Structure-activity relationships of pentamidine-affected ion channel trafficking and dofetilide mediated rescue
Version of Record online: 21 JUN 2013
© 2013 The British Pharmacological Society
British Journal of Pharmacology
Volume 169, Issue 6, pages 1322–1334, July 2013
How to Cite
Varkevisser, R., Houtman, M. J. C., Linder, T., de Git, K. C. G., Beekman, H. D. M., Tidwell, R. R., IJzerman, A. P., Stary-Weinzinger, A., Vos, M. A. and van der Heyden, M. A. G. (2013), Structure-activity relationships of pentamidine-affected ion channel trafficking and dofetilide mediated rescue. British Journal of Pharmacology, 169: 1322–1334. doi: 10.1111/bph.12208
- Issue online: 21 JUN 2013
- Version of Record online: 21 JUN 2013
- Accepted manuscript online: 16 APR 2013 04:30AM EST
- Manuscript Accepted: 4 APR 2013
- Manuscript Revised: 13 FEB 2013
- Manuscript Received: 29 AUG 2012
- EUTrigTreat. Grant Number: HEALTH-F2-2009-241526
- The Austrian Science Fund. Grant Numbers: P22395, W1232
- University of Vienna
- ion channel trafficking;
- drug-induced trafficking defects;
- chemical substructures;
- Long QT syndrome;
- safety pharmacology
Background and Purpose
Drug interference with normal hERG protein trafficking substantially reduces the channel density in the plasma membrane and thereby poses an arrhythmic threat. The chemical substructures important for hERG trafficking inhibition were investigated using pentamidine as a model drug. Furthermore, the relationship between acute ion channel block and correction of trafficking by dofetilide was studied.
hERG and KIR2.1 trafficking in HEK293 cells was evaluated by Western blot and immunofluorescence microscopy after treatment with pentamidine and six pentamidine analogues, and correction with dofetilide and four dofetilide analogues that displayed different abilities to inhibit IKr. Molecular dynamics simulations were used to address mode, number and type of interactions between hERG and dofetilide analogues.
Structural modifications of pentamidine differentially affected plasma membrane levels of hERG and KIR2.1. Modification of the phenyl ring or substituents directly attached to it had the largest effect, affirming the importance of these chemical residues in ion channel binding. PA-4 had the mildest effects on both ion channels. Dofetilide corrected pentamidine-induced hERG, but not KIR2.1 trafficking defects. Dofetilide analogues that displayed high channel affinity, mediated by pi-pi stacks and hydrophobic interactions, also restored hERG protein levels, whereas analogues with low affinity were ineffective.
Conclusions and Implications
Drug-induced trafficking defects can be minimized if certain chemical features are avoided or ‘synthesized out’; this could influence the design and development of future drugs. Further analysis of such features in hERG trafficking correctors may facilitate the design of a non-blocking corrector for trafficking defective hERG proteins in both congenital and acquired LQTS.