Designed azolopyridinium salts block protective antigen pores in vitro and protect cells from anthrax toxin.
Designed azolopyridinium salts block protective antigen pores in vitro and protect cells from anthrax toxin.
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DOI：
10.1371/journal.pone.0066099
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Barth H
中科院分区：
文献类型：
--
作者：
Beitzinger C;Bronnhuber A;Duscha K;Riedl Z;Huber-Lang M;Benz R;Hajós G;Barth H
几种细胞内作用的ab型细菌蛋白毒素，已知通过内吞作用进入细胞，显示产生通道。这适用于保护性抗原（PA），它是炭疽杆菌三方炭疽毒素的结合成分。已有证据表明，炭疽毒素的酶组分在靶细胞内体膜上的易位和七聚体/八聚体PA63结合/易位组分形成的通道是相关的现象。氯喹和一些4-氨基喹诺酮类药物被认为是抗人类恶性疟原虫感染的有效药物，它们以剂量依赖的方式有效阻断pa63通道。本研究表明，当抑制剂和PA63同时加入到膜的同一侧（顺式侧）时，相关带正电荷的杂环偶氮吡啶盐在µM范围内阻断PA63通道，顺式侧对应于酸化的靶细胞内体囊泡的管腔。噪声分析允许对杂环形成堵塞物的动力学进行研究。J774A.1巨噬细胞的体内实验表明，PA63通道功能抑制剂在相同浓度范围内也能有效阻断细胞被致死因子和PA63联合中毒，在体外阻断通道。这些结果有力地支持了致命因子通过pa63通道的转运，并表明本研究中使用的杂环化合物可能代表了开发针对炭疽的新型治疗策略的有吸引力的候选者。
Several intracellular acting bacterial protein toxins of the AB-type, which are known to enter cells by endocytosis, are shown to produce channels. This holds true for protective antigen (PA), the binding component of the tripartite anthrax-toxin of Bacillus anthracis. Evidence has been presented that translocation of the enzymatic components of anthrax-toxin across the endosomal membrane of target cells and channel formation by the heptameric/octameric PA63 binding/translocation component are related phenomena. Chloroquine and some 4-aminoquinolones, known as potent drugs against Plasmodium falciparium infection of humans, block efficiently the PA63-channel in a dose dependent way. Here we demonstrate that related positively charged heterocyclic azolopyridinium salts block the PA63-channel in the µM range, when both, inhibitor and PA63 are added to the same side of the membrane, the cis-side, which corresponds to the lumen of acidified endosomal vesicles of target cells. Noise-analysis allowed the study of the kinetics of the plug formation by the heterocycles. In vivo experiments using J774A.1 macrophages demonstrated that the inhibitors of PA63-channel function also efficiently block intoxication of the cells by the combination lethal factor and PA63 in the same concentration range as they block the channels in vitro. These results strongly argue in favor of a transport of lethal factor through the PA63-channel and suggest that the heterocycles used in this study could represent attractive candidates for development of novel therapeutic strategies against anthrax.
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影响因子：
2.4
作者：
BENZ, R;SCHMID, A;VOSCHEPERKEUTER, GH
通讯作者：
VOSCHEPERKEUTER, GH
DOI：
10.1073/pnas.86.7.2209
发表时间：
1989-04-01
影响因子：
11.1
作者：
BLAUSTEIN, RO;KOEHLER, TM;FINKELSTEIN, A
通讯作者：
FINKELSTEIN, A
影响因子：
8.6
作者：
Bezrukov, SM;Winterhalter, M
通讯作者：
Winterhalter, M
影响因子：
2.9
作者：
Blöcker, D;Bachmeyer, C;Barth, H
通讯作者：
Barth, H
DOI：
10.1083/jcb.200211018
发表时间：
2003-02-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Abrami L;Liu S;Cosson P;Leppla SH;van der Goot FG
通讯作者：
van der Goot FG