
BIOCHEMICAL PHARMACOLOGY
Volume 83, Issue 6, Pages 788-796Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2011.12.023
Keywords
Proteinase 3 (myeloblastin); Azapeptide; Inhibitor; Drug development; Lung diseases
Categories
Funding
- Region Centre
- Fonds Europeen de Developpement Regional
- Fondation Pour la Recherche Medicale (FRM)
- Association Vaincre La Mucoviscidos
Ask authors/readers for more resources
The biological functions of human neutrophil proteinase 3 (PR3) remain unclear because of its close structural resemblance to neutrophil elastase and its apparent functional redundancy with the latter. Thus, all natural inhibitors of PR3 preferentially target neutrophil elastase. We have designed a selective PR3 inhibitor based on the sequence of one of its specific, sensitive FRET substrates. This azapeptide, azapro-3, inhibits free PR3 in solution, PR3 bound to neutrophil membranes, and the PR3 found in crude lung secretions from patients with chronic inflammatory pulmonary diseases. But it does not inhibit significantly neutrophil elastase or cathepsin G. Unlike most of azapeptides, this inhibitor does not form a stable acyl-enzyme complex; it is a reversible competitive inhibitor with a K-i comparable to the K-m of the parent substrate. Low concentrations (60 mu M) of azapro-3 totally inhibited the PR3 secreted by triggered human neutrophils (200,000 cells/100 mu L) and the PR3 in neutrophil homogenates and in lung secretions of patients with lung inflammation for hours. Azapro-3 also resisted proteolysis by all proteases contained in these samples for at least 2 h. (C) 2011 Elsevier Inc. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available