Molecular mechanisms for drug interactions with hERG that cause long QT syndrome.
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.
Stansfeld
Phillip J
PJ
University of Leicester, Department of Cell Physiology & Pharmacology, Leicester, UK. pjs33@le.ac.uk
Sutcliffe
Michael J
MJ
Mitcheson
John S
JS
D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D064420:Drug-Related Side Effects and Adverse Reactions / Q000150:complications* / Q000235:genetics / Q000378:metabolism*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008133:Long QT Syndrome / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human