Comprehensive inhibitor profiling of the Proteus mirabilis metalloprotease virulence factor ZapA (mirabilysin) |
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Authors: | Louise Carson George R. Cathcart Christopher J. Scott Morley D. Hollenberg Brian Walker Howard Ceri Brendan F. Gilmore |
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Affiliation: | aSchool of Pharmacy, Queens University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK;bDepartment of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada;cThe Biofilm Research Group, Department of Biological Sciences, University of Calgary, 2500 University Drive NW, Calgary, AB T2N 1N4, Canada |
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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 and binding site preferences of this important enzyme. This study has revealed a preference for the aromatic residues tyrosine and tryptophan in and aliphatic residues in . From this library, six compounds were identified which exhibited sub- to low-micromolar Ki values. The most potent inactivator, SH–CO2–Y–V–NH2 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. |
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Keywords: | Mirabilysin ZapA Inhibitor N-alpha mercaptoamide Protease Virulence |
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