QT prolongation through hERG K(+) channel blockade: current knowledge and strategies for the early prediction during drug development

Med Res Rev. 2005 Mar;25(2):133-66. doi: 10.1002/med.20019.


Prolongation of the QT interval of the electrocardiogram is a typical effect of Class III antiarrhythmic drugs, achieved through blockade of potassium channels. In the past decade, evidence has accrued that several classes of drugs used for non-cardiovascular indications may prolong the QT interval with the same mechanism (namely, human ether-a-go-go-related gene (hERG) K(+) channel blockade). The great interest in QT prolongation is because of several reasons. First, drug-induced QT prolongation increases the likelihood of a polymorphous ventricular arrhythmia (namely, torsades de pointes, TdP), which may cause syncope and degenerate into ventricular fibrillation and sudden death. Second, the fact that several classes of drugs, such as antihistamines, fluoroquinolones, macrolides, and neuroleptics may cause the long QT syndrome (LQTS) raises the question whether this is a class effect (e.g., shared by all agents of a given pharmacological class) or a specific effect of single agents within a class. There is now consensus that, in most cases, only a few agents within a therapeutic class share the ability to significantly affect hERG K(+) channels. These compounds should be identified as early as possible during drug development. Third, QT prolongation and interaction with hERG K(+) channels have become surrogate markers of cardiotoxicity and have received increasing regulatory attention. This review briefly outlines the mechanisms leading to QT prolongation and the different strategies that can be followed to predict this unwanted effect. In particular, it will focus on the approaches recently proposed for the in silico screening of new compounds.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cation Transport Proteins / chemistry
  • Electrocardiography
  • Ether-A-Go-Go Potassium Channels
  • Humans
  • Inhibitory Concentration 50
  • Long QT Syndrome / genetics*
  • Long QT Syndrome / metabolism*
  • Models, Biological
  • Models, Chemical
  • Potassium / chemistry
  • Potassium Channels / chemistry
  • Potassium Channels, Voltage-Gated / chemistry*
  • Protein Structure, Secondary
  • Structure-Activity Relationship
  • Time Factors
  • Torsades de Pointes / pathology


  • Cation Transport Proteins
  • Ether-A-Go-Go Potassium Channels
  • KCNH6 protein, human
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • Potassium