HERG K+ channel blockade by the novel antiviral drug sophocarpine

Abstract

Human ether-à-go-go-related gene (HERG) encodes the rapid component of the cardiac delayed rectifier K+ current, which has an important role in the repolarization of the cardiac action potential. QT interval prolongation through HERG channel inhibition is associated with a risk of torsade de pointes arrhythmias and is a major challenge for drug development. The effects of the novel antiviral drug sophocarpine (SC) were examined on stably expressed HERG channels in human embryonic kidney (HEK293) cells using a whole-cell patch clamp technique, Western blot analysis and immunofluorescence experiments. SC inhibited HERG channels in a concentration-dependent manner, with an IC50 of 100-300 μM. SC significantly accelerated channel inactivation, recovery from inactivation and onset of inactivation. In addition, it had no effect on channel activation and deactivation. Based on Western blot and immunofluorescence results, SC had no significant effect on the expression of HERG protein. In summary, SC is a potent blocker of HERG K+ channels that functions by changing the channel inactivation kinetics. In addition, SC has no effect on the generation and trafficking of HERG protein. © 2008 Pharmaceutical Society of Japan.