Novel Intramolecular Photoinduced Electron Transfer-Based Probe for the Human Ether-a-go-go-Related Gene (hERG) Potassium Channel

摘要

Drug induced long QT syndrome is a high risk event in clinic, which mainly result from their high affinity with Human Ether-a-go-go-Related Gene (hERG) potassium channel. Therefore, evaluation of the drug’s inhibitory activity against hERG potassium channel is a required step in drug discovery and development. In this study, we developed a series of novel conformation-mediated intramolecular photoinduced electron transfer fluorogenic probe for hERG potassium channel. After careful evaluation, probe N4 and N6 showed good activity and may have a promising application in cell-based hERG potassium channel inhibitory activity assay, as well as potential hERG-associated cardiotoxicity. Compared with other assay methods, such as patch clamp, radio-ligand competitive binding assay, fluorescent polarization and potential-sensitive fluorescent probes, this method is convenient and can also selectively measure the inhibitory activity in the native state of hERG potassium channel. Meanwhile, these probes can also be used for hERG potassium channel imaging without complex washing steps.