Cargando…
Discovery of novel potent ΔF508-CFTR correctors that target the nucleotide binding domain
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 hypo...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Blackwell Publishing Ltd
2013
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799575/ https://www.ncbi.nlm.nih.gov/pubmed/23982976 http://dx.doi.org/10.1002/emmm.201302699 |
_version_ | 1782287896603000832 |
---|---|
author | Odolczyk, Norbert Fritsch, Janine Norez, Caroline Servel, Nathalie da Cunha, Melanie Faria Bitam, Sara Kupniewska, Anna Wiszniewski, Ludovic Colas, Julien Tarnowski, Krzysztof Tondelier, Danielle Roldan, Ariel Saussereau, Emilie L Melin-Heschel, Patricia Wieczorek, Grzegorz Lukacs, Gergely L Dadlez, Michal Faure, Grazyna Herrmann, Harald Ollero, Mario Becq, Frédéric Zielenkiewicz, Piotr Edelman, Aleksander |
author_facet | Odolczyk, Norbert Fritsch, Janine Norez, Caroline Servel, Nathalie da Cunha, Melanie Faria Bitam, Sara Kupniewska, Anna Wiszniewski, Ludovic Colas, Julien Tarnowski, Krzysztof Tondelier, Danielle Roldan, Ariel Saussereau, Emilie L Melin-Heschel, Patricia Wieczorek, Grzegorz Lukacs, Gergely L Dadlez, Michal Faure, Grazyna Herrmann, Harald Ollero, Mario Becq, Frédéric Zielenkiewicz, Piotr Edelman, Aleksander |
author_sort | Odolczyk, Norbert |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3799575 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Blackwell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-37995752013-10-23 Discovery of novel potent ΔF508-CFTR correctors that target the nucleotide binding domain Odolczyk, Norbert Fritsch, Janine Norez, Caroline Servel, Nathalie da Cunha, Melanie Faria Bitam, Sara Kupniewska, Anna Wiszniewski, Ludovic Colas, Julien Tarnowski, Krzysztof Tondelier, Danielle Roldan, Ariel Saussereau, Emilie L Melin-Heschel, Patricia Wieczorek, Grzegorz Lukacs, Gergely L Dadlez, Michal Faure, Grazyna Herrmann, Harald Ollero, Mario Becq, Frédéric Zielenkiewicz, Piotr Edelman, Aleksander EMBO Mol Med Research Articles 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. Blackwell Publishing Ltd 2013-10 2013-08-27 /pmc/articles/PMC3799575/ /pubmed/23982976 http://dx.doi.org/10.1002/emmm.201302699 Text en © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO http://creativecommons.org/licenses/by/2.5/ Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation. |
spellingShingle | Research Articles Odolczyk, Norbert Fritsch, Janine Norez, Caroline Servel, Nathalie da Cunha, Melanie Faria Bitam, Sara Kupniewska, Anna Wiszniewski, Ludovic Colas, Julien Tarnowski, Krzysztof Tondelier, Danielle Roldan, Ariel Saussereau, Emilie L Melin-Heschel, Patricia Wieczorek, Grzegorz Lukacs, Gergely L Dadlez, Michal Faure, Grazyna Herrmann, Harald Ollero, Mario Becq, Frédéric Zielenkiewicz, Piotr Edelman, Aleksander Discovery of novel potent ΔF508-CFTR correctors that target the nucleotide binding domain |
title | Discovery of novel potent ΔF508-CFTR correctors that target the nucleotide binding domain |
title_full | Discovery of novel potent ΔF508-CFTR correctors that target the nucleotide binding domain |
title_fullStr | Discovery of novel potent ΔF508-CFTR correctors that target the nucleotide binding domain |
title_full_unstemmed | Discovery of novel potent ΔF508-CFTR correctors that target the nucleotide binding domain |
title_short | Discovery of novel potent ΔF508-CFTR correctors that target the nucleotide binding domain |
title_sort | discovery of novel potent δf508-cftr correctors that target the nucleotide binding domain |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799575/ https://www.ncbi.nlm.nih.gov/pubmed/23982976 http://dx.doi.org/10.1002/emmm.201302699 |
work_keys_str_mv | AT odolczyknorbert discoveryofnovelpotentdf508cftrcorrectorsthattargetthenucleotidebindingdomain AT fritschjanine discoveryofnovelpotentdf508cftrcorrectorsthattargetthenucleotidebindingdomain AT norezcaroline discoveryofnovelpotentdf508cftrcorrectorsthattargetthenucleotidebindingdomain AT servelnathalie discoveryofnovelpotentdf508cftrcorrectorsthattargetthenucleotidebindingdomain AT dacunhamelaniefaria discoveryofnovelpotentdf508cftrcorrectorsthattargetthenucleotidebindingdomain AT bitamsara discoveryofnovelpotentdf508cftrcorrectorsthattargetthenucleotidebindingdomain AT kupniewskaanna discoveryofnovelpotentdf508cftrcorrectorsthattargetthenucleotidebindingdomain AT wiszniewskiludovic discoveryofnovelpotentdf508cftrcorrectorsthattargetthenucleotidebindingdomain AT colasjulien discoveryofnovelpotentdf508cftrcorrectorsthattargetthenucleotidebindingdomain AT tarnowskikrzysztof discoveryofnovelpotentdf508cftrcorrectorsthattargetthenucleotidebindingdomain AT tondelierdanielle discoveryofnovelpotentdf508cftrcorrectorsthattargetthenucleotidebindingdomain AT roldanariel discoveryofnovelpotentdf508cftrcorrectorsthattargetthenucleotidebindingdomain AT saussereauemiliel discoveryofnovelpotentdf508cftrcorrectorsthattargetthenucleotidebindingdomain AT melinheschelpatricia discoveryofnovelpotentdf508cftrcorrectorsthattargetthenucleotidebindingdomain AT wieczorekgrzegorz discoveryofnovelpotentdf508cftrcorrectorsthattargetthenucleotidebindingdomain AT lukacsgergelyl discoveryofnovelpotentdf508cftrcorrectorsthattargetthenucleotidebindingdomain AT dadlezmichal discoveryofnovelpotentdf508cftrcorrectorsthattargetthenucleotidebindingdomain AT fauregrazyna discoveryofnovelpotentdf508cftrcorrectorsthattargetthenucleotidebindingdomain AT herrmannharald discoveryofnovelpotentdf508cftrcorrectorsthattargetthenucleotidebindingdomain AT olleromario discoveryofnovelpotentdf508cftrcorrectorsthattargetthenucleotidebindingdomain AT becqfrederic discoveryofnovelpotentdf508cftrcorrectorsthattargetthenucleotidebindingdomain AT zielenkiewiczpiotr discoveryofnovelpotentdf508cftrcorrectorsthattargetthenucleotidebindingdomain AT edelmanaleksander discoveryofnovelpotentdf508cftrcorrectorsthattargetthenucleotidebindingdomain |