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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Efficient synthetic inhibitors of anthrax lethal factor
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Efficient synthetic inhibitors of anthrax lethal factor

机译：炭疽致死因子的有效合成抑制剂

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Inhalation anthrax is a deadly disease for which there is currently no effective treatment. Bacillus anthracis lethal factor (LF) metalloproteinase is an integral component of the tripartite anthrax lethal toxin that is essential for the onset and progression of anthrax. We report here on a fragment-based approach that allowed us to develop inhibitors of LF. The small-molecule inhibitors we have designed, synthesized, and tested are highly potent and selective against LF in both in vitro tests and cell-based assays. These inhibitors do not affect the prototype human metalloproteinases that are structurally similar to LF. Initial in vivo evaluation of postexposure efficacy of our inhibitors combined with antibiotic ciprofloxican against B. anthracis resulted in significant protection. Our data strongly indicate that the scaffold of inhibitors we have identified is the foundation for the development of novel, safe, and effective emergency therapy of postexposure inhalation anthrax.
机译：吸入性炭疽是一种致命疾病，目前尚无有效的治疗方法。炭疽杆菌致死因子（LF）金属蛋白酶是三方炭疽致死毒素的组成部分，对于炭疽的发生和发展至关重要。我们在这里报告了一种基于片段的方法，该方法使我们能够开发LF抑制剂。我们设计，合成和测试的小分子抑制剂在体外试验和基于细胞的试验中均具有很强的抗LF选择性。这些抑制剂不影响在结构上类似于LF的原型人类金属蛋白酶。初步体内评估我们的抑制剂与抗生素环丙氟醚联合用药对炭疽芽孢杆菌的暴露后功效，可产生显着的保护作用。我们的数据强烈表明，我们已经确定的抑制剂支架是开发新型，安全，有效的暴露后吸入炭疽紧急治疗的基础。

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