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BeKm-1, a peptide inhibitor of human ether-a-go-go-related gene potassium currents, prolongs QTc intervals in isolated rabbit heart.
J Pharmacol Exp Ther. 2011 Apr; 337(1):2-8.JP

Abstract

Drug-induced cardiac arrhythmia, specifically Torsades de pointes, is associated with QT/QTc interval prolongation, thus prolongation of the QT interval is considered as a biomarker for Torsades de pointes risk (N Engl J Med 350:1013-1022, 2004). Specific inhibition of human ether-a-go-go-related gene (hERG) potassium channels has been recognized as the main mechanism for QT prolongation (Cardiovasc Res 58:32-45, 2003). This mechanism has been demonstrated for a variety of small-molecule agents, which access the inner pore of the hERG channel preferentially from inside the cell. Peptide inhibitors of hERG, such as BeKm-1, interact with the extracellular amino acid residues close to the external pore region of the channel. In this study, the isolated rabbit heart was used to assess whether BeKm-1 could induce QTc prolongation like dofetilide and N-[4-[[1-[2-(6-methyl-2-pyridinyl)ethyl]-4-piperidinyl]carbonyl]phenyl]methanesulfonamide (E-4031). Five hearts were perfused with 10 and 100 nM BeKm-1 sequentially. ECG parameters and left ventricular contractility were measured with spontaneously beating hearts. Both concentrations of BeKm-1 prolonged QTc intervals significantly and concentration-dependently (4.7 and 16.3% at 10 and 100 nM, respectively). When evaluated for their inhibitory effect in a hERG functional assay, BeKm-1, dofetilide, and E-4031 caused QTc prolongation at concentrations that caused significant hERG channel inhibition. Lastly, two polyclonal anti-hERG antibodies were also assessed in the hERG channel assay and found to be devoid of any inhibitory effect. These results indicated that the isolated rabbit heart assay can be used to measure QTc changes caused by specific hERG inhibition by peptides that specifically block the external pore region of the channel.

Authors+Show Affiliations

Department of Investigative Toxicology, Amgen Inc., Thousand Oaks, CA 91320, USA. yqu@amgen.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

21205913

Citation

Qu, Yusheng, et al. "BeKm-1, a Peptide Inhibitor of Human Ether-a-go-go-related Gene Potassium Currents, Prolongs QTc Intervals in Isolated Rabbit Heart." The Journal of Pharmacology and Experimental Therapeutics, vol. 337, no. 1, 2011, pp. 2-8.
Qu Y, Fang M, Gao B, et al. BeKm-1, a peptide inhibitor of human ether-a-go-go-related gene potassium currents, prolongs QTc intervals in isolated rabbit heart. J Pharmacol Exp Ther. 2011;337(1):2-8.
Qu, Y., Fang, M., Gao, B., Chui, R. W., & Vargas, H. M. (2011). BeKm-1, a peptide inhibitor of human ether-a-go-go-related gene potassium currents, prolongs QTc intervals in isolated rabbit heart. The Journal of Pharmacology and Experimental Therapeutics, 337(1), 2-8. https://doi.org/10.1124/jpet.110.176883
Qu Y, et al. BeKm-1, a Peptide Inhibitor of Human Ether-a-go-go-related Gene Potassium Currents, Prolongs QTc Intervals in Isolated Rabbit Heart. J Pharmacol Exp Ther. 2011;337(1):2-8. PubMed PMID: 21205913.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - BeKm-1, a peptide inhibitor of human ether-a-go-go-related gene potassium currents, prolongs QTc intervals in isolated rabbit heart. AU - Qu,Yusheng, AU - Fang,Mei, AU - Gao,Baoxi, AU - Chui,Ray W, AU - Vargas,Hugo M, Y1 - 2010/12/23/ PY - 2011/1/6/entrez PY - 2011/1/6/pubmed PY - 2011/5/20/medline SP - 2 EP - 8 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 337 IS - 1 N2 - Drug-induced cardiac arrhythmia, specifically Torsades de pointes, is associated with QT/QTc interval prolongation, thus prolongation of the QT interval is considered as a biomarker for Torsades de pointes risk (N Engl J Med 350:1013-1022, 2004). Specific inhibition of human ether-a-go-go-related gene (hERG) potassium channels has been recognized as the main mechanism for QT prolongation (Cardiovasc Res 58:32-45, 2003). This mechanism has been demonstrated for a variety of small-molecule agents, which access the inner pore of the hERG channel preferentially from inside the cell. Peptide inhibitors of hERG, such as BeKm-1, interact with the extracellular amino acid residues close to the external pore region of the channel. In this study, the isolated rabbit heart was used to assess whether BeKm-1 could induce QTc prolongation like dofetilide and N-[4-[[1-[2-(6-methyl-2-pyridinyl)ethyl]-4-piperidinyl]carbonyl]phenyl]methanesulfonamide (E-4031). Five hearts were perfused with 10 and 100 nM BeKm-1 sequentially. ECG parameters and left ventricular contractility were measured with spontaneously beating hearts. Both concentrations of BeKm-1 prolonged QTc intervals significantly and concentration-dependently (4.7 and 16.3% at 10 and 100 nM, respectively). When evaluated for their inhibitory effect in a hERG functional assay, BeKm-1, dofetilide, and E-4031 caused QTc prolongation at concentrations that caused significant hERG channel inhibition. Lastly, two polyclonal anti-hERG antibodies were also assessed in the hERG channel assay and found to be devoid of any inhibitory effect. These results indicated that the isolated rabbit heart assay can be used to measure QTc changes caused by specific hERG inhibition by peptides that specifically block the external pore region of the channel. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/21205913/BeKm_1_a_peptide_inhibitor_of_human_ether_a_go_go_related_gene_potassium_currents_prolongs_QTc_intervals_in_isolated_rabbit_heart_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=21205913 DB - PRIME DP - Unbound Medicine ER -