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

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.

SUBMITTER: Li H

PROVIDER: S-EPMC6984391 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Li Hongyu H Valkenier Hennie H Thorne Abigail G AG Dias Christopher M CM Cooper James A JA Kieffer Marion M Busschaert Nathalie N Gale Philip A PA Sheppard David N DN Davis Anthony P AP

Chemical science 20191002 42

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-(<i>p</i>-nitr ...[more]

PMID: 32055336

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Project description:BACKGROUND:People with cystic fibrosis (CF) have increased transport of the salt, sodium across their airway lining. Over-absorption of sodium results in the dehydration of the liquid that lines the airway surface and (along with defective chloride secretion) is a primary defect in people with CF. OBJECTIVES:To determine whether the topical administration of drugs that block sodium transport improves the respiratory condition of people with CF. SEARCH METHODS:We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings. We contacted principal investigators known to work in the field, previous authors and pharmaceutical companies who manufacture ion transport agents for unpublished or follow-up data.Most recent search of the Group's register: 19 December 2013. SELECTION CRITERIA:Published or unpublished randomised controlled trials (RCTs) or quasi-randomised controlled trials of sodium channel blockers compared to placebo or another sodium channel blocker or the same sodium channel blocker at a different dosing regimen. DATA COLLECTION AND ANALYSIS:Two authors independently extracted data. Meta-analysis was limited due to differing study designs. MAIN RESULTS:Five RCTs, with a total of 226 participants, examining the topical administration of the short-acting sodium channel blocker, amiloride, compared to placebo were identified as eligible for inclusion in the review. In three studies over six months, there was a significant difference found in the difference in relative change in FVC in favour of placebo (weighted mean difference 1.51% (95% confidence interval -2.77 to -0.25), although heterogeneity was evident. A two-week study demonstrated that hypertonic saline with amiloride pre-treatment did not result in a significant improvement in respiratory function or mucus clearance, in contrast to pre-treatment with placebo. There were no significant differences identified in other clinically relevant outcomes. AUTHORS' CONCLUSIONS:We found no evidence that the topical administration of a short-acting sodium channel blocker improves respiratory condition in people with cystic fibrosis and some limited evidence of deterioration in lung function.

Dataset Information

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

Publications

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

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