Multiple hERG channel blocking pathways: implications for macromolecules

• Published in: Trends in pharmacological sciences (Regular ed.) Vol. 45; no. 8; pp. 671 - 677
• Main Author: Zünkler, Bernd J.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.08.2024
• Subjects: hERG channel; hERG current blocker; lipid bilayer; pore; turret; turret; lipid bilayer; hERG channel; hERG current blocker; pore
• ISSN: 0165-6147; 1873-3735; 1873-3735
• DOI: 10.1016/j.tips.2024.06.003

Numerous non-cardiovascular drugs induce QT interval prolongations on electrocardiography and life-threatening torsades de pointes cardiac arrhythmias by blocking human ether-à-go-go-related gene (hERG) currents.The canonical binding sites for these small, basic compounds are located in the pore of the channel, accessible from the cytosolic side.Using cryoelectron microscopy, the molecular structures of both the hERG channel without ligand and the hERG channel in complex with a blocker (astemizole) have been recently determined.There are several putative noncanonical binding sites for hERG current blockers located outside the pore; that is, extracellular binding sites [especially the long extracellular loop between S5 and S6 (the ‘turret’)], intracellular binding sites at the channel entrance, hydrophobic pathways to plasma membrane-exposed side pockets, and modification of plasma membrane lipids altering channel gating. Numerous non-cardiovascular drugs have a potential to induce life-threatening torsades de pointes (TdP) ventricular cardiac arrhythmias by blocking human ether-à-go-go-related gene (hERG) currents via binding to the channel’s inner cavity. Identification of the hERG current-inhibiting properties of candidate drugs is performed focusing on binding sites in the channel pore. It has been suggested that biologicals have a low likelihood of hERG current inhibition, since their poor diffusion across the plasma membrane prevents them from reaching the binding site in the channel pore. However, biologicals could influence hERG channel function by binding to ‘unconventional’ noncanonical binding sites. This Opinion gives an overview on noncanonical blockers of hERG channels that might be of relevance for the assessment of the possible torsadogenic potential of macromolecular therapeutics. Numerous non-cardiovascular drugs have a potential to induce life-threatening torsades de pointes (TdP) ventricular cardiac arrhythmias by blocking human ether-à-go-go-related gene (hERG) currents via binding to the channel’s inner cavity. Identification of the hERG current-inhibiting properties of candidate drugs is performed focusing on binding sites in the channel pore. It has been suggested that biologicals have a low likelihood of hERG current inhibition, since their poor diffusion across the plasma membrane prevents them from reaching the binding site in the channel pore. However, biologicals could influence hERG channel function by binding to ‘unconventional’ noncanonical binding sites. This Opinion gives an overview on noncanonical blockers of hERG channels that might be of relevance for the assessment of the possible torsadogenic potential of macromolecular therapeutics.