Details

Autor(en) / Beteiligte

• Varkevisser, R
• Houtman, M J C
• Linder, T
• Git, K C G
• Beekman, H D M
• Tidwell, R R
• IJzerman, A P
• Stary‐Weinzinger, A
• Vos, M A
• Heyden, M A G

Titel

Structure‐activity relationships of pentamidine‐affected ion channel trafficking and dofetilide mediated rescue

Ist Teil von

• British journal of pharmacology, 2013-07, Vol.169 (6), p.1322-1334

Ort / Verlag

England: Blackwell Publishing Ltd

Erscheinungsjahr

2013

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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.