PLoS One | |
A Selective Irreversible Inhibitor of Furin Does Not Prevent Pseudomonas Aeruginosa Exotoxin A-Induced Airway Epithelial Cytotoxicity | |
James A. Reihill1  Brian Walker1  S. Lorraine Martin1  Timothy E. G. Ferguson1  Robert A. Hamilton1  | |
[1] Biomolecular Sciences Research Group, School of Pharmacy, Queen’s University Belfast, Northern Ireland, United Kingdom | |
关键词: Proteases; Serine proteases; Peas; Epithelial cells; Pseudomonas aeruginosa; Cysteine proteases; Irreversible inhibitors; Toxins; | |
DOI : 10.1371/journal.pone.0159868 | |
学科分类:医学(综合) | |
来源: Public Library of Science | |
【 摘 要 】
Many bacterial and viral pathogens (or their toxins), including Pseudomonas aeruginosa exotoxin A, require processing by host pro-protein convertases such as furin to cause disease. We report the development of a novel irreversible inhibitor of furin (QUB-F1) consisting of a diphenyl phosphonate electrophilic warhead coupled with a substrate-like peptide (RVKR), that also includes a biotin tag, to facilitate activity-based profiling/visualisation. QUB-F1 displays greater selectivity for furin, in comparison to a widely used exemplar compound (furin I) which has a chloromethylketone warhead coupled to RVKR, when tested against the serine trypsin-like proteases (trypsin, prostasin and matriptase), factor Xa and the cysteine protease cathepsin B. We demonstrate QUB-F1 does not prevent P. aeruginosa exotoxin A-induced airway epithelial cell toxicity; in contrast to furin I, despite inhibiting cell surface furin-like activity to a similar degree. This finding indicates additional proteases, which are sensitive to the more broad-spectrum furin I compound, may be involved in this process.
【 授权许可】
CC BY
【 预 览 】
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