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Published on: November 11, 2022
Allosteric Modulation of Kv11.1 (hERG) Channels Protects Against Drug-Induced Ventricular Arrhythmias
Zhiyi Yu1, Jia Liu1, Jacobus P D van Veldhoven1
1From the Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (Z.Y., J.P.D.v.V., A.P.I., L.H.H.); Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands (J.L., M.J.S., D.A.P., A.A.F.d.V.); and ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (J.L., A.A.F.d.V.).
Insights
Negative allosteric modulators of the human ether-à-go-go-related gene (Kv11.1) channel, like LUF7244, can prevent drug-induced ventricular arrhythmias. This finding suggests combination therapy may allow continued use of some drugs that unintentionally block Kv11.1.
Area of Science:
- Cardiovascular Pharmacology
- Ion Channel Modulation
- Drug Safety
Background:
- Unintentional blockade of the Kv11.1 (hERG) channel by drugs can cause dangerous ventricular arrhythmias.
- Several widely used medications have been withdrawn due to this proarrhythmic risk.
- Investigating Kv11.1 allosteric modulators offers a potential strategy to mitigate this safety concern.
Purpose of the Study:
- To evaluate the efficacy of Kv11.1 allosteric modulators in preventing drug-induced ventricular arrhythmias.
- To identify specific compounds that act as negative allosteric modulators of the Kv11.1 channel.
- To assess the safety and electrophysiological impact of these modulators on cardiac cells.
Main Methods:
- Utilized [(3)H]dofetilide-binding assays to screen for Kv11.1 allosteric modulators.
- Tested compounds VU0405601, ML-T531, and LUF7244 for their effects on dofetilide binding and Kv11.1 channel activity.
- Employed neonatal rat ventricular myocyte (NRVM) monolayers to assess proarrhythmic effects and cellular electrophysiology.
Main Results:
- LUF7244 demonstrated potent negative allosteric modulation of Kv11.1 channel binding.
- LUF7244 pretreatment prevented astemizole- or sertindole-induced action potential prolongation and early afterdepolarizations in NRVMs.
- NRVMs treated with LUF7244 alone showed normal electrophysiological properties, viability, and contractility.
Conclusions:
- Allosteric modulation of the Kv11.1 channel effectively suppresses drug-induced ventricular arrhythmias in vitro.
- This approach prevents arrhythmogenic changes in action potential characteristics.
- Pharmacological combination therapy with Kv11.1 allosteric modulators may enable the safe clinical use of drugs that unintentionally block the Kv11.1 channel.
Background:
Ventricular arrhythmias as a result of unintentional blockade of the Kv11.1 (hERG [human ether-à-go-go-related gene]) channel are a major safety concern in drug development. In past years, several highly prescribed drugs have been withdrawn for their ability to cause such proarrhythmia. Here, we investigated whether the proarrhythmic risk of existing drugs could be reduced by Kv11.1 allosteric modulators.
Methods And Results:
Using [(3)H]dofetilide-binding assays with membranes of human Kv11.1-expressing human embryonic kidney 293 cells, 2 existing compounds (VU0405601 and ML-T531) and a newly synthesized compound (LUF7244) were found to be negative allosteric modulators of dofetilide binding to the Kv11.1 channel, with LUF7244 showing the strongest effect at 10 μmol/L. The Kv11.1 affinities of typical blockers (ie, dofetilide, astemizole, sertindole, and cisapride) were significantly decreased by LUF7244. Treatment of confluent neonatal rat ventricular myocyte (NRVM) monolayers with astemizole or sertindole caused heterogeneous prolongation of action potential duration and a high incidence of early afterdepolarizations on 1-Hz electric point stimulation, occasionally leading to unstable, self-terminating tachyarrhythmias. Pretreatment of NRVMs with LUF7244 prevented these proarrhythmic effects. NRVM monolayers treated with LUF7244 alone displayed electrophysiological properties indistinguishable from those of untreated NRVM cultures. Prolonged exposure of NRVMs to LUF7244 or LUF7244 plus astemizole did not affect their viability, excitability, and contractility as assessed by molecular, immunological, and electrophysiological assays.
Conclusions:
Allosteric modulation of the Kv11.1 channel efficiently suppresses drug-induced ventricular arrhythmias in vitro by preventing potentially arrhythmogenic changes in action potential characteristics, raising the possibility to resume the clinical use of unintended Kv11.1 blockers via pharmacological combination therapy.
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