離子通道是生命有機(jī)體保持正常功能的基石之一,其介導(dǎo)的生物電信號在心臟跳動,、激素分泌,、信號傳導(dǎo)及認(rèn)知記憶等所有生命過程中均起著關(guān)鍵作用。離子通道在基因水平的突變可導(dǎo)致包括神經(jīng)系統(tǒng),、心血管系統(tǒng)和內(nèi)分泌系統(tǒng)疾病在內(nèi)的多種疾病,,因此是最重要的藥物靶點之一,同時也是藥物安全性評價的指標(biāo)之一,。離子通道功能檢測依賴于對其介導(dǎo)的微小電流的測量,,因技術(shù)手段的限制,化合物篩選通量較低成為離子通道藥物發(fā)現(xiàn)的瓶頸和關(guān)鍵步驟,。
上海藥物所神經(jīng)藥理學(xué)研究國際科學(xué)家工作站自組建以來,,積極進(jìn)行篩選方法和平臺的建設(shè),,現(xiàn)已建成針對包括鉀通道,、TRP通道在內(nèi)的十余種離子通道的較高通量篩選體系。
KCNQ通道是電壓門控鉀通道的第七個家族,,共有五個亞型,,其中KCNQ1主要分布在心臟,其基因突變可導(dǎo)致嚴(yán)重心律失常,;KCNQ2和KCNQ3在神經(jīng)系統(tǒng)興奮性調(diào)節(jié)中起著重要作用,,是癲癇和疼痛等與神經(jīng)興奮性升高相關(guān)疾病的藥物靶點。研究生鄭月明等在利民特聘研究員和高召兵博士指導(dǎo)下,,采用基于熒光的篩選技術(shù),,針對KCNQ通道進(jìn)行藥物篩選,從成藥庫中發(fā)現(xiàn)多個活性化合物,,其中有關(guān)KCNQ1激動劑六氯酚(Hexachlorophene)的工作在PLOS ONE雜志在線發(fā)表,。六氯酚是局部抗炎處方藥pHisoHex的主要活性成分,其對鉀離子通道的調(diào)節(jié)作用為首次報道,。
該項研究取得了國家自然科學(xué)基金,、國家重點基礎(chǔ)研究發(fā)展計劃和國家科技重大專項“重大新藥創(chuàng)制”的資助。(生物谷Bioon.com)
doi:10.1371/journal.pone.0051820
PMC:
PMID:
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.