Anti-inflammatory effects of DX-890, a human neutrophil elastase inhibitor

Dunlevy, Fiona; Martin, S. Lorraine; Courcey, Francine de; Elborn, J. Stuart; Ennis, Madeleine

doi:10.1016/j.jcf.2012.02.003

Cited by 23 publications

(17 citation statements)

References 34 publications

(35 reference statements)

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“…A number of novel synthetic protease inhibitors have been identified for potential use in CF, with POL6014, DX-890, KRP-109, and AZD9668 being examples. POL6014 significantly reduces NE activity without impairing neutrophil function [95] while DX-890 decreases pro-inflammatory cytokine secretion and neutrophil transmigration [96]. KRP-109 may possibly reverse mucus plugging in the CF airways [97].…”

Section: Antiprotease Therapiesmentioning

confidence: 99%

Alpha-1 Antitrypsin—A Target for MicroRNA-Based Therapeutic Development for Cystic Fibrosis

Hunt

Glasgow

Humphreys

et al. 2020

IJMS

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Cystic fibrosis (CF) is an autosomal recessive genetic disorder arising from mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Disruption to normal ion homeostasis in the airway results in impaired mucociliary clearance, leaving the lung more vulnerable to recurrent and chronic bacterial infections. The CF lung endures an excess of neutrophilic inflammation, and whilst neutrophil serine proteases are a crucial part of the innate host defence to infection, a surplus of neutrophil elastase (NE) is understood to create a net destructive effect. Alpha-1 antitrypsin (A1AT) is a key antiprotease in the control of NE protease activity but is ineffective in the CF lung due to the huge imbalance of NE levels. Therapeutic strategies to boost levels of protective antiproteases such as A1AT in the lung remain an attractive research strategy to limit the damage from excess protease activity. microRNAs are small non-coding RNA molecules that bind specific cognate sequences to inhibit expression of target mRNAs. The inhibition of miRNAs which target the SERPINA1 (A1AT-encoding gene) mRNA represents a novel therapeutic approach for CF inflammation. This could involve the delivery of antagomirs that bind and sequester the target miRNA, or target site blockers that bind miRNA recognition elements within the target mRNA to prevent miRNA interaction. Therefore, miRNA targeted therapies offer an alternative strategy to drive endogenous A1AT production and thus supplement the antiprotease shield of the CF lung.

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Section: Antiprotease Therapiesmentioning

confidence: 99%

Alpha-1 Antitrypsin—A Target for MicroRNA-Based Therapeutic Development for Cystic Fibrosis

Hunt

Glasgow

Humphreys

et al. 2020

IJMS

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“…52 In vitro Studies With NE Inhibitors DX-890, an NE inhibitor, reduced NE activity from activated neutrophils (in both patients with CF and healthy control subjects), IL-8 secretion, and neutrophil transmigration. 53 An NE inhibitor (POL6014) was tested in the BAL of six patients with CF and showed comparable NE inhibitory action as that of a1-AT. 54 Finally, aerosolized EPI-hNE4 (depelestat;…”

Section: Cystic Fibrosismentioning

confidence: 99%

The Role of Neutrophil Elastase Inhibitors in Lung Diseases

Polverino

Rosales-Mayor

Dale

et al. 2017

Chest

177

125

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“…12) as well as protein-based inhibitors of NE such as EPI-hNE4/DX-890 (ref. 13,14) have been developed for this purpose. Naturally occurring inhibitors such as a-1 antitrypsin, secretory leukocyte protease inhibitor (SLPI), elafin, and monocyte/NE inhibitor (MNEI) have also attracted a lot of interest.…”

Section: Introductionmentioning

confidence: 99%

A secretory leukocyte protease inhibitor variant with improved activity against lung infection

et al. 2016

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Secretory leukocyte protease inhibitor (SLPI) is an important respiratory tract host defense protein, which is proteolytically inactivated by excessive neutrophil elastase (NE) during chronic Pseudomonas infection in the cystic fibrosis (CF) lung. We generated two putative NE-resistant variants of SLPI by site-directed mutagenesis, SLPI-A16G and SLPI-S15G-A16G, with a view to improving SLPI's proteolytic stability. Both variants showed enhanced resistance to degradation in the presence of excess NE as well as CF patient sputum compared with SLPI-wild type (SLPI-WT). The ability of both variants to bind bacterial lipopolysaccharides and interact with nuclear factor-κB DNA binding sites was also preserved. Finally, we demonstrate increased anti-inflammatory activity of the SLPI-A16G protein compared with SLPI-WT in a murine model of pulmonary Pseudomonas infection. This study demonstrates the increased stability of these SLPI variants compared with SLPI-WT and their therapeutic potential as a putative anti-inflammatory treatment for CF lung disease.

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Anti-inflammatory effects of DX-890, a human neutrophil elastase inhibitor

Abstract: DX-890 reduces NE-mediated transmigration and inflammation. NE inhibition could be useful in managing neutrophilic airway inflammation in CF.

Cited by 23 publications

References 34 publications

Alpha-1 Antitrypsin—A Target for MicroRNA-Based Therapeutic Development for Cystic Fibrosis

Alpha-1 Antitrypsin—A Target for MicroRNA-Based Therapeutic Development for Cystic Fibrosis

The Role of Neutrophil Elastase Inhibitors in Lung Diseases

A secretory leukocyte protease inhibitor variant with improved activity against lung infection

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