ArticleProtein science : a publication of the Protein Society2009
Protease inhibitors derived from elafin and SLPI and engineered to have enhanced specificity towards neutrophil serine proteases.
Article in Protein science : a publication of the Protein Society, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 39 citations in OpenAlex.
- Downregulation of the Transglutaminase 2-NF-κB Inflammatory Axis by a Fusion Protein of Cementoin and Secretory Leukocyte Protease Inhibitor Reduces Corneal Angiogenesis.International journal of molecular sciences · 2026Article
- SputOMICs identifies common and distinct markers in cystic fibrosis and chronic obstructive pulmonary disease.Scientific reports · 2025Article
- The Role ofBiomolecules · 2025Review
- Genetic correlations, shared risk genes and immunity landscapes between COVID-19 and venous thromboembolism: evidence from GWAS and bulk transcriptome data.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2024Article
- Systemic Markers of Lung Function and Forced Expiratory Volume in 1 Second Decline across Diverse Cohorts.Annals of the American Thoracic Society · 2023Article
- The "Elastic Perspective" of SARS-CoV-2 Infection and the Role of Intrinsic and Extrinsic Factors.International journal of molecular sciences · 2022Review
- On the Process of Discovering Leads That Target the Heparin-Binding Site of Neutrophil Elastase in the Sputum of Cystic Fibrosis Patients.Journal of medicinal chemistry · 2019Article
- N-Arylacyl O-sulfonated aminoglycosides as novel inhibitors of human neutrophil elastase, cathepsin G and proteinase 3.Glycobiology · 2016Article
- Transglutaminase binding fusion protein linked to SLPI reduced corneal inflammation and neovascularization.BMC ophthalmology · 2015Article
- A functional variant of elafin with improved anti-inflammatory activity for pulmonary inflammation.Molecular therapy : the journal of the American Society of Gene Therapy · 2015Article
- Structure basis 1/2SLPI and porcine pancreas trypsin interaction.Journal of synchrotron radiation · 2013Article
- Interaction of serine proteases from polymorphonuclear leucocytes with the cell surface and heparin.Inflammation · 2012Article
- Pulmonary proteases in the cystic fibrosis lung induce interleukin 8 expression from bronchial epithelial cells via a heme/meprin/epidermal growth factor receptor/Toll-like receptor pathway.The Journal of biological chemistry · 2011Article
- Secretory leukocyte protease inhibitor (SLPI) is, like its homologue trappin-2 (pre-elafin), a transglutaminase substrate.PloS one · 2011Article
- Neutrophil elastase, proteinase 3, and cathepsin G as therapeutic targets in human diseases.Pharmacological reviews · 2010Review
- Contribution of neutrophils to acute lung injury.Molecular medicine (Cambridge, Mass.)Review
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The secretory leukocyte protease inhibitor (SLPI), elafin, and its biologically active precursor trappin-2 are endogeneous low-molecular weight inhibitors of the chelonianin family that control the enzymatic activity of neutrophil serine proteases (NSPs) like elastase, proteinase 3, and cathepsin G. These inhibitors may be of therapeutic value, since unregulated NSP activities are linked to inflammatory lung diseases. However SLPI inhibits elastase and cathepsin G but not proteinase 3, while elafin targets elastase and proteinase 3 but not cathepsin G. We have used two strategies to design polyvalent inhibitors of NSPs that target all three NSPs and may be used in the aerosol-based treatment of inflammatory lung diseases. First, we fused the elafin domain with the second inhibitory domain of SLPI to produce recombinant chimeras that had the inhibitory properties of both parent molecules. Second, we generated the trappin-2 variant, trappin-2 A62L, in which the P1 residue Ala is replaced by Leu, as in the corresponding position in SLPI domain 2. The chimera inhibitors and trappin-2 A62L are tight-binding inhibitors of all three NSPs with subnanomolar K(i)s, similar to those of the parent molecules for their respective target proteases. We have also shown that these molecules inhibit the neutrophil membrane-bound forms of all three NSPs. The trappin-2 A62L and elafin-SLPI chimeras, like wild-type elafin and trappin-2, can be covalently cross-linked to fibronectin or elastin by a tissue transglutaminase, while retaining their polypotent inhibition of NSPs. Therefore, the inhibitors described herein have the appropriate properties to be further evaluated as therapeutic anti-inflammatory agents.
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