title: Autoprocessing of neutrophil elastase near its active site reduces the efficiency of natural and synthetic elastase inhibitors.
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.
authors: 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.
authors: T
authors: T
authors: Dau
authors: 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.
authors: R S J
authors: RS
authors: Sarker
authors: 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.
authors: A O
authors: AO
authors: Yildirim
authors: 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.
authors: O
authors: O
authors: Eickelberg
authors: 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.
authors: D E
authors: DE
authors: Jenne
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D019272:Leukocyte Elastase / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010455:Peptides / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D053491:Proteinase Inhibitory Proteins, Secretory / Q000494:pharmacology*; D059748:Proteolysis; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D054852:Small Molecule Libraries / Q000494:pharmacology; D000515:alpha 1-Antitrypsin / Q000494:pharmacology
chemical_list: D016207:Cytokines; D010455:Peptides; D053491:Proteinase Inhibitory Proteins, Secretory; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D000515:alpha 1-Antitrypsin; D019272:Leukocyte Elastase