Selective inhibitor of endosomal trafficking pathways exploited by multiple toxins and viruses
Selective inhibitor of endosomal trafficking pathways exploited by multiple toxins and viruses
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DOI：
10.1073/pnas.1302334110
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发表时间：
2013-12-10
影响因子：
11.1
通讯作者：
Bradley, Kenneth A.
中科院分区：
文献类型：
--
作者：
Gillespie, Eugene J.;Ho, Chi-Lee C.;Bradley, Kenneth A.
病原微生物和毒素已经进化出多种机制来进入宿主细胞质，从而对宿主施加毒性作用。一种常见的细胞进入机制需要运输到酸化的内体，这促进了跨宿主膜的易位。为了确定阻断这一过程的小分子抑制剂，对一个包含30,000个小分子的文库进行了筛选，以寻找炭疽致命毒素的抑制剂。在这里，我们报道了4-溴苯甲醛N-（2,6-二甲基苯基）氨基脲，筛选中发现的最活跃的化合物，抑制致命毒素的中毒，并阻止多种其他酸依赖性细菌毒素和病毒进入哺乳动物细胞。这种化合物，我们命名为EGA，也延迟溶酶体靶向和EGF受体的降解，表明它靶向宿主膜运输。相反，EGA不会阻断转铁蛋白的内体循环、蓖麻毒素的逆行运输、吞噬酶体运输或土拉弗朗西斯菌的吞噬体渗透性。此外，EGA不中和酸性细胞器，表明其作用机制不同于ph升高剂，如氯化铵和巴霉素A1。EGA是研究膜运输的有力工具，代表了一类宿主靶向化合物，用于治疗传染病的治疗开发。
Pathogenic microorganisms and toxins have evolved a variety of mechanisms to gain access to the host-cell cytosol and thereby exert virulent effects upon the host. One common mechanism of cellular entry requires trafficking to an acidified endosome, which promotes translocation across the host membrane. To identify small-molecule inhibitors that block this process, a library of 30,000 small molecules was screened for inhibitors of anthrax lethal toxin. Here we report that 4-bromobenzaldehyde N-(2,6-dimethylphenyl) semicarbazone, the most active compound identified in the screen, inhibits intoxication by lethal toxin and blocks the entry of multiple other acid-dependent bacterial toxins and viruses into mammalian cells. This compound, which we named EGA, also delays lysosomal targeting and degradation of the EGF receptor, indicating that it targets host-membrane trafficking. In contrast, EGA does not block endosomal recycling of transferrin, retrograde trafficking of ricin, phagolysosomal trafficking, or phagosome permeabilization by Franciscella tularensis. Furthermore, EGA does not neutralize acidic organelles, demonstrating that its mechanism of action is distinct from pH-raising agents such as ammonium chloride and bafilomycin A1. EGA is a powerful tool for the study of membrane trafficking and represents a class of host-targeted compounds for therapeutic development to treat infectious disease.