HERG-Lite®:: A novel comprehensive high-throughput screen for drug-induced hERG risk
HERG-Lite®:: A novel comprehensive high-throughput screen for drug-induced hERG risk
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DOI：
10.1016/j.vascn.2005.03.008
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发表时间：
2005-07-01
影响因子：
1.9
通讯作者：
Brown, Arthur M.
中科院分区：
文献类型：
--
作者：
Wible, Barbara A.;Hawryluk, Peter;Brown, Arthur M.
简介：非抗心律失常药物（NARD）直接阻断I-Kr是QT间期延长和尖端扭转型室性心动过速（UP）的主要原因，并使hERG钾通道成为心脏毒性药物安全性项目的主要目标。然而，阻断hERG电流并不是药物对复极化电流I-Kr产生不利影响的唯一途径。我们最近发现，临床使用的两种药物不阻断hERG，但通过抑制hERG向细胞表面的运输而产生长QT综合征（LQTS）和UP。为了满足在药物开发过程中早期预测两种类型hERG风险的廉价、快速和全面的检测方法的需求，我们开发了一种新型的基于抗体的荧光检测方法，称为HERG-Lite（R）。方法：HERG-Lite（R）在两种不同的稳定哺乳动物细胞系中监测hERG在细胞表面的表达。一个细胞系作为生物传感器的药物，抑制hERG的贩运，而其他预测hERG阻滞剂的基础上，他们的能力，作为药理学伴侣。在这项研究中，我们使用一组100种药物验证了HERG-Lite（R）检测：50种hERG阻滞剂和50种非阻滞剂。结果：HERG-Lite（R）正确预测了所有100种测试化合物的hERG风险，没有假阳性或假阴性。所有50种hERG阻滞剂在HERG-Lite（R）试验中均被检测为具有hERG风险的药物，并分为两类：B（阻滞剂）和C（复合物;阻滞和运输抑制）。讨论：HERG-Lite（R）是可用于预测药物诱导的hERG风险的最全面的检测方法。它以快速、经济有效的方式准确预测通道阻滞剂和转运抑制剂，是一种有价值的药物安全性非临床检测方法。(c)2005年爱思唯尔公司All rights reserved.
Introduction: Direct block of I-Kr by non-antiarrhythmic drugs (NARDs) is a major cause of QT prolongation and torsades de pointes (UP), and has made the hERG potassium channel a major target of drug safety programs in cardiotoxicity. Block of hERG currents is not the only way that drugs can adversely impact the repolarizing current I-Kr, however. We have shown recently that two drugs in clinical use do not block hERG but produce long QT syndrome (LQTS) and UP by inhibiting trafficking of hERG to the cell surface. To address the need for an inexpensive, rapid, and comprehensive assay to predict both types of hERG risk early in the drug development process, we have developed a novel antibody-based chemiluminescent assay called HERG-Lite (R). Methods: HERG-Lite (R) monitors the expression of hERG at the cell surface in two different stable mammalian cell lines. One cell line acts as a biosensor for drugs that inhibit hERG trafficking, while the other predicts hERG blockers based on their ability to act as pharmacological chaperones. In this study, we have validated the HERG-Lite (R) assay using a panel of 100 drugs: 50 hERG blockers and 50 nonblockers. Results: HERG-Lite (R) correctly predicted hERG risk for all 100 test compounds with no false positives or negatives. All 50 hERG blockers were detected as drugs with hERG risk in the HERG-Lite (R) assay, and fell into two classes: B (for blocker) and C (for complex; block and trafficking inhibition). Discussion: HERG-Lite (R) is the most comprehensive assay available for predicting drug-induced hERG risk. It accurately predicts both channel blockers and trafficking inhibitors in a rapid, cost-effective manner and is a valuable non-clinical assay for drug safety testing. (c) 2005 Elsevier Inc. All rights reserved.