ChemInform Abstract: Synthesis of Peptidyl Fluoromethyl Ketones and Peptidyl α-Keto Esters as Inhibitors of Porcine Pancreatic Elastase, Human Neutrophil Elastase, and Rat and Human Neutrophil Cathepsin G.

ChemInform ◽  
1990 ◽  
Vol 21 (22) ◽  
Author(s):  
N. P. PEET ◽  
J. P. BURKHART ◽  
M. R. ANGELASTRO ◽  
E. L. GIROUX ◽  
S. MEHDI ◽  
...  
Keyword(s):  
Neutrophil Elastase ◽  
Human Neutrophil ◽  
Cathepsin G ◽  
Human Neutrophil Elastase ◽  
Pancreatic Elastase ◽  
Keto Esters ◽  
Porcine Pancreatic Elastase

Inhaled porcine pancreatic elastase causes bronchoconstriction via a bradykinin-mediated mechanism

2000 ◽  
Vol 89 (4) ◽  
pp. 1397-1402 ◽  
Author(s):  
M. Scuri ◽  
R. Forteza ◽  
I. Lauredo ◽  
J. R. Sabater ◽  
Y. Botvinnikova ◽  
...  
Keyword(s):  
Neutrophil Elastase ◽  
Human Neutrophil ◽  
Inflammatory Diseases ◽  
Lavage Fluid ◽  
Chronic Obstructive ◽  
Human Neutrophil Elastase ◽  
Elastase Inhibitor ◽  
Pancreatic Elastase ◽  
Asthmatic Patients ◽  
Porcine Pancreatic Elastase

Neutrophil elastase has been linked to inflammatory lung diseases such as chronic obstructive pulmonary disease, adult respiratory distress syndrome, emphysema, and cystic fibrosis. In guinea pigs, aerosol challenge with human neutrophil elastase causes bronchoconstriction, but the mechanism by which this occurs is not completely understood. Our laboratory previously showed that human neutrophil elastase releases tissue kallikrein (TK) from cultured tracheal gland cells. TK has been identified as the major kininogenase of the airway and cleaves both high- and low-molecular weight kininogen to yield lysyl-bradykinin. Because inhaled bradykinin causes bronchoconstriction and airway hyperresponsiveness in asthmatic patients and allergic sheep, we hypothesized that elastase-induced bronchoconstriction could be mediated by bradykinin. To test this hypothesis, we measured lung resistance (Rl) in sheep before and after inhalation of porcine pancreatic elastase (PPE) alone and after pretreatment with a bradykinin B2 antagonist (NPC-567), the specific human elastase inhibitor ICI 200,355, the histamine H1-antagonist diphenhydramine hydrochloride, the cysteinyl leukotriene 1 receptor antagonist montelukast, or the cyclooxygenase inhibitor indomethacin. Inhaled PPE (125–1,000 μg) caused a dose-dependent increase in Rl. Aerosol challenge with a single 500 μg dose of PPE increased Rlby 132 ± 8% over baseline. This response was blocked by pretreatment with NPC-567 and ICI-200,355 ( n = 6; P < 0.001), whereas treatment with dyphenhydramine hydrochloride, montelukast, or indomethacin failed to block the PPE-induced bronchoconstriction. Consistent with pharmacological data, TK activity in bronchial lavage fluid increased 134 ± 57% over baseline ( n = 5; P < 0.02). We conclude that, in sheep, PPE-induced bronchoconstriction is in part mediated by the generation of bradykinin. Our findings suggest that elastase-kinin interactions may contribute to changes in bronchial tone during inflammatory diseases of the airways.

scholarly journals “Sleeping Beauty” Phenomenon: SuFEx-Enabled Discovery of Selective Covalent Inhibitors of Human Neutrophil Elastase

2019 ◽  
Author(s):  
Qinheng Zheng ◽  
Jordan L. Woehl ◽  
Seiya Kitamura ◽  
Diogo Santos-Martins ◽  
Christopher J. Smedley ◽  
...  
Keyword(s):  
Serine Protease ◽  
Neutrophil Elastase ◽  
Human Neutrophil ◽  
Sleeping Beauty ◽  
Cathepsin G ◽  
Human Neutrophil Elastase ◽  
Biological Assays ◽  
Covalent Inhibitors ◽  
Sulfur Fluoride ◽  
New Generation

<div> <div> <div> <p>Sulfur-Fluoride Exchange (SuFEx) has emerged as the new generation of click chemistry. We report here a SuFEx-enabled approach exploiting the “sleeping beauty” phenomenon of sulfur fluoride compounds in the context of the serendipitous discovery of selective covalent human neutrophil elastase (hNE) inhibitors. Evaluation of an ever-growing collection of SuFExable compounds toward various biological assays unexpectedly yielded a selective and covalent hNE inhibitor, benzene-1,2-disulfonyl fluoride. Derivatization of the initial hit led to a better agent, 2- triflyl benzenesulfonyl fluoride, itself made through a SuFEx trifluoromethylation process, with IC50 = 1.1 μM and ~200-fold selectivity over the homologous neutrophil serine protease, cathepsin G. The optimized probe only modified active hNE and not its denatured form, setting another example of the “sleeping beauty” phenomenon of sulfur fluoride capturing agents for the discovery of covalent medicines. </p> </div> </div> </div>

scholarly journals Effects of human neutrophil elastase (HNE) on neutrophil function in vitro and in inflamed microvessels

Blood ◽  
1993 ◽  
Vol 82 (7) ◽  
pp. 2188-2195 ◽  
Author(s):  
RC Woodman ◽  
PH Reinhardt ◽  
S Kanwar ◽  
FL Johnston ◽  
P Kubes
Keyword(s):  
Neutrophil Elastase ◽  
Human Neutrophil ◽  
Neutrophil Migration ◽  
Specific Inhibitor ◽  
Neutrophil Infiltration ◽  
Cathepsin G ◽  
Neutrophil Adhesion ◽  
Human Neutrophil Elastase

Abstract The primary objective of this study was to test the hypothesis that human neutrophil elastase (HNE) affects neutrophil infiltration (adhesion and emigration) into inflamed vessels. To determine whether HNE contributes to neutrophil adhesion in vivo, intravital microscopy was used to study neutrophil-endothelial cell interactions in single inflamed postcapillary venules. Superfusion of platelet-activating factor (PAF) (100 nmol/L) onto the mesentery caused an increase in neutrophil-neutrophil interactions, neutrophil adhesion to postcapillary venules, and cellular emigration out of the vasculature. Both L658 758 (an elastase-specific inhibitor), and Eglin C (an elastase and cathepsin G inhibitor) significantly attenuated all of these parameters in vivo. To further characterize the mechanism(s) involved, various in vitro parameters were assessed. HNE, but not trypsin, caused a dose-dependent (0.01 to 1.0 microgram/mL) increase in the expression of the beta subunit (CD18) of the CD11/CD18 adhesive glycoprotein complex on neutrophils. An HNE-dependent increase in CD11b expression was also observed; however, HNE did not affect the expression of other neutrophil adhesion molecules (L-selectin), superoxide production, or degranulation. PAF-enhanced CD18 expression on neutrophils and neutrophil migration were both abolished by L658 758 but PAF-induced neutrophil adhesion to endothelial monolayers was not affected by the antiproteinase. The in vitro data suggest that the antiproteinases do not directly prevent neutrophil adhesion in vivo but may be important in other CD18-dependent events such as neutrophil- neutrophil interaction or neutrophil infiltration (chemotaxis). These results translate into an important, rate-limiting role for elastase in the process of leukocyte infiltration and accumulation in inflamed microvessels.

A Cytosolic Inhibitor of Human Neutrophil Elastase and Cathepsin G

1991 ◽  
Vol 50 (6) ◽  
pp. 568-579 ◽  
Author(s):  
Raymond M. Thomas ◽  
William M. Nauseef ◽  
Shankar S. Iyer ◽  
Michael W. Peterson ◽  
Phillip J. Stone ◽  
...  
Keyword(s):  
Neutrophil Elastase ◽  
Human Neutrophil ◽  
Cathepsin G ◽  
Human Neutrophil Elastase ◽  
Cytosolic Inhibitor
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