Journal article
N-Arylacyl O-sulfonated aminoglycosides as novel inhibitors of human neutrophil elastase, cathepsin G and proteinase 3
Glycobiology (Oxford), Vol.26(7), pp.701-709
07/01/2016
DOI: 10.1093/glycob/cww011
PMCID: PMC4976519
PMID: 26850997
Abstract
The balance between neutrophil serine proteases (NSPs) and protease inhibitors (PIs) in the lung is a critical determinant for a number of chronic inflammatory lung diseases such as chronic obstructive pulmonary disease, cystic fibrosis and acute lung injury. During activation at inflammatory sites, excessive release of NSPs such as human neutrophil elastase (HNE), proteinase 3 (Pr3) and cathepsin G (CatG), leads to destruction of the lung matrix and continued propagation of acute inflammation. Under normal conditions, PIs counteract these effects by inactivating NSPs; however, in chronic inflammatory lung diseases, there are insufficient amounts of PIs to mitigate damage. Therapeutic strategies are needed to modulate excessive NSP activity for the clinical management of chronic inflammatory lung diseases. In the study reported here, a panel of
N-
arylacyl
O
-
sulfonated aminoglycosides was screened to identify inhibitors of the NSPs. Dose-dependent inhibitors for each individual serine protease were identified. Select compounds were found to inhibit multiple NSPs, including one lead structure that is shown to inhibit all three NSPs. Two lead compounds identified during the screen for each individual NSP were further characterized as partial mixed inhibitors of CatG. Concentration-dependent inhibition of protease-mediated detachment of lung epithelial cells is demonstrated.
Details
- Title: Subtitle
- N-Arylacyl O-sulfonated aminoglycosides as novel inhibitors of human neutrophil elastase, cathepsin G and proteinase 3
- Creators
- Ioana Craciun - University of IowaAmanda M Fenner - University of IowaRobert J Kerns - University of Iowa College of Pharmacy
- Resource Type
- Journal article
- Publication Details
- Glycobiology (Oxford), Vol.26(7), pp.701-709
- Publisher
- Oxford University Press
- DOI
- 10.1093/glycob/cww011
- PMID
- 26850997
- PMCID
- PMC4976519
- ISSN
- 0959-6658
- eISSN
- 1460-2423
- Grant note
- ; #S10 RR029274-01 and #P30 CA86862 / ; T32GM067795 / ;
- Language
- English
- Date published
- 07/01/2016
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984365884202771
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