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首页> 外文期刊>Biochemistry >Reversible Covalent Reaction of Levosimendan with Cardiac Troponin C in Vitro and in Situ
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Reversible Covalent Reaction of Levosimendan with Cardiac Troponin C in Vitro and in Situ

机译：levosimendan用心肌肌钙蛋白C + I>的可逆共价反应，原位

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The development of calcium sensitizers for the treatment of systolic heart failure presents difficulties, including judging the optimal efficacy and the specificity to target cardiac muscle. The thin filament is an attractive target because cardiac troponin C (cTnC) is the site of calcium binding and the trigger for subsequent contraction. One widely studied calcium sensitizer is levosimendan. We have recently shown that when a covalent cTnC–levosimendan analogue is exchanged into cardiac muscle cells, they become constitutively active, demonstrating the potency of a covalent complex. We have also demonstrated that levosimendan reacts in vitro to form a reversible covalent thioimidate bond specifically with cysteine 84, unique to cTnC. In this study, we use mass spectrometry to show that the in vitro mechanism of action of levosimendan is consistent with an allosteric, reversible covalent inhibitor; to determine whether the presence of the cTnI switch peptide or changes in either Ca~(2+) concentration or pH modify the reaction kinetics; and to determine whether the reaction can occur with cTnC in situ in cardiac myofibrils. Using the derived kinetic rate constants, we predict the degree of covalently modified cTnC in vivo under the conditions studied. We observe that?covalent bond formation would be highest under the acidotic conditions resulting from ischemia and discuss whether the predicted level could be sufficient to have therapeutic value. Irrespective of the in vivo mechanism of action for levosimendan, our results provide a rationale and basis for the development of reversible covalent drugs to target the failing heart.
机译：用于治疗收缩性心力衰竭的钙敏化剂的发展呈现困难，包括判断靶心心肌的最佳疗效和特异性。薄丝是一种吸引力的目标，因为心肌肌钙蛋白C（CTNC）是钙结合的部位和随后收缩的触发器。一种广泛研究的钙敏化剂是Levosimendan。我们最近表明，当将共价CTNC-Levosimendan类似物交换到心肌细胞中时，它们变成了组成型活性，证明了共价络合物的效力。我们还证明左索亚丹丹在体外反应，形成具有CTNC独特的半胱氨酸84的可逆共价硫酸酯键。在这项研究中，我们使用质谱仪表明，左旋蛋白丹丹的体外作用机制与变构，可逆的共价抑制剂一致;为了确定CTNI开关肽是否存在或Ca〜（2+）浓度或pH的变化改性反应动力学;并确定反应是否可以用CTNC 原位在心脏肌原纤维中发生。使用衍生的动力速率常数，我们预测在研究的条件下预测体内共价修饰的CTNC 的程度。我们观察到，在缺血产生的酸性条件下，共价键形成将是最高的，并讨论预测的水平是否足以具有治疗价值。无论左索亚曼丹的体内行动机制如何，我们的结果为靶向失败的心脏瞄准失败的共价药物的发展提供了理由和基础。

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  • 来源
    《Biochemistry》 |2018年第15期|共10页
  • 作者

    BrittneyA. Klein; Béla Reiz; Ian M. Robertson; Malcolm Irving; Liang Li; Yin-Biao Sun; Brian D. Sykes;

  • 作者单位

    Department of Biochemistry Faculty of Medicine and Dentistry University of Alberta Edmonton Alberta T6G 2H7 Canada;

    Department of Chemistry Faculty of Science University of Alberta Edmonton Alberta T6H 2H7 Canada;

    Pharmaceutical and Health Benefits Branch Ministry of Health Government of Alberta Edmonton Alberta T5J 3Z5 Canada;

    Randall Centre for Cell and Molecular Biophysics and British Heart Foundation Centre of Research Excellence King’s College London London SE1 1UL U.K.;

    Department of Chemistry Faculty of Science University of Alberta Edmonton Alberta T6H 2H7 Canada;

    Randall Centre for Cell and Molecular Biophysics and British Heart Foundation Centre of Research Excellence King’s College London London SE1 1UL U.K.;

    Department of Biochemistry Faculty of Medicine and Dentistry University of Alberta Edmonton Alberta T6G 2H7 Canada;

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  • 正文语种 eng
  • 中图分类 生物化学;
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