Molecular prosthetics for CFTR designed for anion selectivity outperform amphotericin B in cultured cystic fibrosis airway epithelia

Jonnathan P Marin-Toledo; Daniel Greenan; Nohemy Celis; Laura Haske; Agnieszka Lewandowska; Christopher K Rakowski; Shashank Shastry; Arun Maji; Kelsie J Green; Taras V Pogorelov; Michael J Welsh; Ian M Thornell; Martin D Burke

doi:10.1101/2025.08.28.671923

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Molecular prosthetics for CFTR designed for anion selectivity outperform amphotericin B in cultured cystic fibrosis airway epithelia

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Molecular prosthetics for CFTR designed for anion selectivity outperform amphotericin B in cultured cystic fibrosis airway epithelia

Jonnathan P Marin-Toledo, Daniel Greenan, Nohemy Celis, Laura Haske, Agnieszka Lewandowska, Christopher K Rakowski, Shashank Shastry, Arun Maji, Kelsie J Green, Taras V Pogorelov, …

bioRxiv

08/28/2025

DOI: 10.1101/2025.08.28.671923

PMCID: PMC12407901

PMID: 40909600

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https://doi.org/10.1101/2025.08.28.671923View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

The ion channel-forming natural product amphotericin B (AmB) can serve as a molecular prosthetic for the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel and thereby restore host defenses in cultured cystic fibrosis (CF) airway epithelia. This is despite the fact that the permeability of AmB-based channels favors cations, and these channels lose their capacity to increase airway surface liquid (ASL) pH in CF airway epithelia at high concentrations. We hypothesize that modifying such channels to favor anion permeability would make them more CFTR-like and thus increase their potential therapeutic effects compared to AmB. Here we show that a synthetic derivative of AmB, AmB-AA, which has an added positively charged appendage and forms ion channels with an improved relative permeability to anions, outperformed AmB in increasing the ASL pH in CF airway epithelia at both low and high concentrations. Further modifications led to another AmB derivative, C2'epiAmB-AA, that also minimized cholesterol binding and thus toxicity to cultured CF airway epithelia and was an effective surrogate for CFTR in primary cultured airway epithelia from people with CF.

Details

Title: Subtitle: Molecular prosthetics for CFTR designed for anion selectivity outperform amphotericin B in cultured cystic fibrosis airway epithelia
Creators: Jonnathan P Marin-Toledo - University of Illinois Urbana-Champaign
Daniel Greenan - University of Illinois Urbana-Champaign
Nohemy Celis - University of Illinois Urbana-Champaign
Laura Haske - University of Illinois Urbana-Champaign
Agnieszka Lewandowska - University of Illinois Urbana-Champaign
Christopher K Rakowski - University of Illinois Urbana-Champaign
Shashank Shastry - University of Illinois Urbana-Champaign
Arun Maji - University of Illinois Urbana-Champaign
Kelsie J Green - University of Illinois Urbana-Champaign
Taras V Pogorelov - University of Illinois Urbana-Champaign
Michael J Welsh - University of Iowa
Ian M Thornell - University of Iowa
Martin D Burke - University of Illinois Urbana-Champaign
Resource Type: Preprint
Publication Details: bioRxiv
DOI: 10.1101/2025.08.28.671923
PMID: 40909600
PMCID: PMC12407901
NLM abbreviation: bioRxiv
ISSN: 2692-8205
eISSN: 2692-8205
Publisher: United States
Language: English
Date posted: 08/28/2025
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: 9984958295202771

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