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Michael Acceptor-Containing Coenzyme A Analogues As Inhibitors of the Atypical Coenzyme A Disulfide Reductase from Staphylococcus aureus

机译:含迈克尔受体的辅酶A与金黄色葡萄球菌非典型辅酶A二硫键还原酶的抑制剂相似

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摘要

Coenzyme A (CoA) analogues containing α,β-unsaturated ester, ketone, and sulfone moieties were prepared by chemo-enzymatic synthesis as inhibitors of coenzyme A disulfide reductase (CoADR), a proven and as yet unexploited drug target in Staphylococcus aureus. Among these Michael acceptor-containing CoA analogues, which were designed to target CoADR’s single essential active site cysteine for conjugate addition, a phenyl vinyl sulfone-containing analogue showed the most potent inhibition with a competitive Ki of 40 nM, and time-dependent inactivation with a second-order rate of inactivation constant of 40 000 s−1·M−1. Our results suggest that electrophilic substrate analogues should be considered as potential inhibitors of other medicinally relevant disulfide reductase enzymes.
机译:通过化学酶促合成制备了含有α,β-不饱和酯,酮和砜部分的辅酶A(CoA)类似物,作为辅酶A二硫化物还原酶(CoADR)的抑制剂,该酶是金黄色葡萄球菌中已被证实且尚未开发的药物靶标。这些旨在包含CoADR的单个必需活性位点半胱氨酸用于缀合物添加的含Michael受体的CoA类似物中,含苯基乙烯基砜的类似物显示出最有效的抑制作用,竞争性K i 为40 nM和时间相关的失活,其失活速率的二级常数为40 000 s -1 ·M -1 。我们的结果表明,亲电子底物类似物应被视为其他药物相关的二硫键还原酶的潜在抑制剂。

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  • 来源
    《Journal of the American Chemical Society》 |2010年第37期|p.12853-12855|共3页
  • 作者单位

    Department of Biochemistry, Stellenbosch University, Private bag X1, Matieland 7602, South Africa;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
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  • 入库时间 2022-08-18 00:50:23

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