Translational toxicology and rescue strategies of the hERG channel dysfunction: biochemical and molecular mechanistic aspects

Zhang, Kaiping; Yang, Baofeng; Li, Baoxin

doi:10.1038/aps.2014.101

Cited by 25 publications

(34 citation statements)

References 95 publications

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“…; Zhang et al . ). To date, most of the identified pharmacological chaperones also show antagonist activity on Kv11.1 channels, so direct clinical application will require an improved pharmacological profile that allows rescue of expression defects without block of K + permeation through the channel.…”

Section: Discussionmentioning

confidence: 97%

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Rescue of protein expression defects may not be enough to abolish the pro‐arrhythmic phenotype of long QT type 2 mutations

Perry

Phan

et al. 2016

The Journal of Physiology

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Key pointsr Most missense long QT syndrome type 2 (LQTS2) mutations result in Kv11.1 channels that show reduced levels of membrane expression.r Pharmacological chaperones that rescue mutant channel expression could have therapeutic potential to reduce the risk of LQTS2-associated arrhythmias and sudden cardiac death, but only if the mutant Kv11.1 channels function normally (i.e. like WT channels) after membrane expression is restored.r Fewer than half of mutant channels exhibit relatively normal function after rescue by low temperature. The remaining rescued missense mutant Kv11.1 channels have perturbed gating and/or ion selectivity characteristics.r Co-expression of WT subunits with gating defective missense mutations ameliorates but does not eliminate the functional abnormalities observed for most mutant channels.r For patients with mutations that affect gating in addition to expression, it may be necessary to use a combination therapy to restore both normal function and normal expression of the channel protein. AbstractIn the heart, Kv11

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Section: Discussionmentioning

confidence: 97%

“…; Zhang et al . ), although none has so far been shown to effectively restore expression defects associated with LQTS2 mutations. Proteasomal inhibitors can also rescue expression of mutant Kv11.1 channels (Kagan et al .…”

Section: Discussionmentioning

confidence: 99%

Rescue of protein expression defects may not be enough to abolish the pro‐arrhythmic phenotype of long QT type 2 mutations

Perry

Phan

et al. 2016

The Journal of Physiology

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“…This inhibition, which occurs by the disruption of hERG channel protein trafficking to the plasma membrane, reduces the cell surface hERG channel density. Drugs may cause acute channel blockade or inhibition of forward trafficking or both [29] . To date, however, no information has been published on the disruption of protein trafficking by PIs, including ATV.…”

Section: Discussionmentioning

confidence: 99%

The protease inhibitor atazanavir blocks hERG K+ channels expressed in HEK293 cells and obstructs hERG protein transport to cell membrane

et al. 2015

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Aim: Atazanavir (ATV) is a HIV-1 protease inhibitor for the treatment of AIDS patients, which is recently reported to provoke excessive prolongation of the QT interval and torsades de pointes (TdP). In order to elucidate its arrhythmogenic mechanisms, we investigated the effects of ATV on the hERG K + channels expressed in HEK293 cells. Methods: hERG K + currents were detected using whole-cell patch clamp recording in HEK293 cells transfected with EGFP-hERG plasmids. The expression of hERG protein was measured with Western blotting. Two mutants (Y652A and F656C) were constructed in the S6 domain within the inner helices of hERG K + channels that were responsible for binding of various drugs. The trafficking of hERG protein was studied with confocal microscopy. Results: Application of ATV (0.01-30 μmol/L) concentration-dependently decreased hERG K + currents with an IC 50 of 5.7±1.8 μmol/L. ATV (10 μmol/L) did not affect the activation and steady-state inactivation of hERG K + currents. Compared with the wild type hERG K + channels, both Y652A and F656C mutants significantly reduced the inhibition of ATV on hERG K + currents. Overnight treatment with ATV (0.1-30 μmol/L) concentration-dependently reduced the amount of fully glycosylated 155 kDa hERG protein without significantly affecting the core-glycosylated 135 kDa hERG protein in the cells expressing the WT-hERG protein. Confocal microscopy studies confirmed that overnight treatment with ATV obstructed the trafficking of hERG protein to the cell membrane. Conclusion: ATV directly blocks hERG K + channels via binding to the residues Y652 and F656 in the S6 domain, and indirectly obstructs the transport of the hERG protein to the cell membrane.

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“…Blockade of hERG channel was found to be associated with an increased duration of ventricular repolarization and prolongation of QT interval (long QT syndrome, or LQTS). hERG potassium channel displays promiscuous interactions with diverse chemical scaffolds [3] . Structurally and functionally unrelated drugs have been shown to block hERG channel, and some of these agents, including terfenadine, astemizole, droperidol and cisapride, etc, have been withdrawn from the market due to their potential to predispose individuals to sudden cardiac death.…”

Section: Introductionmentioning

confidence: 99%

Investigation of miscellaneous hERG inhibition in large diverse compound collection using automated patch-clamp assay

Zou

Wang

et al. 2016

Acta Pharmacol Sin

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Aim: hERG potassium channels display miscellaneous interactions with diverse chemical scaffolds. In this study we assessed the hERG inhibition in a large compound library of diverse chemical entities and provided data for better understanding of the mechanisms underlying promiscuity of hERG inhibition.Methods: Approximately 300 000 compounds contained in Molecular Library Small Molecular Repository (MLSMR) library were tested. Compound profiling was conducted on hERG-CHO cells using the automated patch-clamp platform-IonWorks Quattro TM .Results: The compound library was tested at 1 and 10 μmol/L. IC 50 values were predicted using a modified 4-parameter logistic model. Inhibitor hits were binned into three groups based on their potency: high (IC 50 <1 μmol/L), intermediate (1 μmol/L< IC 50 <10 μmol/L), and low (IC 50 >10 μmol/L) with hit rates of 1.64%, 9.17% and 16.63%, respectively. Six physiochemical properties of each compound were acquired and calculated using ACD software to evaluate the correlation between hERG inhibition and the properties: hERG inhibition was positively correlative to the physiochemical properties ALogP, molecular weight and RTB, and negatively correlative to TPSA. Conclusion: Based on a large diverse compound collection, this study provides experimental evidence to understand the promiscuity of hERG inhibition. This study further demonstrates that hERG liability compounds tend to be more hydrophobic, high-molecular, flexible and polarizable.Keywords: hERG; high-throughput screening; MLSMR library; automated electrophysiology; cardiotoxicity Acta Pharmacologica Sinica (2016) 37: 111−123; doi: 10.1038/aps.2015 Original Article IntroductionThe acquired long QT syndrome is both a threat to public health and a major stumbling block for drug development [1] . It is most often caused through unintended blockade of the cardiac repolarizing potassium channel, I Kr , encoded by the Human Ether-a-go-go related gene (hERG) [2] . Blockade of hERG channel was found to be associated with an increased duration of ventricular repolarization and prolongation of QT interval (long QT syndrome, or LQTS). hERG potassium channel displays promiscuous interactions with diverse chemical scaffolds [3] . Structurally and functionally unrelated drugs have been shown to block hERG channel, and some of these agents, including terfenadine, astemizole, droperidol and cisapride, etc, have been withdrawn from the market due to their potential to predispose individuals to sudden cardiac death. Due to the important implications in both drug discovery [4] and clinical practice, evaluation of hERG liability has been required for any new chemical entities by regulatory agencies according to the ICH S7B guideline since 2005 [5] .Manual patch clamp method is considered as gold standard for ion channel functional evaluation [6] . However the method is very labor-intensive with low throughput, and thus its application in drug discovery is limited. Ion flux assays with surrogate ions of Rubidium (Rb + ) or Thallium (Tl + ) have ...

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Translational toxicology and rescue strategies of the hERG channel dysfunction: biochemical and molecular mechanistic aspects

Cited by 25 publications

References 95 publications

Rescue of protein expression defects may not be enough to abolish the pro‐arrhythmic phenotype of long QT type 2 mutations

Rescue of protein expression defects may not be enough to abolish the pro‐arrhythmic phenotype of long QT type 2 mutations

The protease inhibitor atazanavir blocks hERG K+ channels expressed in HEK293 cells and obstructs hERG protein transport to cell membrane

Investigation of miscellaneous hERG inhibition in large diverse compound collection using automated patch-clamp assay

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