Stereoselective Block of the HERG Potassium Channel by the Class Ia Antiarrhythmic Drug Disopyramide

Overview

Journal Cell Mol Life Sci

Publisher Springer

Specialty Biology

Date 2024 Nov 28

PMID 39607488

Authors

Yihong Zhang

Aziza El Harchi

Andrew F James

Shigetoshi Oiki

Christopher E Dempsey

Jules C Hancox

Affiliations

Soon will be listed here.

Abstract

Potassium channels encoded by human Ether-à-go-go-Related Gene (hERG) are inhibited by diverse cardiac and non-cardiac drugs. Disopyramide is a chiral Class Ia antiarrhythmic that inhibits hERG at clinical concentrations. This study evaluated effects of disopyramide enantiomers on hERG current (I) from hERG expressing HEK 293 cells at 37 °C. S(+) and R(-) disopyramide inhibited wild-type (WT) I with IC values of 3.9 µM and 12.9 µM respectively. The attenuated-inactivation mutant N588K had little effect on the action of S(+) disopyramide but the IC for the R(-) enantiomer was ~ 15-fold that for S(+) disopyramide. The enhanced inactivation mutant N588E only slightly increased the potency of R(-) disopyramide. S6 mutation Y652A reduced S(+) disopyramide potency more than that of R(-) disopyramide (respective IC values ~ 49-fold and 11-fold their WT controls). The F656A mutation also exerted a stronger effect on S(+) than R(-) disopyramide, albeit with less IC elevation. A WT-Y652A tandem dimer exhibited a sensitivity to the enantiomers that was intermediate between that of WT and Y652A, suggesting Y652 groups on adjacent subunits contribute to the binding. Moving the Y (normally at site 652) one residue in the N- terminal (up) direction in N588K hERG markedly increased the blocking potency of R(-) disopyramide. Molecular dynamics simulations using a hERG pore model produced different binding modes for S(+) and R(-) disopyramide consistent with the experimental observations. In conclusion, S(+) disopyramide interacts more strongly with S6 aromatic binding residues on hERG than does R(-) disopyramide, whilst optimal binding of the latter is more reliant on intact inactivation.

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