A small molecule voltage-sensor modulator enhances the function of the cardiac Na_V1.5 channel

The development of new drug molecules targeting voltage-gated ion channels has declined in the last decade, highlighting the need for novel lead compounds with new mechanisms of action. We previously identified NZ-58 as a small-molecule inhibitor of the H_V1 proton channel. At 50 μM NZ-58 also potently blocked voltage-gated Na⁺ and K⁺ channels, but not the non-voltage-gated ones, suggesting an interaction with the voltage-sensor domains (VSDs). At lower concentrations (0.5-10 μM), it altered gating kinetics with minimal amplitude changes. NZ-58 significantly slowed the current activation kinetics of the channels, as well as the VSD-linked fast inactivation of the Na_V1.5 channel, thereby substantially increasing total charge transfer. The loss-of-function Brugada mutant Na_V1.5-R1632C was similarly enhanced by NZ-58, but the effect was not present on slowly inactivating K_V channels. Gating current measurements confirmed a direct effect on VSD movement. The voltage-dependence of activation and steady-state inactivation were not altered in Na_V1.5, but its recovery from inactivation was slowed. NZ-58 was able to bind to the channels in the closed state, not requiring the activated conformation of the VSDs, and it could exert its effects when applied from either side of the membrane. Being non-selective, NZ-58 is not an ideal lead compound for therapeutic ion channel modulation. However, considering that many clinically used ion channel modulators are multi-target "dirty drugs" that still achieve therapeutic benefit, and the unique features of its interactions with voltage-gated channels, we suggest that NZ-58 is worthy of further investigations as a prospective ion channel modulator lead compound.