IndraLab

"Furthermore, this soluble peptide of N-terminus (1-135 AA) was shown to bind to membrane bound KCNH2 ( xref ) suggesting that the truncated mutant KCNH2 protein may affect formation of KCNH2 tetramer leading to abnormal function of potassium channel."

"Unfortunately, hERG1 potassium channel antagonists are strongly associated with cardiac arrhythmias: acquired long QT (aLQT2) and cardiac ventricular fibrillation; these potentially fatal events limit the use of hERG1 blockers for anticancer therapy."

"Background Anti-Sjögren's syndrome-related antigen A-antibodies (anti-Ro/SSA-antibodies) are responsible for a novel form of acquired long-QT syndrome, owing to autoimmune-mediated inhibition of cardiac human ether-a-go-go-related gene-potassium channels."

"Indeed, according to the multihit theory, xref more than 1 factor/hit is necessary in most cases to significantly disturb ventricular repolarization and induce a clinically measurable lengthening of QTc. xref , xref In this view, anti‐Ro/SSA may intriguingly represent a risk factor for QTc prolongation both directly by inhibiting the hERG‐potassium channel and indirectly by affecting the probability that other QT‐prolonging risk factor are at the same time present in the individual subject."

"4,6 IL-6 has been shown to prolong QT directly by inhibiting the hERG-potassium channel and indirectly by inhibiting CYP3A4, increasing the bioavailability of QT-prolonging agents."

"KRO-105714 also had no cardiotoxicity in the hERG potassium channel binding assay (IC 50> 10muM) (Additional file 1 : Table S1B)."

"5HT 1 receptor subtypes have been suggested to account for adverse events due to interactions with HERG cardiac potassium channel and 5-hydroxytryptamine [ xref ]."

"Clarithromycin inhibits autophagy in colorectal cancer by regulating the hERG1 potassium channel interaction with PI3K."

"Specifically, by targeting calcium, potassium, or sodium channels, these autoantibodies lead to significant electrophysiological changes promoting conduction disturbances and/or life‐threatening tachyarrhythmias, both in patients with manifest autoimmune diseases and in apparently healthy individuals. xref , xref , xref Anti‐Ro/SSA is the most investigated anti‐ion channel antibody and its role in the pathogenesis of the congenital heart block via a molecular mimicry‐driven interaction with calcium channels of the fetal conduction system is well established. xref , xref , xref , xref More recently, a growing body of evidence demonstrated that anti‐Ro/SSA‐antibodies can also target the hERG‐potassium channel leading to a novel form of acquired LQTS of autoimmune origin. xref , xref Several clinical studies in adults and newborns provided evidence that subjects who were anti‐Ro/SSA‐positive frequently show a prolonged QTc, xref , xref , xref , xref , xref , xref whose length correlates with circulating autoantibody levels xref , xref , xref and incidence of complex VAs, xref , xref including TdP. xref , xref From a molecular point of view, we established that purified IgG/anti‐Ro/SSA‐52 kDa from patients who were antibody positive with LQTS/TdP acutely inhibited the rapid component of the delayed rectifier potassium current in human embryonic kidney‐293 cells and guinea‐pig ventricular myocytes. xref , xref Such effects, found in both subjects with LQTS with CTD and in patients with TdP without any sign of autoimmune disease, were a result of a specific interaction of the autoantibody with the extracellular loop of the hERG‐potassium channel, between segments S5 and S6 of the pore‐forming subunit, where a significant homology with the Ro/SSA‐52 kDa antigen is present. xref , xref Other authors demonstrated that this region is also critical for the occurrence of the chronic effects of anti‐Ro/SSA‐52 kDa on the channel, that is, reduced expression by triggering channel internalization. xref , xref Finally, we provided evidence that immunization of adult guinea‐pigs with the Ro/SSA‐52 kDa antigens reproduced QTc prolongation in these animals, because of the autoantibody‐mediated prolonging effect on ventricular action potential duration via the rapid component of the delayed rectifier potassium current inhibition. xref Although these data strongly support the role of anti‐Ro/SSA as a novel, nontraditional, risk factor for LQTS/TdP in patients with CTD, information regarding its actual clinical impact on the general population is substantially missing as only studies on relatively small groups of selected patients are currently available. xref , xref , xref , xref , xref , xref , xref , xref , xref "

"32 , 33 In addition, the use of pharmacological treatments for COVID‐19, such as antimalarial agents (hydroxychloroquine/chloroquine) and anti‐viral agents (lopinavir/ritonavir), has been shown to further prolong the QTc interval through inhibition of the hERG‐potassium channel and inhibition of the enzyme cytochrome 450, thereby increasing the risk of QT‐related life‐threatening ventricular arrhythmias, particularly TdP."

"Clarithromycin inhibits autophagy in colorectal cancer by regulating the hERG1 potassium channel interaction with PI3K."

"Pathological CAMK‐II regulation triggers the spontaneous release of electrogenic Ca 2+ via extrusion Na + /Ca 2+ exchanger, phosphorylation of RyR2 resulting in further calcium‐induced calcium release, and gain‐of‐function of L‐type calcium channels and sarcoplasmic endoplasmic reticulum calcium channel (SERCA). xref The net effect of these pathways results in Ca 2+ overload within the cardiomyocyte, causing an increased propensity toward developing EAD and DAD, both of which are prerequisites for developing arrhythmias such as premature ventricular complex (PVC), premature atrial complex (PAC), and even more life‐threatening arrhythmias like VT or VF. xref , xref In addition, the use of pharmacological treatments for COVID‐19, such as antimalarial agents (hydroxychloroquine/chloroquine) and anti‐viral agents (lopinavir/ritonavir), has been shown to further prolong the QTc interval through inhibition of the hERG‐potassium channel and inhibition of the enzyme cytochrome 450, thereby increasing the risk of QT‐related life‐threatening ventricular arrhythmias, particularly TdP. xref Macrolides such as azithromycin and clarithromycin, which are frequently administered to prevent lung bacterial superinfection, have also been reported to prolong the QT interval and increase the risk of TdP. xref , xref Given the wide variety of pharmaceutical and medical approaches in treating COVID‐19 infection, pharmacokinetic and pharmacodynamic drug interactions are needed to be considered to minimize the risk of cardiac arrhythmias."

"The hERG-potassium channel inhibition was tested as a potential off-target effect."

"In addition, compound 12c at 10 μ M did not show any human ether-a-go-go-related gene (hERG) potassium channel binding activity ( xref ), indicating that compound 12c should not have undesirable hERG inhibition known to cause cardiotoxicity. xref "

"Correction : Clarithromycin inhibits autophagy in colorectal cancer by regulating the hERG1 potassium channel interaction with PI3K."

"Drugs, mainly hERG-potassium channel blockers, and electrolyte imbalances (hypokalemia, hypocalcaemia, hypomagnesemia) represent the most frequent causes of acquired LQTS ( xref ; xref )."

"Conclusions: All the antiviral drugs studied here can, in principle, interact with components of the hERG potassium channel canonical binding site, but are likely to differ in their ability to access lateral binding pockets."

"Our findings suggest that all of these agents can, in principle, interact with components of the hERG potassium channel canonical binding site, but with some drug-specific differences in the observed interactions."

"4,5 Pharmacologic treatments for COVID-19, such as hydroxychloroquine/chloroquine and lopinavir/ritonavir, have been shown to prolong QT directly through inhibition of the hERG-potassium channel and indirectly by increasing circulating levels of other concomitant QT-prolonging drugs by cytochrome 450 enzyme inhibition."