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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| Institution: | 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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