Comparison of the binding specificity of two bacterial metalloproteases, LasB of Pseudomonas aeruginosa and ZapA of Proteus mirabilis, using N-alpha mercaptoamide template-based inhibitor analogues
Comparison of the binding specificity of two bacterial metalloproteases, LasB of Pseudomonas aeruginosa and ZapA of Proteus mirabilis, using N-alpha mercaptoamide template-based inhibitor analogues
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DOI：
10.1016/j.bbrc.2012.04.157
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发表时间：
2012-06-01
影响因子：
3.1
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.
奇异变形杆菌的ZapA和铜绿假单胞菌的LasB是条件致病菌的毒力因子，分别是结构上相关的细菌金属蛋白溶酶家族的成员。这些酶分泌在感染部位，在感染过程中发挥关键作用，有助于组织破坏和处理宿主免疫系统的组成部分。因此，抑制这些毒力因子可能代表了一种抗菌策略，减弱了感染病原体的毒力。在此之前，我们已经筛选了一个针对ZapA和LasB的N-α-硫代酰胺二肽抑制剂文库，目的是绘制这两种酶的S1‘结合位点，揭示它们在结合偏好上的显著相似和重要差异。在这里，我们报道了几个基于原始文库中的两个亲本抑制剂的抑制剂类似物的设计、合成和筛选。这一结果为进一步鉴定ZAPA和LasB活性部位结合口袋提供了可能，并突显了开发广谱细菌蛋白酶抑制剂的可能性，该抑制剂有效地对抗热裂解酶和Serralysin金属蛋白酶家族的酶。(C)2012 Elsevier Inc.保留所有权利。
The metalloproteases ZapA of Proteus mirabilis and LasB of Pseudomonas aeruginosa are known to be virulence factors their respective opportunistic bacterial pathogens, and are members of the structurally related serralysin and thermolysin families of bacterial metalloproteases respectively. Secreted at the site of infection, these proteases play a key role in the infection process, contributing to tissue destruction and processing of components of the host immune system. Inhibition of these virulence factors may therefore represent an antimicrobial strategy, attenuating the virulence of the infecting pathogen. Previously we have screened a library of N-alpha mercaptoamide dipeptide inhibitors against both ZapA and LasB, with the aim of mapping the S1' binding site of the enzymes, revealing both striking similarities and important differences in their binding preferences. Here we report the design, synthesis, and screening of several inhibitor analogues, based on two parent inhibitors from the original library. The results have allowed for further characterization of the ZapA and LasB active site binding pockets, and have highlighted the possibility for development of broad-spectrum bacterial protease inhibitors, effective against enzymes of the thermolysin and serralysin metalloprotease families. (C) 2012 Elsevier Inc. All rights reserved.