IndraLab

"Structural biology and computer-assisted drug screening may be an emerging research approach.explored the interaction between potential COVID-19 antiviral therapy and hERG potassium channel pores through computer model simulations based on the cryoelectron microscopic structure of hERG, explaining the differences in the ability of different drugs to enter the lateral binding pocket."

"For instance, terfenadine ( 14 ) was eventually withdrawn from the market ( Estelle and Simons, 1999 ) in several, but not all countries, as they were connected with the risk of Torsades de Pointes an[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

"In cardiomyocytes affected by long-QT syndrome type 2 caused by an A516T mutation in the KCNH2 gene encoding the hERG potassium channel, it was shown that the mutation exerted a dominant-negative effe[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

"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."

"In‐vitro studies strongly suggest that the QTc prolonging effect of ibogaine and its metabolite noribogaine results from inhibition of cardiac hERG‐potassium channels [ xref , xref , xref ]."

"While it has been established that secondary pharmacology is a driving factor in toxicity [ 24–26 ], most existing DL tools aim to anticipate toxicity based on chemical structure or interactions with [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

"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."

"It is caused by the blocking of specific cardiac cellular hERG-potassium channels ( xref ) and can lead to lethal ventricular arrhythmia (torsades de pointes), although the relation between the risk for torsades de pointes and the magnitude of QTc interval prolongation is not strictly linear ( xref ), with the latter nonetheless being an important surrogate marker ( xref )."

"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 "

"In a standard panel for off-target activity, compound 8 did not display significant affinity for the other 163 receptors and ion channels, indicating that compound 8 is a selective ORL1 antagonist (th[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

"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."

"Our goal of SAR study was to find a compound that was potent in both human 5-LO enzyme assay and LTB 4 whole blood assay but with diminished hERG potassium channel binding activity."

"Additionally, the chronic use of chloroquine or HCQ is associated with QTc prolongation by binding to and inhibiting the hERG-potassium channel, thereby blocking the delayed rectifier potassium current leading to prolonged ventricular repolarization."

"The analysis of the SAR trend of these compounds clearly indicated that a small substituent bearing polar group, as shown by 2d , was both beneficial to the improved 5-LO inhibiting activity and dimin[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

"It was recently demonstrated that autoantibodies against the Ro/SSA region (fragment with MW=52 kDa) of hERG-potassium channels are responsible for a novel form of acquired LQT syndrome of autoimmune origin, by directly cross-reacting with the extracellular loop of the hERG-potassium channel pore-forming region, resulting in inhibition of cardiac rapidly activating rectifier potassium (IKr) channels and prolongation of an Action Potential Duration (APD) [ xref ]."

"In the context of cardiomyopathies, most prominent types of autoantibodies are autoantibodies against β1-adrenergic receptors, Ca-channels, Na-K-ATPase (sodium-potassium pump), and hERG-potassium channel."

"The most data in this field have been obtained in the studies focused on the role of anti-β1-adrenergic receptor autoantibodies in SCD pathogenesis (Table xref for the list of studies performed), much less information is available about the autoantibodies generated against Ca-channels, Na-K-ATPase (sodium-potassium pump), and hERG-potassium channels."

"Role of HERG-potassium channel antibodies in the SCD pathogenesis."

"A recent example of the application of toxicogenomics is the discovery that inherited forms of the long QT syndrome can be caused by high affinity drug blockade associated with mutations in the HERG p[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

"Recently, Petroni et al. reported that CAM inhibits autophagic flux in colorectal cancer by regulating the hERG1 potassium channel interaction with PI3K [43]."

"Therefore, DA-6886 displayed a high selectivity for the 5-HT 4 receptor isoforms over other receptors, ion channels and transporters.As shown in Table 4 , DA-6886 exhibited negligible hERG potassium c[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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

"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."

"While it has been established that secondary pharmacology is a driving factor in toxicity [ 24–26 ], most existing DL tools aim to anticipate toxicity based on chemical structure or interactions with [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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

"As shown in Table 1 , while compound 1 demonstrated good starting kinetics and high selectivity against TPO and cytochromes P450 (CYP) inhibition, off-target liabilities include human ether-a-go-go-re[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

"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 "

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

"Another problem in drug development is a possible QT prolongation due to human ether-a-go-go-related gene (hERG) potassium channel binding in the heart."

"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."

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

"To determine the cardiotoxicity of compound 36 , we performed the hERG potassium channel ligand binding assay along with astemizole as a positive control ( Supporting Table 4 )."

"In spite of the improvement in the Eg5 potency and aqueous solubility, introduction of amide or urea moiety to dihydropyrrole core potentiated the IKr potassium channel hERG binding [131] ."

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

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