title: BeKm-1, a peptide inhibitor of human ether-a-go-go-related gene potassium currents, prolongs QTc intervals in isolated rabbit heart.
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.affiliation: Department of Investigative Toxicology, Amgen Inc., Thousand Oaks, CA 91320, USA. yqu@amgen.com
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Qu
authors.forename: Mei
authors.initials: M
authors.lastname: Fang
authors.forename: Baoxi
authors.initials: B
authors.lastname: Gao
authors.forename: Ray W
authors.initials: RW
authors.lastname: Chui
authors.forename: Hugo M
authors.initials: HM
authors.lastname: Vargas
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000502:physiology; D005260:Female; D057809:HEK293 Cells; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D010455:Peptides / Q000494:pharmacology / Q000633:toxicity; D011817:Rabbits; D012604:Scorpion Venoms / Q000494:pharmacology* / Q000633:toxicity
chemical_list: C425305:BeKm-1 toxin; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D010455:Peptides; D012604:Scorpion Venoms