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Potentiator ivacaftor abrogates pharmacological correction of ΔF508 CFTR in cystic fibrosis

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Cholon, Deborah M., Quinney, Nancy L., Fulcher, M. Leslie, Esther, Charles R., Das, Jhuma, Dokholyan, Nikolay V., Randell, Scott H., Boucher, Richard C. +1 more·2014·Science Translational Medicine
DOI 10.1126/scitranslmed.3008680PMC PMC4272825
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Abstract

Ivacaftor, a CFTR potentiator drug used for cystic fibrosis, destabilizes rescued ΔF508 CFTR and interferes with the action of drugs that correct CFTR function.

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  • Chronic treatment with 1 μM VX-770 significantly decreased functional correction by VX-809 in the presence of acute potentiator addition.

    “Chronic treatment with 1 μM VX-770, a concentration that is therapeutically reached in respiratory epithelia (34), was reported to significantly decrease the functional correction by VX-809 in the presence of acute potentiator addition (Figure 3, A and B), as observed in CF-HBE (35, 36) and CF-HNE (21).”

    From Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination (2020) · cites this paper as [36]

    The Results section on dose dependence (Fig. 4; page unavailable) reports that chronic 1 µM VX-770 reduced VX-809-corrected functional responses and eliminated responses to acute VX-770. It does not report a statistically significant reduction for 1 µM versus VX-809 alone; the stated significant comparison is between the 1 µM and 5 µM conditions. (LLM, conf=0.84)

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Cited by

Sorted by citations

Authors
Cholon, D. M., Quinney, N. L., Fulcher, M. L., Esther, C. R., Das, J., Dokholyan, N. V., Randell, S. H., Boucher, R. C., & Gentzsch, M.
Affiliations
University of North Carolina at Chapel Hill (US)
Corresponding author
Gentzsch, Martina
ORCID
Venue
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Published
2014-07-23
Volume
6
Issue
246
Pages
246ra96-246ra96
ISSN
  • 1946-6234 (ISSN-L)
  • 1946-6242
DOI
10.1126/scitranslmed.3008680
PMC
PMC4272825
OpenAlex
W2124886725
Cited by
320
References
2
Citations by year
2026: 8 · 2025: 10 · 2024: 18 · 2023: 14 · 2022: 21 · 2021: 22 · 2020: 33 · 2019: 26 · 2018: 44 · 2017: 27 · 2016: 43 · 2015: 44 · 2014: 10
FWCI
31.60
Type
journal article
Language
en
Open access
Locations
  • Science Translational Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • UNC Libraries
Funders
  • Else Kröner-Fresenius-Stiftung
  • National Institutes of Health (5k23hl089708-05, DK065988, ES10126)
  • National Heart, Lung, and Blood Institute (K23-HL089708, 1K23HL089708, P01HL110873, HL110873, DK065988)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK065988)
  • National Institute of Environmental Health Sciences (P30ES010126)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Inhalation and Respiratory Drug Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Keywords
cystic fibrosis, CFTR, F508del mutation, ivacaftor, lumacaftor, CFTR potentiators, CFTR correctors, drug combination effects, chronic drug administration, airway epithelial cells, G551D mutation
MeSH terms
Aminophenols, Bronchi, Cystic Fibrosis, Dose-Response Relationship, Drug, Epithelial Cells, Humans, Models, Molecular, Quinolones, Cystic Fibrosis Transmembrane Conductance Regulator, Mutant Proteins, Protein Stability

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