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A novel triple combination of pharmacological chaperones improves F508del-CFTR correction
Pharmacological chaperones (e.g. VX-809, lumacaftor) that bind directly to F508del-CFTR and correct its mislocalization are promising therapeutics for Cystic Fibrosis (CF). However to date, individual correctors provide only ~4% improvement in lung function measured as FEV1, suggesting that multiple...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065411/ https://www.ncbi.nlm.nih.gov/pubmed/30061653 http://dx.doi.org/10.1038/s41598-018-29276-y |
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author | Carlile, Graeme W. Yang, Qi Matthes, Elizabeth Liao, Jie Radinovic, Stevo Miyamoto, Carol Robert, Renaud Hanrahan, John W. Thomas, David Y. |
author_facet | Carlile, Graeme W. Yang, Qi Matthes, Elizabeth Liao, Jie Radinovic, Stevo Miyamoto, Carol Robert, Renaud Hanrahan, John W. Thomas, David Y. |
author_sort | Carlile, Graeme W. |
collection | PubMed |
description | Pharmacological chaperones (e.g. VX-809, lumacaftor) that bind directly to F508del-CFTR and correct its mislocalization are promising therapeutics for Cystic Fibrosis (CF). However to date, individual correctors provide only ~4% improvement in lung function measured as FEV1, suggesting that multiple drugs will be needed to achieve substantial clinical benefit. Here we examine if multiple sites for pharmacological chaperones exist and can be targeted to enhance the rescue of F508del-CFTR with the premise that additive or synergistic rescue by multiple pharmacological chaperones compared to single correctors indicates that they have different sites of action. First, we found that a combination of the pharmacological chaperones VX-809 and RDR1 provide additive correction of F508del-CFTR. Then using cellular thermal stability assays (CETSA) we demonstrated the possibility of a third pharmacologically important site using the novel pharmacological chaperone tool compound 4-methyl-N-[3-(morpholin-4-yl) quinoxalin-2-yl] benzenesulfonamide (MCG1516A). All three pharmacological chaperones appear to interact with the first nucleotide-binding domain (NBD1). The triple combination of MCG1516A, RDR1, and VX-809 restored CFTR function to >20% that of non-CF cells in well differentiated HBE cells and to much higher levels in other cell types. Thus the results suggest the presence of at least three distinct sites for pharmacological chaperones on F508del-CFTR NBD1, encouraging the development of triple corrector combinations. |
format | Online Article Text |
id | pubmed-6065411 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-60654112018-08-06 A novel triple combination of pharmacological chaperones improves F508del-CFTR correction Carlile, Graeme W. Yang, Qi Matthes, Elizabeth Liao, Jie Radinovic, Stevo Miyamoto, Carol Robert, Renaud Hanrahan, John W. Thomas, David Y. Sci Rep Article Pharmacological chaperones (e.g. VX-809, lumacaftor) that bind directly to F508del-CFTR and correct its mislocalization are promising therapeutics for Cystic Fibrosis (CF). However to date, individual correctors provide only ~4% improvement in lung function measured as FEV1, suggesting that multiple drugs will be needed to achieve substantial clinical benefit. Here we examine if multiple sites for pharmacological chaperones exist and can be targeted to enhance the rescue of F508del-CFTR with the premise that additive or synergistic rescue by multiple pharmacological chaperones compared to single correctors indicates that they have different sites of action. First, we found that a combination of the pharmacological chaperones VX-809 and RDR1 provide additive correction of F508del-CFTR. Then using cellular thermal stability assays (CETSA) we demonstrated the possibility of a third pharmacologically important site using the novel pharmacological chaperone tool compound 4-methyl-N-[3-(morpholin-4-yl) quinoxalin-2-yl] benzenesulfonamide (MCG1516A). All three pharmacological chaperones appear to interact with the first nucleotide-binding domain (NBD1). The triple combination of MCG1516A, RDR1, and VX-809 restored CFTR function to >20% that of non-CF cells in well differentiated HBE cells and to much higher levels in other cell types. Thus the results suggest the presence of at least three distinct sites for pharmacological chaperones on F508del-CFTR NBD1, encouraging the development of triple corrector combinations. Nature Publishing Group UK 2018-07-30 /pmc/articles/PMC6065411/ /pubmed/30061653 http://dx.doi.org/10.1038/s41598-018-29276-y Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Carlile, Graeme W. Yang, Qi Matthes, Elizabeth Liao, Jie Radinovic, Stevo Miyamoto, Carol Robert, Renaud Hanrahan, John W. Thomas, David Y. A novel triple combination of pharmacological chaperones improves F508del-CFTR correction |
title | A novel triple combination of pharmacological chaperones improves F508del-CFTR correction |
title_full | A novel triple combination of pharmacological chaperones improves F508del-CFTR correction |
title_fullStr | A novel triple combination of pharmacological chaperones improves F508del-CFTR correction |
title_full_unstemmed | A novel triple combination of pharmacological chaperones improves F508del-CFTR correction |
title_short | A novel triple combination of pharmacological chaperones improves F508del-CFTR correction |
title_sort | novel triple combination of pharmacological chaperones improves f508del-cftr correction |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065411/ https://www.ncbi.nlm.nih.gov/pubmed/30061653 http://dx.doi.org/10.1038/s41598-018-29276-y |
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