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Autoprocessing of neutrophil elastase near its active site reduces the efficiency of natural and synthetic elastase inhibitors.

Nat. Commun. 6:6722 (2015)
Open Access Gold as soon as Publ. Version/Full Text is submitted to ZB.
An imbalance between neutrophil-derived proteases and extracellular inhibitors is widely regarded as an important pathogenic mechanism for lung injury. Despite intense efforts over the last three decades, attempts to develop small-molecule inhibitors for neutrophil elastase have failed in the clinic. Here we discover an intrinsic self-cleaving property of mouse neutrophil elastase that interferes with the action of elastase inhibitors. We show that conversion of the single-chain (sc) into a two-chain (tc) neutrophil elastase by self-cleavage near its S1 pocket altered substrate activity and impaired both inhibition by endogenous α-1-antitrypsin and synthetic small molecules. Our data indicate that autoconversion of neutrophil elastase decreases the inhibitory efficacy of natural α-1-antitrypsin and small-molecule inhibitors, while retaining its pathological potential in an experimental mouse model. The so-far overlooked occurrence and properties of a naturally occurring tc-form of neutrophil elastase necessitates the redesign of small-molecule inhibitors that target the sc-form as well as the tc-form of neutrophil elastase.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Human-leukocyte Elastase; Alpha-1-antitrypsin Deficiency; Alpha(1)-proteinase Inhibitor; Proteinase-inhibitors; Crystal-structure; Serine Proteases; Chymotrypsin; Evolution; Emphysema; Diseases
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Quellenangaben Volume: 6, Issue: , Pages: , Article Number: 6722 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed