Discovery of novel potent ΔF508‐CFTR correctors that target the nucleotide binding domain

EMBO Molecular Medicine

Norbert Odolczyk³  Janine Fritsch⁶  Caroline Norez¹  Nathalie Servel⁶  Melanie Faria da Cunha⁶  Sara Bitam⁶  Anna Kupniewska⁶  Ludovic Wiszniewski⁴  Julien Colas⁶  Krzysztof Tarnowski⁷  Danielle Tondelier⁶  Ariel Roldan⁸  Emilie L. Saussereau⁶  Patricia Melin-Heschel¹  Grzegorz Wieczorek³  Gergely L. Lukacs⁸  Michal Dadlez⁷  Grazyna Faure⁵  Harald Herrmann²  Mario Ollero⁶  Frédéric Becq¹  Piotr Zielenkiewicz³ 

[1] Université de Poitiers, Institut de Physiologie et Biologie Cellulaires, Poitiers, France;Department of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany;Department of Bioinformatics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warszawa, Poland;Epithelix SARL, CH-1228 Plan-Les-Ouates, Geneva, Switzerland;Unité Récepteurs-Canaux; Institut Pasteur, CNRS, Paris, France;INSERM, U845, Paris, France;Laboratory of Mass Spectrometry, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warszawa, Poland;Department of Physiology, McGill University, Montreal, Canada

关键词: CFTR;    chloride channel;    cystic fibrosis;    drug discovery;    ΔF508‐CFTR correctors;   

DOI  :  10.1002/emmm.201302699

来源: Wiley

【 摘 要 】

Abstract

The deletion of Phe508 (ΔF508) in the first nucleotide binding domain (NBD1) of CFTR is the most common mutation associated with cystic fibrosis. The ΔF508-CFTR mutant is recognized as improperly folded and targeted for proteasomal degradation. Based on molecular dynamics simulation results, we hypothesized that interaction between ΔF508-NBD1 and housekeeping proteins prevents ΔF508-CFTR delivery to the plasma membrane. Based on this assumption we applied structure-based virtual screening to identify new low-molecular-weight compounds that should bind to ΔF508-NBD1 and act as protein–protein interaction inhibitors. Using different functional assays for CFTR activity, we demonstrated that in silico-selected compounds induced functional expression of ΔF508-CFTR in transfected HeLa cells, human bronchial CF cells in primary culture, and in the nasal epithelium of homozygous ΔF508-CFTR mice. The proposed compounds disrupt keratin8-ΔF508-CFTR interaction in ΔF508-CFTR HeLa cells. Structural analysis of ΔF508-NBD1 in the presence of these compounds suggests their binding to NBD1. We conclude that our strategy leads to the discovery of new compounds that are among the most potent correctors of ΔF508-CFTR trafficking defect known to date.

【 授权许可】

CC BY   
Copyright © 2013 EMBO Molecular Medicine

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.