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Cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis: current perspectives

View Article: PubMed Central - PubMed

ABSTRACT

Mutations of the CFTR gene cause cystic fibrosis (CF), the most common recessive monogenic disease worldwide. These mutations alter the synthesis, processing, function, or half-life of CFTR, the main chloride channel expressed in the apical membrane of epithelial cells in the airway, intestine, pancreas, and reproductive tract. Lung disease is the most critical manifestation of CF. It is characterized by airway obstruction, infection, and inflammation that lead to fatal tissue destruction. In spite of great advances in early and multidisciplinary medical care, and in our understanding of the pathophysiology, CF is still considerably reducing the life expectancy of patients. This review highlights the current development in pharmacological modulators of CFTR, which aim at rescuing the expression and/or function of mutated CFTR. While only Kalydeco® and Orkambi® are currently available to patients, many other families of CFTR modulators are undergoing preclinical and clinical investigations. Drug repositioning and personalized medicine are particularly detailed in this review as they represent the most promising strategies for restoring CFTR function in CF.

No MeSH data available.


Related in: MedlinePlus

Predicted topology of CFTR protein.Notes: It is composed of two repeated units made of a MSD followed by a NBD. The two repeated units are linked by a R domain. The MSDs consist of six hydrophobic transmembrane helices (or TMD). Several transmembrane helices contain one or more charged amino acids that control anion permeability. Extracellular loop 4 (between TMD7 and TMD8) contains two N-glycosylation sites.Abbreviations: CFTR, cystic fibrosis transmembrane conductance regulator; MSD, membrane-spanning domain; NBD, nucleotide-binding domain; TMD: transmembrane domain; R, regulatory domain.
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f2-cpaa-8-127: Predicted topology of CFTR protein.Notes: It is composed of two repeated units made of a MSD followed by a NBD. The two repeated units are linked by a R domain. The MSDs consist of six hydrophobic transmembrane helices (or TMD). Several transmembrane helices contain one or more charged amino acids that control anion permeability. Extracellular loop 4 (between TMD7 and TMD8) contains two N-glycosylation sites.Abbreviations: CFTR, cystic fibrosis transmembrane conductance regulator; MSD, membrane-spanning domain; NBD, nucleotide-binding domain; TMD: transmembrane domain; R, regulatory domain.

Mentions: The CFTR gene contains 27 exons spanning 250 kb on the long arm of chromosome 7 (7q31.2).8,9 The encoded mRNA is ~6.5 kb long and is translated into a protein of 1,480 amino acids. The CFTR protein belongs to the adenosine triphosphate (ATP)-binding cassette (ABC) transporters and functions as an adenosine 3′,5′-cyclic monophosphate (cAMP)-regulated chloride channel in a variety of polarized epithelial cells.10 The predicted protein structure is shown in Figure 2.


Cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis: current perspectives
Predicted topology of CFTR protein.Notes: It is composed of two repeated units made of a MSD followed by a NBD. The two repeated units are linked by a R domain. The MSDs consist of six hydrophobic transmembrane helices (or TMD). Several transmembrane helices contain one or more charged amino acids that control anion permeability. Extracellular loop 4 (between TMD7 and TMD8) contains two N-glycosylation sites.Abbreviations: CFTR, cystic fibrosis transmembrane conductance regulator; MSD, membrane-spanning domain; NBD, nucleotide-binding domain; TMD: transmembrane domain; R, regulatory domain.
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Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC5036583&req=5

f2-cpaa-8-127: Predicted topology of CFTR protein.Notes: It is composed of two repeated units made of a MSD followed by a NBD. The two repeated units are linked by a R domain. The MSDs consist of six hydrophobic transmembrane helices (or TMD). Several transmembrane helices contain one or more charged amino acids that control anion permeability. Extracellular loop 4 (between TMD7 and TMD8) contains two N-glycosylation sites.Abbreviations: CFTR, cystic fibrosis transmembrane conductance regulator; MSD, membrane-spanning domain; NBD, nucleotide-binding domain; TMD: transmembrane domain; R, regulatory domain.
Mentions: The CFTR gene contains 27 exons spanning 250 kb on the long arm of chromosome 7 (7q31.2).8,9 The encoded mRNA is ~6.5 kb long and is translated into a protein of 1,480 amino acids. The CFTR protein belongs to the adenosine triphosphate (ATP)-binding cassette (ABC) transporters and functions as an adenosine 3′,5′-cyclic monophosphate (cAMP)-regulated chloride channel in a variety of polarized epithelial cells.10 The predicted protein structure is shown in Figure 2.

View Article: PubMed Central - PubMed

ABSTRACT

Mutations of the CFTR gene cause cystic fibrosis (CF), the most common recessive monogenic disease worldwide. These mutations alter the synthesis, processing, function, or half-life of CFTR, the main chloride channel expressed in the apical membrane of epithelial cells in the airway, intestine, pancreas, and reproductive tract. Lung disease is the most critical manifestation of CF. It is characterized by airway obstruction, infection, and inflammation that lead to fatal tissue destruction. In spite of great advances in early and multidisciplinary medical care, and in our understanding of the pathophysiology, CF is still considerably reducing the life expectancy of patients. This review highlights the current development in pharmacological modulators of CFTR, which aim at rescuing the expression and/or function of mutated CFTR. While only Kalydeco® and Orkambi® are currently available to patients, many other families of CFTR modulators are undergoing preclinical and clinical investigations. Drug repositioning and personalized medicine are particularly detailed in this review as they represent the most promising strategies for restoring CFTR function in CF.

No MeSH data available.


Related in: MedlinePlus