In vitro and in vivo characterisation of the novel neutrophil elastase inhibitor BI 1323495

2020 ◽  
Author(s):  
Stefan Kreideweiss ◽  
Annette Schuler-Metz ◽  
Christian Gnamm ◽  
Stefan Peters ◽  
Thorsten Oost
Keyword(s):  
Neutrophil Elastase ◽  
The Novel ◽  
Neutrophil Elastase Inhibitor ◽  
Elastase Inhibitor

scholarly journals Novel and Modified Neutrophil Elastase Inhibitor Loaded in Topical Formulations for Psoriasis Management

Pharmaceutics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 358 ◽  
Author(s):  
Andreia Nunes ◽  
Joana Marto ◽  
Lídia Maria Gonçalves ◽  
Sandra Simões ◽  
Rita Félix ◽  
...  
Keyword(s):  
Serine Protease ◽  
Neutrophil Elastase ◽  
In Vitro Cytotoxicity ◽  
Human Neutrophil Elastase ◽  
Therapeutic Effects ◽  
Neutrophil Elastase Inhibitor ◽  
Analytical Methodology ◽  
Elastase Inhibitor

Human neutrophil elastase (HNE) is a serine protease that degrades matrix proteins. An excess of HNE may trigger several pathological conditions, such as psoriasis. In this work, we aimed to synthesize, characterize and formulate new HNE inhibitors with a 4-oxo-β-lactam scaffold with less toxicity, as well as therapeutic index in a psoriasis context. HNE inhibitors with 4-oxo-β-lactam scaffolds were synthesized and characterized by NMR, FTIR, melting point, mass spectrometry and elemental analysis. In vitro cytotoxicity and serine protease assays were performed. The compound with the highest cell viability (AAN-16) was selected to be incorporated in an emulsion (AAN-16 E) and in a microemulsion (AAN-16 ME). Formulations were characterized in terms of organoleptic properties, pH, rheology, droplet size distribution, in vitro drug release and in vivo psoriatic activity. All compounds were successfully synthesized according to analytical methodology, with good yields. Both formulations presented suitable physicochemical properties. AAN-16 E presented the most promising therapeutic effects in a murine model of psoriasis. Overall, new HNE inhibitors were synthesized with high and selective activity and incorporated into topical emulsions with potential to treat psoriasis.

Role of neutrophil elastase in allergen-induced lysozyme secretion in the dog trachea

1992 ◽  
Vol 73 (2) ◽  
pp. 695-700 ◽  
Author(s):  
E. Tabachnik ◽  
A. Schuster ◽  
W. M. Gold ◽  
J. A. Nadel
Keyword(s):  
Neutrophil Elastase ◽  
Late Phase ◽  
Allergen Exposure ◽  
Phase Response ◽  
Submucosal Gland ◽  
Neutrophil Elastase Inhibitor ◽  
Elastase Inhibitor ◽  
Specific Allergen

To test our hypothesis that neutrophil elastase plays a role in airway hypersecretion associated with the allergic late-phase response, using an isolated tracheal segment system in vivo and measuring lysozyme activity in the perfusate of the lumen as a marker of submucosal gland secretion over 8 h, we studied the response of five allergic dogs to ragweed. The dogs were exposed on separate occasions to specific allergen, to allergen vehicle, and to allergen in the presence of a selective neutrophil elastase inhibitor, ICI 200,355. Allergen exposure caused a marked increase in lysozyme secretion that was significantly increased at 4, 6, and 8 h compared with controls and ICI 200,355-treated dogs. Neutrophil elastase appeared in the perfusate after allergen exposure and was positively correlated with lysozyme secretion at 8 h. These findings suggest that neutrophil elastase plays an important role as a secretagogue in the allergic late-phase response.

scholarly journals Oxidized mucus proteinase inhibitor: a fairly potent neutrophil elastase inhibitor

1994 ◽  
Vol 303 (1) ◽  
pp. 61-68 ◽  
Author(s):  
C Boudier ◽  
J G Bieth
Keyword(s):  
Rate Constant ◽  
Neutrophil Elastase ◽  
Proteinase Inhibitor ◽  
Enzyme Inhibitor ◽  
Fold Increase ◽  
Upper Respiratory Tract ◽  
Neutrophil Elastase Inhibitor ◽  
Active Centre ◽  
Elastase Inhibitor

N-chlorosuccinimide oxidizes one of the methionine residues of mucus proteinase inhibitor with a second-order rate constant of 1.5 M-1.s-1. Cyanogen bromide cleavage and NH2-terminal sequencing show that the modified residue is methionine-73, the P′1 component of the inhibitor's active centre. Oxidation of the inhibitor decreases its neutrophil elastase inhibitory capacity but does not fully abolish it. The kinetic parameters describing the elastase-oxidized inhibitor interaction are: association rate constant kass. = 2.6 x 10(5) M-1.s-1, dissociation rate constant kdiss. = 2.9 x 10(-3) s-1 and equilibrium dissociation constant Ki = 1.1 x 10(-8) M. Comparison with the native inhibitor indicates that oxidation decreases kass. by a factor of 18.8 and increases kdiss. by a factor of 6.4, and therefore leads to a 120-fold increase in Ki. Yet, the oxidized inhibitor may still act as a potent elastase inhibitor in the upper respiratory tract where its concentration is 500-fold higher than Ki, i.e. where the elastase inhibition is pseudo-irreversible. Experiments in vitro with fibrous human lung elastin, the most important natural substrate of elastase, support this view: 1.35 microM elastase is fully inhibited by 5-6 microM oxidized inhibitor whether the enzyme-inhibitor complex is formed in the presence or absence of elastin and whether elastase is pre-adsorbed on elastin or not.

scholarly journals Elastase Release by Transmigrating Neutrophils Deactivates Endothelial-bound SDF-1α and Attenuates Subsequent T Lymphocyte Transendothelial Migration

2004 ◽  
Vol 200 (6) ◽  
pp. 713-724 ◽  
Author(s):  
Ravi M. Rao ◽  
Travis V. Betz ◽  
Deanna J. Lamont ◽  
Michael B. Kim ◽  
Sunil K. Shaw ◽  
...  
Keyword(s):  
T Lymphocyte ◽  
Neutrophil Elastase ◽  
Umbilical Vein ◽  
Transendothelial Migration ◽  
Cell Phenotype ◽  
Neutrophil Elastase Inhibitor ◽  
Elastase Inhibitor ◽  
Stromal Cell Derived Factor ◽  
Umbilical Vein Endothelial Cells

Leukocyte trafficking to sites of inflammation follows a defined temporal pattern, and evidence suggests that initial neutrophil transendothelial migration modifies endothelial cell phenotype. We tested the hypothesis that preconditioning of human umbilical vein endothelial cells (HUVEC) by neutrophils would also modify the subsequent transendothelial migration of T lymphocytes across cytokine-stimulated HUVEC in an in vitro flow assay. Using fluorescence microscopy, preconditioning of HUVEC by neutrophils was observed to significantly reduce the extent of subsequent stromal cell–derived factor-1α (SDF-1α [CXCL12])-mediated T lymphocyte transendothelial migration, without reducing accumulation. In contrast, recruitment of a second wave of neutrophils was unaltered. Conditioned medium harvested after transendothelial migration of neutrophils or supernatants from stimulated neutrophils mediated a similar blocking effect, which was negated using a specific neutrophil elastase inhibitor. Furthermore, T lymphocyte transendothelial migration was inhibited by treatment of HUVEC with purified neutrophil elastase, which selectively cleaved the amino terminus of HUVEC-bound SDF-1α, which is required for its chemotactic activity. The reduction in T lymphocyte transendothelial migration was not observed using a different chemokine, ELC (CCL19), and was not reversed by replenishment of SDF-1α, indicating endothelial retention of the inactivated chemokine. In summary, transmigrating neutrophils secrete localized elastase that is protected from plasma inhibitors, and thereby modulate trafficking of other leukocyte subsets by altering the endothelial-associated chemotactic activities.

In Vivo Adenovirus-Mediated Expression of Human Pre-Elafin, a Potent Neutrophil Elastase Inhibitor

CHEST Journal ◽  
1997 ◽  
Vol 111 (6) ◽  
pp. 128S-129S ◽  
Author(s):  
Jean-Michel Sallenave ◽  
Zhou Xing ◽  
Frank Graham ◽  
Jack Gauldie
Keyword(s):  
Neutrophil Elastase ◽  
Neutrophil Elastase Inhibitor ◽  
Elastase Inhibitor

scholarly journals Characterization of the SARS-CoV-2 coronavirus X4-like accessory protein

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Olanrewaju Ayodeji Durojaye ◽  
Nkwachukwu Oziamara Okoro ◽  
Arome Solomon Odiba
Keyword(s):  
Rapid Development ◽  
Protein A ◽  
The Novel ◽  
Quality Model ◽  
A Value ◽  
Model Protein ◽  
Novel Coronavirus ◽  
Global Threat

Abstract Background The novel coronavirus SARS-CoV-2 is currently a global threat to health and economies. Therapeutics and vaccines are in rapid development; however, none of these therapeutics are considered as absolute cure, and the potential to mutate makes it necessary to find therapeutics that target a highly conserved regions of the viral structure. Results In this study, we characterized an essential but poorly understood coronavirus accessory X4 protein, a core and stable component of the SARS-CoV family. Sequence analysis shows a conserved ~ 90% identity between the SARS-CoV-2 and previously characterized X4 protein in the database. QMEAN Z score of the model protein shows a value of around 0.5, within the acceptable range 0–1. A MolProbity score of 2.96 was obtained for the model protein and indicates a good quality model. The model has Ramachandran values of φ = − 57o and ψ = − 47o for α-helices and values of φ = − 130o and ψ = + 140o for twisted sheets. Conclusions The protein data obtained from this study provides robust information for further in vitro and in vivo experiment, targeted at devising therapeutics against the virus. Phylogenetic analysis further supports previous evidence that the SARS-CoV-2 is positioned with the SL-CoVZC45, BtRs-BetaCoV/YN2018B and the RS4231 Bat SARS-like corona viruses.

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