Block of wild-type and inactivation-deficient human ether-a-go-go-related gene K+ channels by halofantrine.

Halofantrine is an antimalarial drug developed as a treatment of P. falciparum resistant to chloroquine. However, halofantrine can also induce long QT syndrome (LQTS) and torsades de pointes, a potentially life-threatening ventricular arrhythmia. Drug-induced LQTS is usually caused by block of the human ether-a-go-go-related gene (HERG) channels that conduct the rapid delayed rectifier K(+) current, I(Kr), in the heart. Here we show that halofantrine preferentially blocks open and inactivated HERG channels heterologously expressed in Xenopus laevis oocytes. The half-maximal inhibitory concentration (IC(50)) for block of wild-type (WT) HERG was 1.0 microM. As we reported previously for other HERG channel blockers, the potency of halofantrine was reduced by mutation to Ala of aromatic residues (Y652, F656) located in the S6 domain, or a Val (V625) located in the pore helix. Halofantrine at a concentration 10 microM did not affect the transient outward potassium channel, Kv4.3, the slow delayed rectifier potassium channel, KvLQT1+minK and inward rectifier potassium channel, Kir2.1. An inactivation deficient mutant (G628C/S631C HERG) was only slightly less sensitive (IC(50)=2.0 microM). The rate of block onset by halofantrine at 0 mV was used to estimate the apparent association (k(on)) and dissociation (k(off)) rate constants for drug binding. For WT and G628C/S631C HERG, k(on) was similar (0.0114 and 0.0163 M(-1)/s(-1) respectively). In contrast, k(off) was significantly faster for G628C/S631C (0.357 s(-1)) than WT (0.155 s(-1)), and explains the observed decrease in drug potency for the inactivation-deficient mutant channel. We conclude that halofantrine requires channels to open before it can gain access to its binding site located in the central cavity of the HERG channel.