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Updated: Aug 7, 2026

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Molecular mechanisms for drug interactions with hERG that cause long QT syndrome
Phillip J Stansfeld1, Michael J Sutcliffe, John S Mitcheson
1University of Leicester, Department of Cell Physiology & Pharmacology, Leicester, UK. pjs33@le.ac.uk
Abstract:
The human ether-a-go-go-related gene (hERG) encodes the pore-forming alpha-subunit of a voltage-gated potassium (K(+)) channel. A variety of unrelated compounds reduce K(+ )current in the heart by blocking the pore or disrupting trafficking of the hERG channel to the membrane surface. This induces a syndrome known as long QT, which arises from abnormalities in action potential repolarisation and can degenerate into lethal cardiac arrhythmias. As a result, this undesirable side effect has severely hindered safe drug development. This review describes progress in understanding the molecular basis for drug binding to hERG, outlines the characteristics of hERG ligands and discusses experimental and in silico approaches for identifying compounds with QT liabilities. Recent developments should enable recognition of hERG-positive compounds at the early stages of their development.
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