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Towards next generation therapies for cystic fibrosis: Folding, function and pharmacology of CFTR()

The treatment of cystic fibrosis (CF) has been transformed by orally-bioavailable small molecule modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), which restore function to CF mutants. However, CFTR modulators are not available to all people with CF and better modulators...

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Autores principales: Bose, Samuel J., Krainer, Georg, Ng, Demi R.S., Schenkel, Mathias, Shishido, Hideki, Yoon, Jae Seok, Haggie, Peter M., Schlierf, Michael, Sheppard, David N., Skach, William R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052731/
https://www.ncbi.nlm.nih.gov/pubmed/31902693
http://dx.doi.org/10.1016/j.jcf.2019.12.009
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author Bose, Samuel J.
Krainer, Georg
Ng, Demi R.S.
Schenkel, Mathias
Shishido, Hideki
Yoon, Jae Seok
Haggie, Peter M.
Schlierf, Michael
Sheppard, David N.
Skach, William R.
author_facet Bose, Samuel J.
Krainer, Georg
Ng, Demi R.S.
Schenkel, Mathias
Shishido, Hideki
Yoon, Jae Seok
Haggie, Peter M.
Schlierf, Michael
Sheppard, David N.
Skach, William R.
author_sort Bose, Samuel J.
collection PubMed
description The treatment of cystic fibrosis (CF) has been transformed by orally-bioavailable small molecule modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), which restore function to CF mutants. However, CFTR modulators are not available to all people with CF and better modulators are required to prevent disease progression. Here, we review selectively recent advances in CFTR folding, function and pharmacology. We highlight ensemble and single-molecule studies of CFTR folding, which provide new insight into CFTR assembly, its perturbation by CF mutations and rescue by CFTR modulators. We discuss species-dependent differences in the action of the F508del-CFTR mutation on CFTR expression, stability and function, which might influence pharmacological studies of CFTR modulators in CF animal models. Finally, we illuminate the identification of combinations of two CFTR potentiators (termed co-potentiators), which restore therapeutically-relevant levels of CFTR activity to rare CF mutations. Thus, mechanistic studies of CFTR folding, function and pharmacology inform the development of highly effective CFTR modulators.
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spelling pubmed-70527312020-03-09 Towards next generation therapies for cystic fibrosis: Folding, function and pharmacology of CFTR() Bose, Samuel J. Krainer, Georg Ng, Demi R.S. Schenkel, Mathias Shishido, Hideki Yoon, Jae Seok Haggie, Peter M. Schlierf, Michael Sheppard, David N. Skach, William R. J Cyst Fibros Article The treatment of cystic fibrosis (CF) has been transformed by orally-bioavailable small molecule modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), which restore function to CF mutants. However, CFTR modulators are not available to all people with CF and better modulators are required to prevent disease progression. Here, we review selectively recent advances in CFTR folding, function and pharmacology. We highlight ensemble and single-molecule studies of CFTR folding, which provide new insight into CFTR assembly, its perturbation by CF mutations and rescue by CFTR modulators. We discuss species-dependent differences in the action of the F508del-CFTR mutation on CFTR expression, stability and function, which might influence pharmacological studies of CFTR modulators in CF animal models. Finally, we illuminate the identification of combinations of two CFTR potentiators (termed co-potentiators), which restore therapeutically-relevant levels of CFTR activity to rare CF mutations. Thus, mechanistic studies of CFTR folding, function and pharmacology inform the development of highly effective CFTR modulators. Elsevier 2020-03 /pmc/articles/PMC7052731/ /pubmed/31902693 http://dx.doi.org/10.1016/j.jcf.2019.12.009 Text en © 2020 The Authors. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bose, Samuel J.
Krainer, Georg
Ng, Demi R.S.
Schenkel, Mathias
Shishido, Hideki
Yoon, Jae Seok
Haggie, Peter M.
Schlierf, Michael
Sheppard, David N.
Skach, William R.
Towards next generation therapies for cystic fibrosis: Folding, function and pharmacology of CFTR()
title Towards next generation therapies for cystic fibrosis: Folding, function and pharmacology of CFTR()
title_full Towards next generation therapies for cystic fibrosis: Folding, function and pharmacology of CFTR()
title_fullStr Towards next generation therapies for cystic fibrosis: Folding, function and pharmacology of CFTR()
title_full_unstemmed Towards next generation therapies for cystic fibrosis: Folding, function and pharmacology of CFTR()
title_short Towards next generation therapies for cystic fibrosis: Folding, function and pharmacology of CFTR()
title_sort towards next generation therapies for cystic fibrosis: folding, function and pharmacology of cftr()
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052731/
https://www.ncbi.nlm.nih.gov/pubmed/31902693
http://dx.doi.org/10.1016/j.jcf.2019.12.009
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