HERG-Lite®: A novel comprehensive high-throughput screen for drug-induced hERG risk
| Autor: | Barbara A. Wible, Peter Hawryluk, Glenn E. Kirsch, Eckhard Ficker, Yuri A. Kuryshev, Arthur Brown |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Drug
congenital hereditary and neonatal diseases and abnormalities Drug-Related Side Effects and Adverse Reactions media_common.quotation_subject Long QT syndrome hERG Drug Evaluation Preclinical Torsades de pointes Pharmacology Toxicology QT interval Cell Line Predictive Value of Tests Torsades de Pointes Potassium Channel Blockers Humans Medicine cardiovascular diseases media_common Cardiotoxicity biology business.industry medicine.disease Potassium channel Long QT Syndrome Pharmaceutical Preparations Drug development Potassium Channels Voltage-Gated Luminescent Measurements biology.protein business |
| Zdroj: | Journal of Pharmacological and Toxicological Methods. 52:136-145 |
| ISSN: | 1056-8719 |
| DOI: | 10.1016/j.vascn.2005.03.008 |
| Popis: | Direct block of I(Kr) by non-antiarrhythmic drugs (NARDs) is a major cause of QT prolongation and torsades de pointes (TdP), 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 TdP 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.HERG-Lite 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 assay using a panel of 100 drugs: 50 hERG blockers and 50 nonblockers.HERG-Lite 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 assay, and fell into two classes: B (for blocker) and C (for complex; block and trafficking inhibition).HERG-Lite 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. |
| Databáze: | OpenAIRE |
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