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: Louise Carson, George R Cathcart, Christopher J Scott, Morley D Hollenberg, Brian Walker, Howard Ceri, Brendan F Gilmore
• Journal: Biochimie (Biochimie) Vol. 93 Issue 10 Pg. 1824-7 (Oct 2011) ISSN: 1638-6183 [Electronic] France
• PMID: 21762758 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Chemical References

• Bacterial Proteins
• Enzyme Inhibitors
• Virulence Factors
• Metalloproteases

Topics

• Bacterial Proteins (antagonists & inhibitors)
• Enzyme Inhibitors (chemistry, pharmacology)
• Metalloproteases (antagonists & inhibitors)
• Proteus mirabilis (enzymology)
• Virulence Factors (antagonists & inhibitors)