Early Cardiotoxicity Evaluation By High Throughput Screening Of HERG Potassium Channel On Cell

Long QT syndrome can result in ventricular arrhythmia (torsade de pointes) and sudden death. hERG channel inhibition through drugs is now recognized as a common reason for the acquired form of long QT syndrome. So nowadays, hERG channel is becoming a hot research aspect all over the world. Many drugs have been withdrawn from the market because of the heart adverse reaction:long QT syndrome, due to their inhibition of hERG channel. Therefore Food and Drug Administration regulations now require the assessment of compound activity on the hERG channel. And it has become an important part of the safety evaluation in the process of new drug application.To detect compound effects on human ether-a’-go-go related gene (hERG) potassium channels, In addition to radioactive ligand displacement tests, there are two other common approaches. The one is surrogate ion-based flux assays, the other is electrophysiological recordings. The former is much high-throughput, whereas the latter measure the effects on ion channel directly. Electropysiology has been thought the golden standard for detecting ion channel. But it is expensive, high-level, and low-throughput; it is not a good approache to select profile large compound libraries.Surrogate ion-based flux assay takes advantage of well known permeability of potassium channels to thallium (T1+) ions, with some stimulus, thallium flows into the cells and channel activity can be detected with a proprietary indicator dye that increases in cytosolic fluorescence. It is high-throughput, quickly and relatively easy. But, at the same time, we met considerable technical challenges druing the founding of this method. Currents passing through ion channels are often transient and small and require special stimulus to activate, all of these can give us challenges for High-throughput screening.To provide a general basis for detecting assays to profile large compound libraries for hERG activity, we conducted parallel flux and electrophysiological assays of 3 different compounds on transfected HEK293 cell, compare the relative effectiveness of these two methods. Our results indicate that at the conventional drug testing concentration 10.0 uM, the two methods have good overall correlation, as a result, we can use flux assay in initial screening for cardiac safety profiling of unknown compounds. In a word, we have founded an efficient way for rapidly profile hERG liabilities of large collection of naive compounds.