Comprehensive inhibitor profiling of the Proteus mirabilis metalloprotease virulence factor ZapA (mirabilysin)
Comprehensive inhibitor profiling of the Proteus mirabilis metalloprotease virulence factor ZapA (mirabilysin)
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DOI：
10.1016/j.biochi.2011.06.030
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发表时间：
2011-10-01
期刊：
影响因子：
3.9
通讯作者：
Gilmore, Brendan F.
中科院分区：
文献类型：
--
作者：
Carson, Louise;Cathcart, George R.;Gilmore, Brendan F.
在这项研究中，我们首次报告了奇异变形杆菌金属蛋白酶毒力因子ZapA（奇异溶素）的综合抑制剂谱，使用160个化合物聚焦的N-α巯基酰胺二肽文库，以绘制这种重要酶的S（1）'和S（2）'结合位点偏好。该研究揭示了P中的芳香族残基酪氨酸和色氨酸以及P（2 ′）中的脂肪族残基的偏好。从这个库中，鉴定出六种化合物，它们表现出亚至低微摩尔K（i）值。最有效的灭活剂SH-CO（2）-Y-V-NH（2）能够阻止ZapA介导的热变性伊加水解，表明这些抑制剂可能能够在定殖和感染期间保护宿主蛋白质免受ZapA的侵害。(C)2011年Elsevier Masson SAS。All rights reserved.
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; 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. (C) 2011 Elsevier Masson SAS. All rights reserved.