title: A Selective Irreversible Inhibitor of Furin Does Not Prevent Pseudomonas Aeruginosa Exotoxin A-Induced Airway Epithelial Cytotoxicity.
abstract: 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.
authors.affiliation: Biomolecular Sciences Research Group, School of Pharmacy, Queen's University Belfast, Northern Ireland, United Kingdom.
authors.forename: Timothy E G
authors.initials: TE
authors.lastname: Ferguson
authors.affiliation: Biomolecular Sciences Research Group, School of Pharmacy, Queen's University Belfast, Northern Ireland, United Kingdom.
authors.forename: James A
authors.identifier: http://orcid.org/0000-0001-8599-5198
authors.initials: JA
authors.lastname: Reihill
authors.affiliation: Biomolecular Sciences Research Group, School of Pharmacy, Queen's University Belfast, Northern Ireland, United Kingdom.
authors.forename: Brian
authors.initials: B
authors.lastname: Walker
authors.affiliation: Biomolecular Sciences Research Group, School of Pharmacy, Queen's University Belfast, Northern Ireland, United Kingdom.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hamilton
authors.affiliation: Biomolecular Sciences Research Group, School of Pharmacy, Queen's University Belfast, Northern Ireland, United Kingdom.
authors.forename: S Lorraine
authors.initials: SL
authors.lastname: Martin
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000633:toxicity*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects* / Q000382:microbiology; D005098:Exotoxins / Q000633:toxicity*; D045683:Furin / Q000037:antagonists & inhibitors*; D006801:Humans; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity
chemical_list: D000900:Anti-Bacterial Agents; D001427:Bacterial Toxins; D004791:Enzyme Inhibitors; D005098:Exotoxins; D009842:Oligopeptides; D063065:Organophosphonates; C000621539:QUB-F1; D045683:Furin