Structural implications of hERG K⁺ channel block by a high-affinity minimally structured blocker.

ABSTRACT: Cardiac potassium channels encoded by human ether-à-go-go-related gene (hERG) are major targets for structurally diverse drugs associated with acquired long QT syndrome. This study characterized hERG channel inhibition by a minimally structured high-affinity hERG inhibitor, Cavalli-2, composed of three phenyl groups linked by polymethylene spacers around a central amino group, chosen to probe the spatial arrangement of side chain groups in the high-affinity drug-binding site of the hERG pore. hERG current (I_hERG) recorded at physiological temperature from HEK293 cells was inhibited with an IC₅₀ of 35.6 nm with time and voltage dependence characteristic of blockade contingent upon channel gating. Potency of Cavalli-2 action was markedly reduced for attenu

SUBMITTER: Helliwell MV 

PROVIDER: S-EPMC5936838 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature