Dissociative States: hERG Channel (Kv11.1) Modulators That Enhance Dissociation of Drugs From Their Blocking Receptor

HomeCirculation: Arrhythmia and ElectrophysiologyVol. 9, No. 4Dissociative States: hERG Channel (Kv11.1) Modulators That Enhance Dissociation of Drugs From Their Blocking Receptor Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBDissociative States: hERG Channel (Kv11.1) Modulators That Enhance Dissociation of Drugs From Their Blocking ReceptorPotential New Therapeutic Drugs Saman Rezazadeh, PhD, MD and Henry Duff, MD Saman RezazadehSaman Rezazadeh From the Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. and Henry DuffHenry Duff From the Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. Originally published12 Apr 2016https://doi.org/10.1161/CIRCEP.116.004003Circulation: Arrhythmia and Electrophysiology. 2016;9:e004003Sudden cardiac death secondary to drug-induced long QT syndrome is a major safety concern and has led to withdrawal of several high-profile drugs, such as cisapride and astemizole, from the market. Although these drugs have different chemical structures, they all block the rapid delayed rectifier K+ current (IKr) with high potency. The hERG channel (Kv11.1) encoded by the hERG gene is responsible for this current. This channel has a high affinity for wide spectrum of compounds compared with other ion channels mainly because of the presence of unique aromatic amino acids in the S6 domain of hERG.1 This in turn has created a major challenge for development of new drugs.2 In fact, it is now a routine practice in the pharmaceutical industry to screen compounds for their ability to block hERG early in preclinical safety assessments according to the Food and Drug Administration guidelines. This in turn leads to elimination of a large number of potentially beneficial compounds from chemical libraries.See Article by Yu et alInterestingly, screening libraries of compounds for their blocking effect on hERG has resulted in discovery of many hERG activators/modulators. These drugs increase current flow through hERG via various mechanisms that include slowing of deactivation, removal of inactivation, and facilitation of activation.3 In theory, hERG channel activators could have the potential to normalize the QT interval in acquired or congenital long QT syndromes.4 In fact, the proarrhythmic effects of dofetilide can be reversed, in vitro, by application of hERG channel activators.5 The draw back in the use of hERG activators clinically has been their inherent ability to shorten the QT interval, possibly to the point of causing arrhythmia.Given the strain that is placed on drug discovery and also withdrawal of several previously successful drugs because of their QT prolonging properties, it is important to develop reproducible, physiological, and clinically translatable techniques to examine the effect of hERG channel activators and their interaction with long QT inducing drugs. In this issue, Yu et al,6 by using membranes of HEK 293 cells expressing hERG for in vitro radioligand assay, show that a newly synthesized hERG modulator (LUF7244) diminishes the binding affinity of potent hERG blockers, such as dofetilide, astemizole, sertindole, and cisapride. Increased concentrations of this modulator resulted in reduced specific binding of radioactive dofetilide, with Hill coefficient >1, suggesting allosteric interaction rather than direct competition for the same binding site. This notion was fortified by demonstration of altered dissociation rate constant in the presence of LUF7244. This is in agreement with previous findings that openers/modulators may exert their effect by interacting with the channel at sites separate from the pore, where the class III drugs bind.7 Interestingly, the authors showcase a clever mean to assay the effect of LUF7244 on hERG channel blockers in a physiological setting by using cultured neonatal rate ventricular myocytes. They used high-resolution optical mapping to record action potentials from cells grown to confluence. With this technique, LUF7244 reversed the prolonging effect of astemizole on action potential duration and prevented induction of early after depolarization. Surprisingly, in the absence of hERG blockers, LUF7244 did not shorten action potential duration.Lack of shortening of action potential duration by LUF7244 was not examined further in their article. This could be because of off-target effect of LUF7244 on other ion channels. For example, NS1643, a known activator of hERG, blocks KCNQ1 current, which is responsible for slow delayed rectifier K+ current (IKs).8 If the ratio of blocking activity at hERG and KCNQ1 balance each other out, then action potential duration will not change significantly, which could be a beneficial feature as it would prevent short QT syndrome. Therefore, it is important to assess the effect of LUF7244 and future hERG activators on a range of ion channels to ensure the absence of unwanted off-target effect.This article raises 2 interesting questions. First, can hERG modulators/activators be used in combination with drugs that are known to block hERG to mitigate the long QT side effect? This has an immense clinical prospect because it will allow for reintroduction of previously successful drugs and can potentially accelerate drug discovery and development. A significant number of chemicals are eliminated from libraries during drug discovery because of their affinity to hERG. Therefore, by having the ability to counteract this effect, there will be more compounds available to screen for use in variety of diseases. In the future, through mapping the binding site and mechanism of action of various activators, more potent activators will surely be developed.The second question is can the assays developed by Yu et al6 be used as a high throughput screening strategy? Although patch clamp remains the gold standard in studying the biophysical properties of channels and determining the details by which drugs interact with them, it is technically challenging with low throughput. Here, the authors demonstrate the use of cultured neonatal rat myocytes and optical mapping to assess for action potential duration. Neonatal cardiomyocytes have the ability to grow, divide, and differentiate; therefore, they can be used for long-term cell culture applications. Consequently, combination of these cells and high-resolution optical mapping can potentially be expanded to a high throughput screening modality. The advantage of this technique over existing assays is that it is a physiological screen, capable of determining the effect of a compound on the action potential duration and potential for evoking early after depolarization. Even so, patch-clamp studies of LUF7244 seem essential to clarify its detailed molecular mechanism(s) of action. A detailed understanding of its state-dependent pharmacological affects seems critical. Site-directed mutagenesis may provide insights as to the topology of its allosteric-binding site on the hERG (KCNH2) channel. Enhanced description of its electrophysiological effects seems an important next step.A recent article by Yu et al9 proposes interesting potential mechanism(s) for increased dissociation of 3H-dofetilide and 3H-astemizole from the hERG channel by an allosteric modulator (LUF6200). Potassium ions both enhance the allosteric effect of LUF6200 and shift the LUF6200 dose–response curve to the left. Furthermore, their studies suggested a positive cooperativity between LUF6200 and potassium ions. Residence of potassium ions in the selectivity filter of hERG is critical to the C-type inactivation process. Moreover, C-type inactivation state seems to play a pivotal role in stabilizing the dofetilide-associated state of the channel by preventing its dissociation. Alteration of the residence of potassium ions near the C-type inactivation gate (selectivity filter) would shift voltage dependence of inactivation. Modifying C-type inactivation would thus allow dissociation of dofetilide and astemizole from its binding site in the pore. Patch-clamp studies will be necessary to test this hypothesis. Even so, there could be >1 binding site in hERG or binding sites in other ion channels that can indirectly alter dissociation of dofetilide and astemizole from their binding sites. Further studies of this interesting new compound are warranted.DisclosuresThe authors have received funding from the Alberta Heart and Stroke Foundation.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Henry J. Duff, MD, University of Calgary, HRIC GC73, 3280 Hospital Dr NW, Calgary, AB T2N 4N1, Canada. E-mail [email protected]References1. Sanguinetti MC, Mitcheson JS.Predicting drug-hERG channel interactions that cause acquired long QT syndrome.Trends Pharmacol Sci. 2005; 26:119–124. doi: 10.1016/j.tips.2005.01.003.CrossrefMedlineGoogle Scholar2. Haverkamp W, Breithardt G, Camm AJ, Janse MJ, Rosen MR, Antzelevitch C, Escande D, Franz M, Malik M, Moss A, Shah R.The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology.Eur Heart J. 2000; 21:1216–1231. doi: 10.1053/euhj.2000.2249.CrossrefMedlineGoogle Scholar3. Zhou J, Augelli-Szafran CE, Bradley JA, Chen X, Koci BJ, Volberg WA, Sun Z, Cordes JS.Novel potent human ether-a-go-go-related gene (hERG) potassium channel enhancers and their in vitro antiarrhythmic activity.Mol Pharmacol. 2005; 68:876–884. doi: 10.1124/mol.105.014035.CrossrefMedlineGoogle Scholar4. Seebohm G.Activators of cation channels: potential in treatment of channelopathies.Mol Pharmacol. 2005; 67:585–588. doi: 10.1124/mol.104.010173.CrossrefMedlineGoogle Scholar5. Kang J, Chen XL, Wang H, Ji J, Cheng H, Incardona J, Reynolds W, Viviani F, Tabart M, Rampe D.Discovery of a small molecule activator of the human ether-a-go-go-related gene (HERG) cardiac K+ channel.Mol Pharmacol. 2005; 67:827–836. doi: 10.1124/mol.104.006577.CrossrefMedlineGoogle Scholar6. Yu Z, Liu J, van Veldhoven JPD, IJzerman AP, Schalij MJ, Pijnappels DA, Heitman LH, de Vries AAF.Allosteric modulation of Kv11.1 (hERG) channels protects against drug-induced ventricular arrhythmias.Circ Arrhythm Electrophysiol. 2016; 9:e003439. doi: 10.1161/CIRCEP.115.003439.LinkGoogle Scholar7. Potet F, Lorinc AN, Chaigne S, Hopkins CR, Venkataraman R, Stepanovic SZ, Lewis LM, Days E, Sidorov VY, Engers DW, Zou B, Afshartous D, George AL, Campbell CM, Balser JR, Li M, Baudenbacher FJ, Lindsley CW, Weaver CD, Kupershmidt S.Identification and characterization of a compound that protects cardiac tissue from human Ether-à-go-go-related gene (hERG)-related drug-induced arrhythmias.J Biol Chem. 2012; 287:39613–39625. doi: 10.1074/jbc.M112.380162.CrossrefMedlineGoogle Scholar8. Hansen RS, Diness TG, Christ T, Demnitz J, Ravens U, Olesen SP, Grunnet M.Activation of human ether-a-go-go-related gene potassium channels by the diphenylurea 1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea (NS1643).Mol Pharmacol. 2006; 69:266–277. doi: 10.1124/mol.105.015859.CrossrefMedlineGoogle Scholar9. Yu Z, Klaasse E, Heitman LH, Ijzerman AP.Allosteric modulators of the hERG K(+) channel: radioligand binding assays reveal allosteric characteristics of dofetilide analogs.Toxicol Appl Pharmacol. 2014; 274:78–86. doi: 10.1016/j.taap.2013.10.024.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By van Veldhoven J, Campostrini G, van Gessel C, Ward-van Oostwaard D, Liu R, Mummery C, Bellin M and IJzerman A (2021) Targeting the Kv11.1 (hERG) channel with allosteric modulators. Synthesis and biological evaluation of three novel series of LUF7346 derivatives, European Journal of Medicinal Chemistry, 10.1016/j.ejmech.2020.113033, 212, (113033), Online publication date: 1-Feb-2021. April 2016Vol 9, Issue 4 Advertisement Article InformationMetrics © 2016 American Heart Association, Inc.https://doi.org/10.1161/CIRCEP.116.004003PMID: 27071827 Originally publishedApril 12, 2016 Keywordsaction potentialseditorialslong QT syndromePDF download Advertisement SubjectsAnimal Models of Human DiseaseArrhythmiasElectrophysiologyIon Channels/Membrane TransportSudden Cardiac Death

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