Effects of COVID-19 drugs chloroquine, hydroxychloroquine, azithromycin and remdesivir on hERG expression and function

Abstract

A prolongation of the cardiac action potential may present itself as long QT syndrome (LQTS). LQTS can occur as a side effect of a wide variety of medications. A common cause of drug induced LQTS is through drug interactions with the human ether-á-go-go related gene (hERG) potassium channel or the KCNQ1+KCNE1 potassium channel. These channels produce the rapidly and slowly activating delayed rectifier currents in the human heart, IKr and IKs, respectively. IKr and IKs are repolarizing currents of the ventricular action potential and are key determinants of QT interval length. The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 has led to unprecedented healthcare challenges. In the treatment of COVID-19 there have been investigations into repurposing existing medications and using them to treat the disease in “off-label” use. Drug safety concerns have arisen from reports of QT prolongation in patients receiving certain off-label COVID-19 drugs. In my study, I investigated the effects of chloroquine, hydroxychloroquine, azithromycin and remdesivir on hERG and KCNQ1+KCNE1 channel function. My results show that chloroquine and hydroxychloroquine acutely blocked IhERG with an IC50 of 3 µM, and 23.4 µM respectively. Azithromycin and remdesivir did not acutely effect IhERG. When these drugs were added to the cell culture medium at 10 µM for 24 hours, remdesivir increased IhERGas well as hERG mature channel protein expression by 2-fold. The other 3 drugs tested had no chronic effect on hERG. Results from real time qPCR indicate that the increase in mature hERG protein expression is through an increase in hERG mRNA through an unknown mechanism of action. None of the four drugs tested had either acute or chronic effects on KNCQ1+KCNE1 at 10 µM. These results provide insight into reports of QT prolongation from the use of off label COVID-19 drugs, as well as show discovery of an unknown mechanism by which IhERG and hERG mature protein expression is increased by remdesivir treatment.