ArticleNature medicine2018
Structure-guided combination therapy to potently improve the function of mutant CFTRs.
Article in Nature medicine, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 88 papers.
What it found
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The trial behind it
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Who cites it
88 citing papers in PubMed, 138 citations in OpenAlex.
- Triple potentiator combinations increase the functional correction of several CFTR gating mutants.npj drug discovery · 2026Article
- RFFL antisense oligonucleotides: A novel stabilization strategy to broaden the reach of CFTR modulator therapy.Molecular therapy. Nucleic acids · 2026Article
- RFFL-mediated protein quality control limits functional rescue of TRID-CFTR modulator combination therapy for cystic fibrosis nonsense mutations.Cellular and molecular life sciences : CMLS · 2026Article
- Antisense oligonucleotide targeting the E3 ligase RFFL potentiates CFTR modulator efficacy in CF primary bronchial epithelial cells.Molecular therapy. Nucleic acids · 2025Article
- Proteostasis landscapes of cystic fibrosis variants reveal drug response vulnerability.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Target Identification with Live-Cell Photoaffinity Labeling and Mechanism of Action Elucidation of ARN23765, a Highly Potent CFTR Corrector.Journal of medicinal chemistry · 2025Article
- Unraveling the Mechanism of Action, Binding Sites, and Therapeutic Advances of CFTR Modulators: A Narrative Review.Current issues in molecular biology · 2025Review
- CFTR dictates monocyte adhesion by facilitating integrin clustering but not activation.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Proteostasis Landscapes of Cystic Fibrosis Variants Reveals Drug Response Vulnerability.bioRxiv : the preprint server for biology · 2025Article
- Inflammatory response in CF airway epithelial cells: a comparative study of modulators and wild-type CFTR rescue.Frontiers in pharmacology · 2025Article
- ATP-Binding Cassette and Solute Carrier Transporters: Understanding Their Mechanisms and Drug Modulation Through Structural and Modeling Approaches.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Rational correction of pathogenic conformational defects in HTRA1.Nature communications · 2024Article
- Potentiation of BKCa channels by cystic fibrosis transmembrane conductance regulator correctors VX-445 and VX-121.The Journal of clinical investigation · 2024Article
- Functional Consequences of CFTR Interactions in Cystic Fibrosis.International journal of molecular sciences · 2024Review
- Article
- A uniquely efficacious type of CFTR corrector with complementary mode of action.Science advances · 2024Article
- Organic Synthesis and Current Understanding of the Mechanisms of CFTR Modulator Drugs Ivacaftor, Tezacaftor, and Elexacaftor.Molecules (Basel, Switzerland) · 2024Review
- CFTR Modulators: From Mechanism to Targeted Therapeutics.Handbook of experimental pharmacology · 2024Article
- Readthrough-induced misincorporated amino acid ratios guide mutant-specific therapeutic approaches for two CFTR nonsense mutations.Frontiers in pharmacology · 2024Article
- Ligand-based virtual-screening identified a novel CFTR ligand which improves the defective cell surface expression of misfolded ABC transporters.Frontiers in pharmacology · 2024Article
28 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
22 authors at 3 institutions in 3 countries.
Funding
Abstract
Available corrector drugs are unable to effectively rescue the folding defects of CFTR-ΔF508 (or CFTR-F508del), the most common disease-causing mutation of the cystic fibrosis transmembrane conductance regulator, a plasma membrane (PM) anion channel, and thus to substantially ameliorate clinical phenotypes of cystic fibrosis (CF). To overcome the corrector efficacy ceiling, here we show that compounds targeting distinct structural defects of CFTR can synergistically rescue mutant expression and function at the PM. High-throughput cell-based screens and mechanistic analysis identified three small-molecule series that target defects at nucleotide-binding domain (NBD1), NBD2 and their membrane-spanning domain (MSD) interfaces. Although individually these compounds marginally improve ΔF508-CFTR folding efficiency, function and stability, their combinations lead to ~50-100% of wild-type-level correction in immortalized and primary human airway epithelia and in mouse nasal epithelia. Likewise, corrector combinations were effective against rare missense mutations in various CFTR domains, probably acting via structural allostery, suggesting a mechanistic framework for their broad application.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.