Journal article
Molecular Prosthetics and CFTR Modulators Additively Increase Secretory HCO 3 - Flux in Cystic Fibrosis Airway Epithelia
ACS chemical biology, Vol.20(11), pp.2630-2636
11/21/2025
DOI: 10.1021/acschembio.5c00473
PMCID: PMC12893403
PMID: 41114840
Abstract
Cystic fibrosis (CF) is caused by loss-of-function mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel predominantly expressed on the apical membrane of epithelial cells. Reduced Cl– and HCO3– secretion due to dysfunctional CFTR results in a decrease in lung function and is the leading cause of morbidity in individuals with CF. Recent therapies, known as highly effective CFTR modulator therapy (HEMT), help improve the lung function in individuals with specific CF-causing mutations by enhancing the folding, trafficking, and gating of CFTR. However, variability in HEMT responsiveness leads to suboptimal clinical outcomes in some people with CF undergoing modulator therapy. A potential strategy is to complement their function with a CFTR-independent mechanism. One possibility is the use of ion channel-forming small molecules such as amphotericin B, which has shown promise in restoring function and host defenses in CF airway disease models. Amphotericin B functions as a molecular prosthetic for CFTR and may thus complement CFTR modulators. Here, we show that cotreatment of CF airway epithelia with HEMT and amphotericin B results in greater increases in both HCO3– secretory flux and ASL pH compared to treatment with either agent alone. These findings suggest that coadministration of CFTR modulators and molecular prosthetics may provide additive therapeutic benefits for individuals with CF.
Details
- Title: Subtitle
- Molecular Prosthetics and CFTR Modulators Additively Increase Secretory HCO 3 - Flux in Cystic Fibrosis Airway Epithelia
- Creators
- Nohemy Celis - University of Illinois Urbana-ChampaignDanforth P Miller - Cystetic Medicines, Inc., San Carlos, California 94070, United StatesThomas E Tarara - Cystetic Medicines, Inc., San Carlos, California 94070, United StatesJeffry G Weers - Cystetic Medicines, Inc., San Carlos, California 94070, United StatesIan M Thornell - University of IowaMichael J Welsh - University of IowaMartin D Burke - University of Illinois Urbana-Champaign
- Resource Type
- Journal article
- Publication Details
- ACS chemical biology, Vol.20(11), pp.2630-2636
- DOI
- 10.1021/acschembio.5c00473
- PMID
- 41114840
- PMCID
- PMC12893403
- NLM abbreviation
- ACS Chem Biol
- ISSN
- 1554-8929
- eISSN
- 1554-8937
- Publisher
- American Chemical Society
- Grant note
- National Institute of General Medical Sciences: 5T32 GM136629-04 NIH
We are grateful for Cystetic Medicines (C0673 Studies with Amphotericin B Cystetic for Inhalation) and the NIH (MIRA R35GM118185 to MDB) for funding this work. We thank the NIH for funding support for N.C., a Predoctoral Fellow (5T32 GM136629-04), who was also partially supported by the UIUC Peixin He and Xiaoming Chen PhD4 Graduate Fellowship.
- Language
- English
- Electronic publication date
- 10/20/2025
- Date published
- 11/21/2025
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Fraternal Order of Eagles Diabetes Research Center; Neurosurgery; Internal Medicine
- Record Identifier
- 9985016015602771
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