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Dau, T. ; Sarker, R.S. ; Yildirim, A.Ö. ; Eickelberg, O. ; Jenne, D.

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

Nat. Commun. 6:6722 (2015)

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Open Access Gold as soon as Publ. Version/Full Text is submitted to ZB.

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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

Journal Nature Communications

Quellenangaben Volume: 6, Article Number: 6722

Publisher Nature Publishing Group

Publishing Place London

Reviewing status Peer reviewed

Institute(s) Institute of Lung Health and Immunity (LHI)