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

Dau, T., Sarker, R. S. J., Yildirim, A. O., Eickelberg, O., & Jenne, D. E. (2015). Autoprocessing of neutrophil elastase near its active site reduces the efficiency of natural and synthetic elastase inhibitors. Nature Communications, 6: 6722. doi:10.1038/ncomms7722.

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 Creators:
Dau, T., Author
Sarker, R. S. J., Author
Yildirim, A. O., Author
Eickelberg, O., Author
Jenne, D. E.1, Author           
Affiliations:
1Research Group: Enzymes and Inhibitors in Chronic Lung Disease / Jenne, MPI of Neurobiology, Max Planck Society, ou_1950284              

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Free keywords: HUMAN-LEUKOCYTE ELASTASE; ALPHA-1-ANTITRYPSIN DEFICIENCY; ALPHA(1)-PROTEINASE INHIBITOR; PROTEINASE-INHIBITORS; CRYSTAL-STRUCTURE; SERINE PROTEASES; CHYMOTRYPSIN; EVOLUTION; EMPHYSEMA; DISEASES
 Abstract: 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 alpha-1-antitrypsin and synthetic small molecules. Our data indicate that autoconversion of neutrophil elastase decreases the inhibitory efficacy of natural alpha-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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Language(s): eng - English
 Dates: 2015-04-10
 Publication Status: Issued
 Pages: 8
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000353701700001
DOI: 10.1038/ncomms7722
 Degree: -

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Title: Nature Communications
  Abbreviation : Nat. Commun.
Source Genre: Journal
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Affiliations:
Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 6 Sequence Number: 6722 Start / End Page: - Identifier: ISSN: 2041-1723
CoNE: https://pure.mpg.de/cone/journals/resource/2041-1723