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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Anthrax lethal factor inhibition
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Anthrax lethal factor inhibition

机译：炭疽致死因子抑制

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摘要

The primary virulence factor of Bacillus anthracis is a secreted zinc-dependent metalloprotease toxin known as lethal factor (LF) that is lethal to the host through disruption of signaling pathways, cell destruction, and circulatory shock. Inhibition of this proteolyt-ic-based LF toxemia could be expected to provide therapeutic value in combination with an antibiotic during and immediately after an active anthrax infection. Herein is shown the crystal structure of an intimate complex between a hydroxamate, (2R)-2-[(4-fluoro-3-methylphenyl)sulfonylamino]-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide, and LF at the LF-active site. Most importantly, this molecular interaction between the hydroxamate and the LF active site resulted in (ⅰ) inhibited LF protease activity in an enzyme assay and protected macrophages against recombinant LF and protective antigen in a cell-based assay, (ⅱ) 100% protection in a lethal mouse toxemia model against recombinant LF and protective antigen, (ⅲ) ≈50% survival advantage to mice given a lethal challenge of B. anthracis Sterne vegetative cells and to rabbits given a lethal challenge of 8. anthracis Ames spores and doubled the mean time to death in those that died in both species, and (ⅳ) 100% protection against B. anthracis spore challenge when used in combination therapy with ciprofloxacin in a rabbit "point of no return" model for which ciprofloxacin alone provided 50% protection. These results indicate that a small molecule, hydroxamate LF inhibitor, as revealed herein, can ameliorate the toxemia characteristic of an active B. anthracis infection and could be a vital adjunct to our ability to combat anthrax.
机译：炭疽芽孢杆菌的主要毒力因子是一种分泌的锌依赖性金属蛋白酶毒素，称为致死因子（LF），可通过破坏信号通路，破坏细胞和循环休克对宿主致死。可以预期，这种基于蛋白水解的LF毒血症的抑制在活性炭疽感染期间和之后立即与抗生素联合使用具有治疗价值。此处显示了异羟肟酸酯，（2R）-2-[（（4-氟-3-甲基苯基）磺酰基氨基] -N-羟基-2-（四氢-2H-吡喃-4-基）之间的紧密配合物的晶体结构。乙酰胺和LF活性位点的LF。最重要的是，异羟肟酸酯与LF活性位点之间的这种分子相互作用导致（ⅰ）在酶法测定中抑制了LF蛋白酶的活性，并在基于细胞的测定法中保护了巨噬细胞免受重组LF和保护性抗原的侵袭，（ⅱ）100％的保护作用是一种针对重组LF和保护性抗原的致死性小鼠毒血症模型，对遭受炭疽芽孢杆菌Sterne植物细胞致死性攻击的小鼠和对兔致死性炭疽杆菌Ames孢子致死率均值提高一倍，（double）≈50％生存优势在两种动物中均死亡的时间；（ⅳ）与环丙沙星联合治疗的兔子“无返点”模型中，环丙沙星单独提供50％的保护时，对炭疽芽孢杆菌的孢子攻击具有100％的保护作用。这些结果表明，如本文所揭示的小分子异羟肟酸酯LF抑制剂可改善活性炭疽杆菌感染的毒血症特征，并且可能是我们抵抗炭疽的能力的重要辅助物。

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