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 common cause for drugs to induce LQTS is through impairing the function of the cardiac potassium channel encoded by the human ether-a-go-go-related­ gene (hERG) which is important for cardiac repolarization. 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 another cardiac repolarizing potassium channel encoded by KCNQ1+KCNE1. Clinically relevant drug concentrations for these four drugs are in the single-digit µM range. Thus, from the point of view of cardiac repolarizing potassium channels, while chloroquine may bear some potential LQTS risk, the risk for the other three drugs hydroxychloroquine, azithromycin, and remdesivir are low, although they may nevertheless warrant monitoring for risk of cardiac arrhythmias. (This work was supported by the Canadian Institutes of Health Research [PJT 152862] to S. Z.).