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

T Dau; R S J Sarker; A O Yildirim; O Eickelberg; D E Jenne

doi:10.1038/ncomms7722

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

Nat Commun. 2015 Apr 10:6:6722. doi: 10.1038/ncomms7722.

Authors

T Dau¹, R S J Sarker¹, A O Yildirim¹, O Eickelberg¹, D E Jenne²

Affiliations

¹ Comprehensive Pneumology Center, Institute of Lung Biology and Disease (iLBD), University Hospital, Ludwig Maximilians University and Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Max-Lebsche-Platz 31, 81377 Munich, Germany.
² 1] Comprehensive Pneumology Center, Institute of Lung Biology and Disease (iLBD), University Hospital, Ludwig Maximilians University and Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Max-Lebsche-Platz 31, 81377 Munich, Germany [2] Max Planck Institute of Neurobiology, Am Klopferspitz 18, D-82152 Martinsried, Germany.

PMID: 25857284
DOI: 10.1038/ncomms7722

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 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Catalytic Domain
Cytokines / biosynthesis
Female
Gene Expression
HEK293 Cells
Humans
Leukocyte Elastase / administration & dosage
Leukocyte Elastase / antagonists & inhibitors
Leukocyte Elastase / chemistry
Leukocyte Elastase / metabolism*
Lung / drug effects*
Lung / enzymology
Lung / pathology
Macrophages / drug effects
Macrophages / pathology
Mice
Mice, Inbred C57BL
Molecular Sequence Data
Neutrophils / drug effects*
Neutrophils / enzymology
Neutrophils / pathology
Peptides / administration & dosage
Peptides / antagonists & inhibitors
Peptides / chemistry
Peptides / metabolism*
Proteinase Inhibitory Proteins, Secretory / pharmacology*
Proteolysis
Pulmonary Emphysema / chemically induced
Pulmonary Emphysema / drug therapy*
Pulmonary Emphysema / enzymology
Pulmonary Emphysema / pathology
Recombinant Proteins / administration & dosage
Recombinant Proteins / chemistry
Recombinant Proteins / metabolism
Sequence Homology, Amino Acid
Small Molecule Libraries / pharmacology
alpha 1-Antitrypsin / pharmacology

Substances

Cytokines
Peptides
Proteinase Inhibitory Proteins, Secretory
Recombinant Proteins
Small Molecule Libraries
alpha 1-Antitrypsin
Leukocyte Elastase