Structure-activity relationships of pentamidine-affected ion channel trafficking and dofetilide mediated rescue
| Autor: | Adriaan P. IJzerman, M. Houtman, M A Vos, Anna Stary-Weinzinger, H D M Beekman, Rosanne Varkevisser, Tobias Linder, M. A. G. van der Heyden, K. C. G. de Git, Richard R. Tidwell |
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| Rok vydání: | 2013 |
| Předmět: |
Pharmacology
congenital hereditary and neonatal diseases and abnormalities 0303 health sciences biology Chemistry hERG Kir2.1 Dofetilide Potassium channel blocker 030204 cardiovascular system & hematology 03 medical and health sciences 0302 clinical medicine medicine biology.protein Biophysics Structure–activity relationship cardiovascular diseases Ion channel binding Ion channel 030304 developmental biology medicine.drug Pentamidine |
| Zdroj: | British Journal of Pharmacology |
| ISSN: | 0007-1188 |
| DOI: | 10.1111/bph.12208 |
| Popis: | 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. Experimental Approach 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. Key Results 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. |
| Databáze: | OpenAIRE |
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