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Cited by 287Cystic Fibrosis Research AdvancesIon Transport and Channel RegulationInhalation and Respiratory Drug Delivery

Some gating potentiators, including VX-770, diminish ΔF508-CFTR functional expression

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Veit, Guido, Avramescu, Radu G., Perdomo, Doranda, Phuan, Puay-Wah, Bagdany, Miklos, Apaja, Pirjo M., Borot, Florence, Szollosi, Daniel +5 more·2014·Science Translational Medicine
DOI 10.1126/scitranslmed.3008889PMC PMC4467693
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Abstract

Ivacaftor, a potentiator of ΔF508-CFTR channel function in cystic fibrosis, reduces the ability of corrector drugs to rescue the ΔF508-CFTR membrane trafficking defect.

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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 [35]

    The Results section on chloride conductance reports that 24 hours of VX-770 reduced VX-809–corrected ΔF508-CFTR current in primary HBE cells, with current measured after acute potentiator addition. But the reported chronic dose for those functional measurements was 100 nM, not the claimed 1 μM; our copy mentions 1 μM in a different, pulse-chase experiment (Materials and Methods). No page numbers are available in our copy. (LLM, conf=0.88)

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Authors
Veit, G., Avramescu, R. G., Perdomo, D., Phuan, P.-W., Bagdany, M., Apaja, P. M., Borot, F., Szollosi, D., Wu, Y.-S., Finkbeiner, W. E., Hegedus, T., Verkman, A. S., & Lukacs, G. L.
Affiliations
  • McGill University (CA)
  • University of California, San Francisco (US)
  • Department of Physiology, McGill University, Montréal, Quebec H3G 1Y6, Canada.
  • MTA-SE Molecular Biophysics Research Group, Hungarian Academy of Sciences, 1444 Budapest, Hungary.
ORCID
Venue
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Published
2014-07-23
Volume
6
Issue
246
Pages
246ra97-246ra97
ISSN
  • 1946-6234 (ISSN-L)
  • 1946-6242
DOI
10.1126/scitranslmed.3008889
PMC
PMC4467693
OpenAlex
W2004155358
Cited by
287
References
2
Citations by year
2026: 5 · 2025: 12 · 2024: 14 · 2023: 11 · 2022: 15 · 2021: 16 · 2020: 26 · 2019: 29 · 2018: 37 · 2017: 32 · 2016: 41 · 2015: 41 · 2014: 8
FWCI
31.10
Type
journal article
Language
en
Open access
Locations
  • Science Translational Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Repository of the Academy's Library (Library of the Hungarian Academy of Sciences) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Canadian Institutes of Health Research
  • National Institute of Diabetes and Digestive and Kidney Diseases (NIH DK72517, R01DK075302, P30DK072517)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Inhalation and Respiratory Drug Delivery
Keywords
cystic fibrosis, CFTR, F508del mutation, ivacaftor, lumacaftor, CFTR correctors, protein folding, endoplasmic reticulum, protein stability, second-site suppressor mutations
MeSH terms
Aminophenols, Bronchi, Cell Membrane, Chlorides, Cystic Fibrosis, Endocytosis, Epithelial Cells, Humans, Mutation, Suppression, Genetic, Time Factors, Quinolones, Down-Regulation, Ion Channel Gating, Cystic Fibrosis Transmembrane Conductance Regulator

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