The human ether-a-go-go (hERG) gene encodes the voltage-activated, potassium-selective channel that regulates the repolarisation phase in the cardiac action potential. Genetic mutations in these channels are primarily attributed to the cause of Type 2 Long QT syndrome (LQT2) which can lead to sudden death. More than 200 putative disease-causing mutations in hERG have been identified in affected families to date.
Over the last two decades, several compounds have been proposed as pharmacological rescuers in long QT syndrome. Among these, ICA-1055754 and RPR260243, are prominent candidates based on preliminary studies in animal models.
Here we propose to rationalise the action of these molecules, as well as of newly developed within an ongoing collaboration, by using molecular dynamics simulations. We will systematically compare their effect on ions permeation and conformational dynamics with the wild-type protein and with mutations known to increase the activity of the protein.
This comparison will ideally reveal pattern of interactions to be exploited to modulate the behaviour of the channel and that consequently will guide and support parallel experiments aiming to improve IKr activators. This project is a new line of development intended to pursue from these early steps to a first in clinical trial study.
University of Milano, Italy