A Selective Irreversible Inhibitor of Furin Does Not Prevent Pseudomonas Aeruginosa Exotoxin A-Induced Airway Epithelial Cytotoxicity

PLoS One

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