离子通道是生命有机体保持正常功能的基石之一，其介导的生物电信号在心脏跳动、激素分泌、信号传导及认知记忆等所有生命过程中均起着关键作用。离子通道在基因水平的突变可导致包括神经系统、心血管系统和内分泌系统疾病在内的多种疾病，因此是最重要的药物靶点之一，同时也是药物安全性评价的指标之一。离子通道功能检测依赖于对其介导的微小电流的测量，因技术手段的限制，化合物筛选通量较低成为离子通道药物发现的瓶颈和关键步骤。
上海药物所神经药理学研究国际科学家工作站自组建以来，积极进行筛选方法和平台的建设，现已建成针对包括钾通道、TRP通道在内的十余种离子通道的较高通量筛选体系。
KCNQ通道是电压门控钾通道的第七个家族，共有五个亚型，其中KCNQ1主要分布在心脏，其基因突变可导致严重心律失常；KCNQ2和KCNQ3在神经系统兴奋性调节中起着重要作用，是癫痫和疼痛等与神经兴奋性升高相关疾病的药物靶点。研究生郑月明等在利民特聘研究员和高召兵博士指导下，采用基于荧光的筛选技术，针对KCNQ通道进行药物筛选，从成药库中发现多个活性化合物，其中有关KCNQ1激动剂六氯酚（Hexachlorophene）的工作在PLOS ONE杂志在线发表。六氯酚是局部抗炎处方药pHisoHex的主要活性成分，其对钾离子通道的调节作用为首次报道。
该项研究取得了国家自然科学基金、国家重点基础研究发展计划和国家科技重大专项“重大新药创制”的资助。(生物谷Bioon.com)
doi:10.1371/journal.pone.0051820
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Hexachlorophene Is a Potent KCNQ1/KCNE1 Potassium Channel Activator Which Rescues LQTs Mutants
Yueming Zheng, Xuejing Zhu, Pingzheng Zhou, Xi Lan, Haiyan Xu, Min Li mail, Zhaobing Gao
The voltage-gated KCNQ1 potassium channel is expressed in cardiac tissues, and coassembly of KCNQ1 with an auxiliary KCNE1 subunit mediates a slowly activating current that accelerates the repolarization of action potential in cardiomyocytes. Mutations of KCNQ1 genes that result in reduction or loss of channel activity cause prolongation of repolarization during action potential, thereby causing long QT syndrome (LQTs). Small molecule activators of KCNQ1/KCNE1 are useful both for understanding the mechanism of the complex activity and for developing therapeutics for LQTs. In this study we report that hexachlorophene (HCP), the active component of the topical anti-infective prescription drug pHisoHex, is a KCNQ1/KCNE1 activator. HCP potently increases the current amplitude of KCNQ1/KCNE1 expressed by stabilizing the channel in an open state with an EC50 of 4.61±1.29 μM. Further studies in cardiomyocytes showed that HCP significantly shortens the action potential duration at 1 μM. In addition, HCP is capable of rescuing the loss of function of the LQTs mutants caused by either impaired activation gating or phosphatidylinositol-4,5-bisphosphate (PIP2) binding affinity. Our results indicate HCP is a novel KCNQ1/KCNE1 activator and may be a useful tool compound for the development of LQTs therapeutics.
