Aurintricarboxylic acid blocks in vitro and in vivo activity of YopH, an essential virulent factor of Yersinia pestis, the agent of plague
Aurintricarboxylic acid blocks in vitro and in vivo activity of YopH, an essential virulent factor of Yersinia pestis, the agent of plague
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DOI：
10.1074/jbc.m307152200
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发表时间：
2003-10-24
影响因子：
4.8
通讯作者：
Zhang, ZY
中科院分区：
文献类型：
--
作者：
Liang, FB;Huang, ZH;Zhang, ZY
耶尔森菌是从胃肠道综合征到黑死病等人类疾病的病原体。滥用诸如鼠疫耶尔森氏菌等传染物作为恐怖武器和大规模毁灭性战争工具的风险越来越大。YopH是一种重要的毒力因子，其蛋白酪氨酸磷酸酶（PTP）活性是耶尔森氏菌致病性所必需的。因此，有相当大的兴趣开发有效的和选择性的YopH抑制剂作为新的抗鼠疫剂。我们筛选了720种结构多样的市售羧酸，并鉴定出26种IC50值低于100 muM的YopH抑制剂。最有效和特异性的YopH抑制剂是金羧酸（ATA），其对YopH的K-i值为5 nM，对一组哺乳动物PTPs具有6-120倍的选择性。为了确定ATA是否可以在细胞环境中阻断YopH的活性，我们研究了ATA对转染YopH的人Jurkat细胞中t细胞信号传导的影响。我们发现YopH严重降低t细胞受体诱导的细胞酪氨酸磷酸化、ERK1/2活性和白介素-2转录活性。我们证明ATA可以有效阻断YopH的抑制活性，恢复正常的t细胞功能。这些结果为选择性靶向YopH的小分子抑制剂可能在治疗上有用的假设提供了概念证明。此外，预计有效和选择性的YopH抑制剂，如ATA，应该是描述鼠疫和其他由耶尔森菌感染引起的致病性疾病中YopH的细胞靶点的有用试剂。
Yersinia are causative agents in human diseases ranging from gastrointestinal syndromes to Bubonic Plague. There is increasing risk of misuse of infectious agents, such as Yersinia pestis, as weapons of terror as well as instruments of warfare for mass destruction. YopH is an essential virulence factor whose protein-tyrosine phosphatase (PTP) activity is required for Yersinia pathogenicity. Consequently, there is considerable interest in developing potent and selective YopH inhibitors as novel anti-plague agents. We have screened a library of 720 structurally diverse commercially available carboxylic acids and identified 26 YopH inhibitors with IC50 values below 100 muM. The most potent and specific YopH inhibitor is aurintricarboxylic acid (ATA), which exhibits a K-i value of 5 nM for YopH and displays 6-120-fold selectivity in favor of YopH against a panel of mammalian PTPs. To determine whether ATA can block the activity of YopH in a cellular context, we have examined the effect of ATA on T-cell signaling in human Jurkat cells transfected with YopH. We show that YopH severely decreases the T-cell receptor-induced cellular tyrosine phosphorylation, ERK1/2 activity, and interleukin-2 transcriptional activity. We demonstrate that ATA can effectively block the inhibitory activity of YopH and restore normal T-cell function. These results provide a proof-of-concept for the hypothesis that small molecule inhibitors that selectively target YopH may be therapeutically useful. In addition, it is expected that potent and selective YopH inhibitors, such as ATA, should be useful reagents to delineate YopH's cellular targets in plague and other pathogenic conditions caused by Yersinia infection.