COVID-19 Drugs Chloroquine and Hydroxychloroquine, but Not Azithromycin and Remdesivir, Block hERG Potassium Channels

Drug-induced long QT syndrome (LQTS) is an established cardiac side effect of a wide range of medications, which represents a significant concern for drug safety. The rapidly (IKr) and slowly activating delayed rectifier K+ current (IKs) mediated by channels encoded by the human ether-a-go-go-related- gene (hERG) and KCNQ1+KCNE1, respectively, are two main currents responsible for ventricular repolarization. The common cause for drugs to induce LQTS is through impairing the hERG channel. For the recent emergence of COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), several drugs have been investigated as potential therapies, however there are concerns about their QT prolongation risk. Here we study the effects of chloroquine, hydroxychloroquine, azithromycin, and remdesivir on hERG channels. Our results showed that while chloroquine acutely blocked hERG current (IhERG) with an IC50 of 3.0 µM, hydroxychloroquine acutely blocked IhERG 8-fold less potently, with an IC50 of 23.4 µM. Azithromycin and remdesivir did not acutely affect IhERG When these drugs at 10 µM were added to the cell culture medium for 24 h, remdesivir increased IhERG by two-fold, which was associated with an increased mature hERG channel expression. In addition, these four drugs did not acutely or chronically affect KCNQ1+KCNE1 channels. Our data provide insight into COVID-19 drug-associated LQTS and cardiac safety concerns. Significance Statement This work demonstrates that among off-label potential COVID-19 treatment drugs chloroquine, hydroxychloroquine, azithromycin, and remdesivir, the former two drugs block hERG potassium channels while the latter two drugs do not. All four drugs do not affect KCNQ1+KCNE1. As hERG and KCNQ1+KCNE1 are two main K+ channels responsible for ventricular repolarization, and most drugs that induce long QT syndrome (LQTS) do so by impairing hERG channels, our data provide insight into COVID-19 drug-associated LQTS and cardiac safety concerns.