Engineering a peptide inhibitor towards the KCNQ1/KCNE1 potassium channel (IKs)
Engineering a peptide inhibitor towards the KCNQ1/KCNE1 potassium channel (IKs)
复制标题
针对 KCNQ1/KCNE1 钾通道 (IK) 设计肽抑制剂
DOI：
10.1016/j.peptides.2015.07.002
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发表时间：
2015-09-01
期刊：
影响因子：
3
通讯作者：
Chen, Zongyun
中科院分区：
文献类型：
--
作者：
Hu, Youtian;Chen, Jing;Chen, Zongyun
KCNQ 1/KCNE 1通道（I-Ks）在心脏的生理和病理过程中起着重要作用，但目前还没有研究到对该通道起作用的多肽。本研究发现天然蝎毒对KCNQ 1/KCNE 1通道电流几乎没有抑制作用。基于这一观察结果，我们尝试使用三种天然蝎毒素ChTX，BmKTX和OmTx 2作为模板，具有两种不同的结构折叠，以工程化针对KCNQ 1/KCNE 1通道的有效肽抑制剂。药理实验表明，当我们用1 μ M的MT 2肽（BmKTX毒素衍生的类似物）筛选时，KCNQ 1/KCNE 1通道电流可以被有效地抑制。浓度依赖性实验表明，MT 2抑制KCNQ 1/KCNE 1通道，IC 50值为4.6 +/- 1.9 μ M。突变实验表明，MT 2多肽可能是利用Lys 26残基与KCNQ 1/KCNE 1通道相互作用。以MT 2为新模板，我们进一步设计了一个更有效的MT 2 -2肽，它选择性地抑制KCNQ 1/KCNE 1通道，IC 50为1.51 +/- 0.62 μ M。总之，这项工作提供了一个非常有效的KCNQ 1/KCNE 1通道肽抑制剂到目前为止，并强调了分子策略在开发天然毒素不敏感孤儿受体的有效肽抑制剂中的作用。(C)2015 Elsevier Inc. All rights reserved.
The KCNQ1/KCNE1 channel (I-Ks) plays important roles in the physiological and pathological process of heart, but no potent peptide acting on this channel has been reported. In this work, we found that the natural scorpion venom hardly inhibited KCNQ1/KCNE1 channel currents. Based on this observation, we attempted to use three natural scorpion toxins ChTX, BmKTX and OmTx2 with two different structural folds as templates to engineer potent peptide inhibitors towards the KCNQ1/KCNE1 channel. Pharmacological experiments showed that when we screen with 1 mu M MT2 peptide, an analog derived from BmKTX toxin, KCNQ1/KCNE1 channel currents could be effectively inhibited. Concentration-dependent experiments showed that MT2 inhibited the KCNQ1/KCNE1 channel with an IC50 value of 4.6 +/- 1.9 mu M. The mutagenesis experiments indicated that MT2 peptide likely used Lys26 residue to interact with the KCNQ1/KCNE1 channel. With MT2 as a new template, we further designed a more potent MT2-2 peptide, which selectively inhibited the KCNQ1/KCNE1 channel with an IC50 of 1.51 +/- 0.62 mu M. Together, this work provided a much potent KCNQ1/KCNE1 channel peptide inhibitor so far, and highlighted the role of molecular strategy in developing potent peptide inhibitors for the natural toxin-insensitive orphan receptors. (C) 2015 Elsevier Inc. All rights reserved.