Structure‐activity relationships of pentamidine‐affected ion channel trafficking and dofetilide mediated rescue. (21st June 2013)

• Record Type: Journal Article
• Authors: Varkevisser, R; Houtman, M J C; Linder, T; de, K C G; Beekman, H D M; Tidwell, R R; IJzerman, A P; Stary‐Weinzinger, A; Vos, M A; van der, M A G
• Is Part Of: British journal of pharmacology. Volume 169:Number 6(2013:Jul.)
• Page Start: 1322
• Page End: 1334
• Publication Date: 2013-06-21
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12208
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12208-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>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.</p> </sec> <sec id="bph12208-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>hERG and K<sub>IR</sub>2.1 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 <italic>I</italic><sub>Kr</sub>. Molecular dynamics simulations were used to address mode, number and type of interactions between hERG and dofetilide analogues.</p> </sec> <sec id="bph12208-sec-0003" sec-type="section"> <title>Key Results</title> <p>Structural modifications of pentamidine differentially affected plasma membrane levels of hERG and K<sub>IR</sub>2.1. 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 K<sub>IR</sub>2.1 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.</p> </sec> <sec id="bph12208-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>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.</p> </sec> </abstract>