CFTR

Official Full Name

CF transmembrane conductance regulator

Organism

Homo sapiens

GeneID

1080

Background

This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

Synonyms

CF; MRP7; ABC35; ABCC7; CFTR/MRP; TNR-CFTR; dJ760C5.1;

Bio Chemical Class

ABC transporter

Protein Sequence

MQRSPLEKASVVSKLFFSWTRPILRKGYRQRLELSDIYQIPSVDSADNLSEKLEREWDRELASKKNPKLINALRRCFFWRFMFYGIFLYLGEVTKAVQPLLLGRIIASYDPDNKEERSIAIYLGIGLCLLFIVRTLLLHPAIFGLHHIGMQMRIAMFSLIYKKTLKLSSRVLDKISIGQLVSLLSNNLNKFDEGLALAHFVWIAPLQVALLMGLIWELLQASAFCGLGFLIVLALFQAGLGRMMMKYRDQRAGKISERLVITSEMIENIQSVKAYCWEEAMEKMIENLRQTELKLTRKAAYVRYFNSSAFFFSGFFVVFLSVLPYALIKGIILRKIFTTISFCIVLRMAVTRQFPWAVQTWYDSLGAINKIQDFLQKQEYKTLEYNLTTTEVVMENVTAFWEEGFGELFEKAKQNNNNRKTSNGDDSLFFSNFSLLGTPVLKDINFKIERGQLLAVAGSTGAGKTSLLMVIMGELEPSEGKIKHSGRISFCSQFSWIMPGTIKENIIFGVSYDEYRYRSVIKACQLEEDISKFAEKDNIVLGEGGITLSGGQRARISLARAVYKDADLYLLDSPFGYLDVLTEKEIFESCVCKLMANKTRILVTSKMEHLKKADKILILHEGSSYFYGTFSELQNLQPDFSSKLMGCDSFDQFSAERRNSILTETLHRFSLEGDAPVSWTETKKQSFKQTGEFGEKRKNSILNPINSIRKFSIVQKTPLQMNGIEEDSDEPLERRLSLVPDSEQGEAILPRISVISTGPTLQARRRQSVLNLMTHSVNQGQNIHRKTTASTRKVSLAPQANLTELDIYSRRLSQETGLEISEEINEEDLKECFFDDMESIPAVTTWNTYLRYITVHKSLIFVLIWCLVIFLAEVAASLVVLWLLGNTPLQDKGNSTHSRNNSYAVIITSTSSYYVFYIYVGVADTLLAMGFFRGLPLVHTLITVSKILHHKMLHSVLQAPMSTLNTLKAGGILNRFSKDIAILDDLLPLTIFDFIQLLLIVIGAIAVVAVLQPYIFVATVPVIVAFIMLRAYFLQTSQQLKQLESEGRSPIFTHLVTSLKGLWTLRAFGRQPYFETLFHKALNLHTANWFLYLSTLRWFQMRIEMIFVIFFIAVTFISILTTGEGEGRVGIILTLAMNIMSTLQWAVNSSIDVDSLMRSVSRVFKFIDMPTEGKPTKSTKPYKNGQLSKVMIIENSHVKKDDIWPSGGQMTVKDLTAKYTEGGNAILENISFSISPGQRVGLLGRTGSGKSTLLSAFLRLLNTEGEIQIDGVSWDSITLQQWRKAFGVIPQKVFIFSGTFRKNLDPYEQWSDQEIWKVADEVGLRSVIEQFPGKLDFVLVDGGCVLSHGHKQLMCLARSVLSKAKILLLDEPSAHLDPVTYQIIRRTLKQAFADCTVILCEHRIEAMLECQQFLVIEENKVRQYDSIQKLLNERSLFRQAISPSDRVKLFPHRNSSKCKSKPQIAALKEETEEEVQDTRL

Open

Disease

Bowel habit change, Chronic obstructive pulmonary disease, Cystic fibrosis, Intrathoracic organs injury, Viral intestinal infection

Approved Drug

4 +

Clinical Trial Drug

10 +

Discontinued Drug

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Detailed Information

Cystic fibrosis transmembrane conductance regulator (CFTR) is a multi-domain membrane protein that belongs to the family of adenine nucleotide-binding cassette transporters consisting of two nucleotide binding domains (NBDs), two transmembrane domains and a unique regulatory domain. It is expressed in the submucosal glands, airway surface epithelium, and many other epithelial organs. CFTR functions as an anion channel, which is regulated by protein kinase A-dependent phosphorylation of its regulatory domain and binding of ATP to the NBDs, and conducts bicarbonate and Cl^-. Mutations in CFTR result in a basic ion transport defect, which is characterized by deficient cyclic adenosine monophosphate-dependent anion secretion and enhanced ENaC-mediated Na⁺ absorption in cystic fibrosis (CF) airways.

Figure 1. CFTR, basic ion transport defects and cystic fibrosis lung disease (Mall M A, Hartl D. 2014)

CFTR Mutations

So far, more than 2,000 CFTR mutations have been identified in CF patients, a significant number for a 1480-residue protein, even though a subset of these variations is likely to have no functional consequence. The approximately 200 mutations that are known to cause CF are traditionally classified based on how they affect the encoded protein, in other words, whether they reduce or abolish the production of the full-length CFTR polypeptide (truncation mutations, Class I; alternative splicing, Class V), impair protein trafficking/maturation (Class II), damage regulation of channel gating (Class III) or anion permeation by the open channel pore (Class IV), or reduce the lifetime of the channel protein in the apical membrane (Class VI). The most common mutation is a deletion of phenylalanine at position 508 (DF508) in NBD1, which impairs protein folding, plasma membrane expression, stability and function of CFTR. Other mutants, such as G551D and R117H, are expressed on the cell membrane but do not gate properly. Currently, most treatments offer symptomatic relief, including pancreatic enzyme supplements to aid digestion, antibiotics to prevent and treat infection, mucus-thinning drugs to clear the airway, and lung transplants.

CFTR Modulators

Recently, a class of drugs termed CFTR modulators have become available for subgroups of people with CF. There are several modes of action of CFTR modulators, but they differ fundamentally from other CF therapies in that they are designed to improve or even restore the function of defective CFTR protein and are effective for people with only certain CFTR variants. Highly effective CFTR modulators can provide transformational benefit to people with CF, producing improvements across multiple relevant endpoints in clinical trials and care [lung function, risk of pulmonary exacerbation, weight, linear growth, respiratory symptoms, rate of lung function (e.g. FEV1) decline over time, mucociliary clearance, inflammatory burden, intestinal pH, sweat chloride (SC), detection of CF pathogens, etc.]. Thus, an important goal of the CF research and care community is to provide CFTR-based therapies to every individual with CF. Conceptually, this includes highly effective CFTR modulators, but can also be extended to nucleotide and cell-based strategies (such as gene transfer, mRNA correction or replacement, chromosomal mutation correction by gene editing, stem cell replacement).

CFTR modulators are small molecules that target specific defects caused by mutations in the CFTR gene and they can be divided into five main groups: read-through agents, correctors, potentiators, stabilizers and amplifiers.

Rescuing the Protein Synthesis: Read-through agents could benefit CF patients bearing class I mutations, as the presence of a premature stop codon (class Ia) precludes protein synthesis of full-length CFTR.
Rescuing the Protein Folding and Trafficking: Correctors are small-molecules that enhance the conformational stability of CFTR, leading to greater efficacy of protein folding and rescuing the trafficking of the mature CFTR to the plasma membrane (PM).
Restoring the Channel Conductance: Potentiators are drugs that increase channel open probability, enhancing CFTR channel activity.
Stabilizing the Protein at the Cell Surface: Stabilizers are agents that anchor the CFTR channel at the PM and decrease protein degradation rate, thus correcting the instability of class VI mutants.
Correcting the Splicing: Antisense oligonucleotides-based therapy is an emerging method to correct class V mutations caused by alternative splicing that generates aberrant mRNA variants.

Currently, Vertex Pharmaceuticals has developed two correctors and one potentiator, which are available to patients. Besides, many other candidates to enhance the function of CFTR are in the drug discovery pipeline. All of these CFTR modulators were discovered by intensive high throughput screening and iterative medicinal chemistry optimization. The presence of CFTR modulators in the market has affected positively the clinical outcomes of CF patients, representing a new dawn in their lives. Although there is still a long way to go in completely restoring a healthy life for all CF patients, research from the bench to the clinic is moving forward at an accelerated pace toward precision medicines.

References:

Mall M A, Hartl D. CFTR: cystic fibrosis and beyond. 2014.
Liu F, et al. Structural identification of a hotspot on CFTR for potentiation. Science, 2019, 364(6446): 1184-1188.
Clancy J P, et al. CFTR modulator theratyping: current status, gaps and future directions. Journal of Cystic Fibrosis, 2019, 18(1): 22-34.
Csanády L, et al. Structure, gating, and regulation of the CFTR anion channel. Physiological Reviews, 2019, 99(1): 707-738.
Lopes-Pacheco M. CFTR modulators: shedding light on precision medicine for cystic fibrosis. Frontiers in pharmacology, 2016, 7: 275.

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