Molecular Insights into the Rescue Mechanism of an hERG Activator Against Severe LQT2 Mutations

Mutations in the hERG potassium channel are a major cause of long QT syndrome type 2 (LQT2), which can lead to sudden cardiac death. The hERG channel plays a critical role in the repolarization of the myocardial action potential, and loss-of-function mutations prolong cardiac repolarization. In this study, we investigated the efficacy and mechanism of ICA-105574, an hERG activator, in shortening the duration of cardiac repolarization in severe LQT2 variants. We characterized the in vivo efficacy of ICA-105574 in shortening the QT duration in an animal model and the in vitro I _Kr current in cellular models mimicking severe hERG channel mutations (A561V, G628S, and L779P). We then used molecular dynamics simulations to investigate the molecular mechanisms of ICA-105574 action. In vivo, ICA-105574 significantly shortened the QT interval. LQT2 mutations drastically reduced I _Kr amplitude and suppressed tail currents in cellular models. ICA-105574 restored I _Kr in A561V and G628S. Finally, in silico data showed that ICA-105574 stabilizes a pattern of interactions similar to gain-of-function SQT1 mutations and can reverse the G628S modifications, through an allosteric network linking the binding site to the selectivity filter and the S5P turret helix, thereby restoring its K ⁺ ion permeability. Our results support the development of hERG activators as pharmacological molecules against some severe LQT2 mutations and suggest that molecular dynamics simulations can be used to test the ability of molecules to modulate hERG function in silico, paving the way for the rational design of new hERG activators.