Pharmacological activation of thehERGK⁺channel for the management of the longQTsyndrome: A review

Abstract

In the human heart, the rapid delayed rectifier K+ current (IKr) contributes significantly to ventricular action potential (AP) repolarization and to set the duration of the QT interval of the surface electrocardiogram (ECG). The pore‐forming (α) subunit of the IKr channel is encoded by KCNH2 or human ether‐à‐go‐go‐related gene 1 (hERG1). Impairment of hERG function through either gene mutation (congenital) or pharmacological blockade by diverse drugs in clinical use (acquired) can cause a prolongation of the AP duration (APD) reflected onto the surface ECG as a prolonged QT interval or Long QT Syndrome (LQTS). LQTS can increase the risk of triggered activity of ventricular cardiomyocytes and associated life‐threatening arrhythmia. Current treatments all focus on reducing the incidence of arrhythmia or terminating it after its onset but there is to date no prophylactic treatment for the pharmacological management of LQTS. A new class of hERG modulators (agonists) have been suggested through direct interaction with the hERG channel to shorten the action potential duration (APD) and/or increase the postrepolarisation refractoriness period (PRRP) of ventricular cardiomyocytes protecting thereby against triggered activity and associated arrhythmia. Although promising drug candidates, there remain major obstacles to their clinical development. The aim of this review is to summarize the latest advances as well as the limitations of this proposed pharmacotherapy.

hERG stereoselective modulation by mexiletine‐derived ureas: Molecular docking study, synthesis, and biological evaluation

“…None of the stereoisomers increased the threshold of ac‐arrhythmia, with the intrinsic activities being at the most 11%: such a mild effect was observed that the EC 50 values were not determined. Looking at the flip side, being known that hERG agonists are associated with a substantial risk of proarrhythmia, [ 13,46,47 ] no arrhythmogenic effect was observed, this result highlighting the inability of our compounds to alter cardiac rhythm as a side effect.…”

“…Notably, both the tested stereoisomers proved to have mixed mechanisms by combining properties of the different types of the hERG potassium channel activators. Considering that Type 2 activators have been reported as drugs with a risk of repolarization overcorrection that could itself be pro‐arrhythmic, [ 46,47 ] unlike Type 1 activators, [ 48,49 ] the observed mixed mechanism suggests a safer cardiac profile for the most potent RS isomer compared with both the previously reported RR enantiomer and the other Type 2 activators reported in the literature.…”

Molecular Insights into the Rescue Mechanism of an hERG Activator Against Severe LQT2 Mutations.

“…While high-throughput virtual screening has primarily focused on the evaluation of a substantial number of drug-induced arrhythmic compounds, it has also unexpectedly revealed agonists (activators) that can induce inward rectification of I Kr (24). The intricate mechanistic properties of each of these compounds show distinct differences, including delayed deactivation, inhibition of C-type inactivation, increased channel open probability, or a combination of these effects, while also indicating unique binding interactions between each activator and the channel (25). Several activators have been studied as potential candidates for different congenital LQTS mutations (25).…”

“…It is worth noting that the behavior of these activators may vary between different mutants. Nevertheless, most activators primarily target the C-type inactivation mechanism and represent a novel approach to the prevention of ventricular arrhythmias associated with LQTS (25). One such compound is ICA-105574, a derivative of 3-nitro-n-(4-phenoxyphenyl) benzamide and is the most potent I Kr activator to date (26, 27).…”

“…The intricate mechanistic properties of each of these compounds show distinct differences, including delayed deactivation, inhibition of C-type inactivation, increased channel open probability, or a combination of these effects, while also indicating unique binding interactions between each activator and the channel (25). Several activators have been studied as potential candidates for different congenital LQTS mutations (25). However, they carry the risk of inducing early repolarization, leading to an excessive correction of action potential duration (APD), which could ultimately shorten the QT interval to proarrhythmic levels (i.e., SQT).…”