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Anion carriers as potential treatments for cystic fibrosis: transport in cystic fibrosis cells, and additivity to channel-targeting drugs

Anion carriers as potential treatments for cystic fibrosis: transport in cystic fibrosis cells, and additivity to channel-targeting drugs
Anion carriers as potential treatments for cystic fibrosis: transport in cystic fibrosis cells, and additivity to channel-targeting drugs
Defective anion transport is a hallmark of the genetic disease cystic fibrosis (CF). One approach to restore anion transport to CF cells utilises alternative pathways for transmembrane anion transport, including artificial anion carriers (anionophores). Here, we screened 22 anionophores for biological activity using fluorescence emission from the halide-sensitive yellow fluorescent protein. Three compounds possessed anion transport activity similar to or greater than that of a bis-(p-nitrophenyl)ureidodecalin previously shown to have promising biological activity. Anion transport by these anionophores was concentration-dependent and persistent. All four anionophores mediated anion transport in CF cells, and their activity was additive to rescue of the predominant disease-causing variant F508del-CFTR using the clinically-licensed drugs lumacaftor and ivacaftor. Toxicity was variable but minimal at the lower end. The results provide further evidence that anionophores, by themselves or together with other treatments that restore anion transport, offer a potential therapeutic strategy for CF.
1478-6524
9663-9672
Li, Hongyu
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Valkenier, Hennie
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Thorne, Abigail G.
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Dias, Christopher M.
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Cooper, James A.
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Kieffer, Marion
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Busschaert, Nathalie
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Gale, Philip
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Sheppard, David N.
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Davis, Anthony P.
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Li, Hongyu
ecf34b99-1d3d-49c1-be7b-5edee54a6a2e
Valkenier, Hennie
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Thorne, Abigail G.
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Dias, Christopher M.
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Cooper, James A.
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Kieffer, Marion
b4fe810e-3d01-4158-8314-9b533155c5d4
Busschaert, Nathalie
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Gale, Philip
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Sheppard, David N.
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Davis, Anthony P.
dc9078a1-2baf-4e8a-9baf-15cd06467541

Li, Hongyu, Valkenier, Hennie, Thorne, Abigail G., Dias, Christopher M., Cooper, James A., Kieffer, Marion, Busschaert, Nathalie, Gale, Philip, Sheppard, David N. and Davis, Anthony P. (2019) Anion carriers as potential treatments for cystic fibrosis: transport in cystic fibrosis cells, and additivity to channel-targeting drugs. Chemical Science, 2019 (10), 9663-9672. (doi:10.1039/C9SC04242C).

Record type: Article

Abstract

Defective anion transport is a hallmark of the genetic disease cystic fibrosis (CF). One approach to restore anion transport to CF cells utilises alternative pathways for transmembrane anion transport, including artificial anion carriers (anionophores). Here, we screened 22 anionophores for biological activity using fluorescence emission from the halide-sensitive yellow fluorescent protein. Three compounds possessed anion transport activity similar to or greater than that of a bis-(p-nitrophenyl)ureidodecalin previously shown to have promising biological activity. Anion transport by these anionophores was concentration-dependent and persistent. All four anionophores mediated anion transport in CF cells, and their activity was additive to rescue of the predominant disease-causing variant F508del-CFTR using the clinically-licensed drugs lumacaftor and ivacaftor. Toxicity was variable but minimal at the lower end. The results provide further evidence that anionophores, by themselves or together with other treatments that restore anion transport, offer a potential therapeutic strategy for CF.

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Accepted/In Press date: 9 September 2019
e-pub ahead of print date: 2 October 2019

Identifiers

Local EPrints ID: 435468
URI: http://eprints.soton.ac.uk/id/eprint/435468
ISSN: 1478-6524
PURE UUID: ffd2002e-1837-4c0e-92c7-e7fc792bc908
ORCID for Philip Gale: ORCID iD orcid.org/0000-0001-9751-4910

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Date deposited: 07 Nov 2019 17:30
Last modified: 15 Sep 2021 01:44

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Contributors

Author: Hongyu Li
Author: Hennie Valkenier
Author: Abigail G. Thorne
Author: Christopher M. Dias
Author: James A. Cooper
Author: Marion Kieffer
Author: Nathalie Busschaert
Author: Philip Gale ORCID iD
Author: David N. Sheppard
Author: Anthony P. Davis

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