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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

Overview of the most advance CFTR modulators in preclinical and clinical studies, with regard to the class of CFTR mutations and the primary defect of the corresponding mutant protein.Abbreviations: CFTR, cystic fibrosis transmembrane conductance regulator; PTC, premature termination codon; EGCG, epigallocatechin gallate; ER, endoplasmic reticulum; Ub, ubiquitin; mRNA, messenger RNA.
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f3-cpaa-8-127: Overview of the most advance CFTR modulators in preclinical and clinical studies, with regard to the class of CFTR mutations and the primary defect of the corresponding mutant protein.Abbreviations: CFTR, cystic fibrosis transmembrane conductance regulator; PTC, premature termination codon; EGCG, epigallocatechin gallate; ER, endoplasmic reticulum; Ub, ubiquitin; mRNA, messenger RNA.

Mentions: With the development of high-throughput screening (HTS) assays allowing rapid screening of thousands of small molecules, many families of chemical structures have been identified. Thanks to expanding knowledge of the structure and function of CFTR, and to increased understanding of the different functional consequences of CFTR mutations, structure–activity relationship and optimization of the most promising lead compounds have led to a series of potential pharmacological therapies for CF to correct CFTR defects at different levels.114–117 CFTR modulators can be categorized according to the class of mutation or dysfunction that they aim at targeting (Figure 3 and Table 2).


Cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis: current perspectives
Overview of the most advance CFTR modulators in preclinical and clinical studies, with regard to the class of CFTR mutations and the primary defect of the corresponding mutant protein.Abbreviations: CFTR, cystic fibrosis transmembrane conductance regulator; PTC, premature termination codon; EGCG, epigallocatechin gallate; ER, endoplasmic reticulum; Ub, ubiquitin; mRNA, messenger RNA.
© Copyright Policy
Related In: Results  -  Collection

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

f3-cpaa-8-127: Overview of the most advance CFTR modulators in preclinical and clinical studies, with regard to the class of CFTR mutations and the primary defect of the corresponding mutant protein.Abbreviations: CFTR, cystic fibrosis transmembrane conductance regulator; PTC, premature termination codon; EGCG, epigallocatechin gallate; ER, endoplasmic reticulum; Ub, ubiquitin; mRNA, messenger RNA.
Mentions: With the development of high-throughput screening (HTS) assays allowing rapid screening of thousands of small molecules, many families of chemical structures have been identified. Thanks to expanding knowledge of the structure and function of CFTR, and to increased understanding of the different functional consequences of CFTR mutations, structure–activity relationship and optimization of the most promising lead compounds have led to a series of potential pharmacological therapies for CF to correct CFTR defects at different levels.114–117 CFTR modulators can be categorized according to the class of mutation or dysfunction that they aim at targeting (Figure 3 and Table 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