title: Comprehensive inhibitor profiling of the Proteus mirabilis metalloprotease virulence factor ZapA (mirabilysin).
abstract: In this study we report for the first time the comprehensive inhibitor profiling of the Proteus mirabilis metalloprotease virulence factor ZapA (mirabilysin) using a 160 compound focused library of N-alpha mercaptoamide dipeptides, in order to map the S(1)(') and S(2)(') binding site preferences of this important enzyme. This study has revealed a preference for the aromatic residues tyrosine and tryptophan in P(1)(') and aliphatic residues in P(2)('). From this library, six compounds were identified which exhibited sub- to low-micromolar K(i) values. The most potent inactivator, SH-CO(2)-Y-V-NH(2) was capable of preventing ZapA-mediated hydrolysis of heat-denatured IgA, indicating that these inhibitors may be capable of protecting host proteins against ZapA during colonisation and infection.
authors.affiliation: School of Pharmacy, Queens University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Carson
authors.forename: George R
authors.initials: GR
authors.lastname: Cathcart
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Scott
authors.forename: Morley D
authors.initials: MD
authors.lastname: Hollenberg
authors.forename: Brian
authors.initials: B
authors.lastname: Walker
authors.forename: Howard
authors.initials: H
authors.lastname: Ceri
authors.forename: Brendan F
authors.initials: BF
authors.lastname: Gilmore
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D045726:Metalloproteases / Q000037:antagonists & inhibitors*; D011513:Proteus mirabilis / Q000201:enzymology*; D037521:Virulence Factors / Q000037:antagonists & inhibitors*
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D037521:Virulence Factors; D045726:Metalloproteases