hERG potassium channels and the structural basis of drug-induced arrhythmias

Chem Res Toxicol. 2008 May;21(5):1005-10. doi: 10.1021/tx800035b. Epub 2008 May 1.

Abstract

hERG potassium channels have a critical role in the normal electrical activity of the heart. The block of hERG channels can cause the drug-induced form of long QT syndrome, a cardiac disorder that carries an increased risk of cardiac arrhythmias and sudden death. hERG channels are extraordinarily sensitive to block by large numbers of structurally diverse drugs. In previous years, the risk of compounds causing this cardiotoxic side effect has been a common reason for the failure of compounds in preclinical safety trials. Pharmaceutical companies have successfully utilized and developed higher throughput techniques for the early detection of compounds that block hERG, and this has helped reduce the number of compounds that fail in the late stages of development. Nevertheless, this screening-based approach is expensive, consumes chemistry resources, and bypasses the problem rather than shedding light on it. Crystal structures of potassium channels have facilitated studies into the structural basis for the gating and block of hERG channels. Most drugs bind within the inner cavity, and the individual amino acids that form the drug binding site have been identified by site-directed mutagenesis approaches. Gating processes have an important influence on the drug-binding site. Recent advances in our understanding of channel activation and inactivation are providing insight into why hERG channels are more susceptible to block than other K (+) channels. Knowledge of the structure of the drug-binding site and precise nature of interactions with drug molecules should assist efforts to develop drugs without the propensity to cause cardiac arrhythmias.

Publication types

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

MeSH terms

  • Arrhythmias, Cardiac / chemically induced*
  • Arrhythmias, Cardiac / metabolism*
  • Binding Sites
  • Cardiotoxins / chemistry
  • Cardiotoxins / toxicity*
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
  • Ether-A-Go-Go Potassium Channels / chemistry*
  • Ether-A-Go-Go Potassium Channels / metabolism*
  • Humans
  • Pharmaceutical Preparations / chemistry
  • Protein Conformation

Substances

  • Cardiotoxins
  • Ether-A-Go-Go Potassium Channels
  • Pharmaceutical Preparations