CFTR F508del binds CFTR correctors

Stable Identifier
R-HSA-9700266
Type
Reaction [binding]
Species
Homo sapiens
Compartment
cytosol, endoplasmic reticulum membrane
ReviewStatus
5/5
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CFTR F508del binds CFTR correctors
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Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR is a chloride channel in the apical membrane of epithelial cells where it functions to maintain salt and fluid homeostasis. CF is the most common autosomal recessive disease in Caucasian populations. It is a life-limiting condition, with respiratory failure secondary to end-stage lung disease as the main cause of mortality. The majority of disease-causing mutations lead to misfolding of CFTR, including the deletion of phenylalanine at position 508, F508del, occurring in around 90% of patient alleles. Misfolding results in a defective channel where the mutant protein is either released to the cell surface, where it displays dysfunctionality, or is retained in the ER and translocated into the cytosol for degradation by the proteasome.

CFTR correctors have been developed that rescue misfolded mutant CFTRs from the ER that can then translocate to the cell surface to allow any mutant to gain functionality (Mijnders et al. 2017). Small molecule CFTR correctors such as the approved drugs elexacaftor, lumacaftor and tezacaftor and the next-generation corrector bamocaftor have the potential to improve up to 90% of CF patients with the F508del mutation when combined with a CFTR potentiator such as ivacaftor (Keating et al. 2018, Davies et al. 2018, Heijerman et al. 2019).
Literature References
PubMed ID Title Journal Year
30334692 VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles

Rowe, SM, McKone, EF, Daines, C, Xuan, F, Young, T, Ramsey, BW, Burr, L, Mall, MA, Keating, D, Sass, LA, Robertson, S, Waltz, D, Tullis, E, Taylor-Cousar, JL, VX16-445-001 Study Group, -, Van Goor, F, Marigowda, G, Savage, J, Moskowitz, SM, McKee, CM, Simard, C

N. Engl. J. Med. 2018
31679946 Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial

Van Braeckel, E, Rowe, SM, McKone, EF, Xuan, F, Ramsey, BW, Zhang, Y, Mall, MA, McCoy, KS, Waltz, D, Tullis, E, Downey, DG, Taylor-Cousar, JL, X17-445-103 Trial Group, -, Heijerman, HGM, Ahluwalia, N, Marigowda, G, Moskowitz, SM, McKee, CM, Welter, JJ, Sosnay, PR, Simard, C

Lancet 2019
29055231 Correcting CFTR folding defects by small-molecule correctors to cure cystic fibrosis

Mijnders, M, Braakman, I, Kleizen, B

Curr Opin Pharmacol 2017
30334693 VX-659-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles

Horsley, A, Rowe, SM, McKone, EF, Xuan, F, Young, T, Ramsey, BW, Mall, MA, Uluer, A, Plant, BJ, Prais, D, Davies, JC, Shilling, RA, Robertson, S, Waltz, D, Tullis, E, Taylor-Cousar, JL, Van Goor, F, Moskowitz, SM, McKee, CM, Brown, C, VX16-659-101 Study Group, -, Simard, C

N. Engl. J. Med. 2018
Participants
Input
Output
Participates
as an event of
Disease
Name Identifier Synonyms
cystic fibrosis DOID:1485 mucoviscidosis, CF
Authored
Jassal, B  (2021-03-25)
Reviewed
Huddart, R  (2022-03-01)
Created
Jassal, B  (2020-09-15)
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