LUF7244 plus Dofetilide Rescues Aberrant K_v11.1 Trafficking and Produces Functional I_Kv11.1

Abstract

Kv11.1 (hERG) channels play a critical role in repolarization of cardiomyocytes during the cardiac action potential (AP). Drug mediated Kv11.1 blockade results in AP prolongation, which poses an increased risk of sudden cardiac death.Many drugs, like pentamidine, interfere with normal Kv11.1 forward trafficking and thus reduce functional Kv11.1 channel densities. Although class III antiarrhythmics, e.g. dofetilide, rescue congenital and acquired forward trafficking defects, this is of little use due to their simultaneous acute channel blocking effect. We aimed to test the ability of a combination of dofetilide plus LUF7244, a Kv11.1 allosteric modulator/activator, to rescue Kv11.1 trafficking and produce functional Kv11.1 current. LUF7244 treatment by itself did not disturb or rescue WT or G601S Kv11.1 trafficking as shown by western blot and immunofluorescence microcopy analysis. Pentamidine-decreased maturation of WT Kv11.1 levels was rescued by 10 μM dofetilide or 10 μM dofetilide + 5 μM LUF7244. In trafficking defective G601S Kv11.1 cells, dofetilide (10 μM) or dofetilide+LUF7244 (10+5 μM) restored Kv11.1 trafficking also, as demonstrated by western blot and immunofluorescence microscopy. LUF7244 (10 μM) increased IKv11.1 despite the presence of dofetilide (1 μM) in WT Kv11.1 cells. In G601S expressing cells, long-term treatment (24-48 h) with LUF7244 (10 μM) and dofetilide (1 μM) increased IKv11.1 compared to non-treated, or acutely treated cells. We conclude that dofetilide plus LUF7244 rescues Kv11.1 trafficking and produces functional IKv11.1. Thus, combined administration of This article has not been copyedited and formatted. The final version may differ from this version.

The ERG1 K+ Channel and Its Role in Neuronal Health and Disease

“…These drugs, however, are linked to drug-induced LQT ( Spector et al, 1996 ). Recently, it was found that the use of blockers and activators in combination could increase the functional expression of ERG1 channels ( Qile et al, 2019 , 2020 ), raising the possibility that these treatments could be used together to increase channel trafficking to the plasma membrane. Nevertheless, these maneuvers need to be studied further, because there is a high possibility that increasing the mutant ERG1 channels will result in additional problems, such as changes in gating or permeability, which could worsen LQT2 or their impact on neuronal function.…”

Pharmacological activation of the hERG K+ channel for the management of the long QT syndrome: A review

“…Further experimental investigations are, however, required to highlight the exact underlying mechanism. Another potential use of great clinical relevance for LUF7244 was highlighted in a recent study showing that pretreatment with a combination of LUF7244 and the high affinity inhibitor dofetilide, but not LUF7244 alone, enhanced the membrane expression of both WT and trafficking defective LQT2‐associated G601S hERG mutant 25 . Class III antiarrhythmic drugs such as dofetilide have been reported to rescue the expression of trafficking defective hERG channels but because of their I Kr / I hERG inhibitory properties, this has been of little clinical relevance 25 .…”

“…13,14 Another proposed target has been the selective activation of I Kr /I hERG by small activator drug molecules (hERG agonists) to increase repolarization reserve and counteract LQTS-associated triggered activity. This potential mechanism-based therapy has been investigated in several in vitro, in vivo, and in silico studies [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] for the management of the effects of both LQT2-associated mutations to hERG1 20,[24][25][26][27][28] and/or pharmacological blockade of the hERG channel. [16][17][18][19][20][21]23,31 Although promising drug candidates, there are still major drawbacks to their preclinical development and consequently none of these drug molecules have to date been trialled in clinical settings.…”

Long QT Syndrome Type 2: Emerging Strategies for Correcting Class 2 KCNH2 (hERG) Mutations and Identifying New Patients

“…However, they could lead to abnormal shortening of the QT interval and increase the risk for deadly arrhythmias like ventricular fibrillation. Qile and colleagues (2020) determined whether the functional expression of Class 2 LQT2 Kv11.1 channels could be increased by culturing cells in I Kr blockers and the I Kr activator LUF7244 [58,59]. LUF7244 is an allosteric I Kr activator that counteracts I Kr blocker induced arrhythmias in dogs.…”