title: Efficient, non-toxic anion transport by synthetic carriers in cells and epithelia.
abstract: Transmembrane anion transporters (anionophores) have potential for new modes of biological activity, including therapeutic applications. In particular they might replace the activity of defective anion channels in conditions such as cystic fibrosis. However, data on the biological effects of anionophores are scarce, and it remains uncertain whether such molecules are fundamentally toxic. Here, we report a biological study of an extensive series of powerful anion carriers. Fifteen anionophores were assayed in single cells by monitoring anion transport in real time through fluorescence emission from halide-sensitive yellow fluorescent protein. A bis-(p-nitrophenyl)ureidodecalin shows especially promising activity, including deliverability, potency and persistence. Electrophysiological tests show strong effects in epithelia, close to those of natural anion channels. Toxicity assays yield negative results in three cell lines, suggesting that promotion of anion transport may not be deleterious to cells. We therefore conclude that synthetic anion carriers are realistic candidates for further investigation as treatments for cystic fibrosis.
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Biomedical Sciences Building, University Walk, Bristol BS8 1TD, UK.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Li
authors.affiliation: School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, UK.
authors.forename: Hennie
authors.initials: H
authors.lastname: Valkenier
authors.affiliation: School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, UK.
authors.forename: Luke W
authors.initials: LW
authors.lastname: Judd
authors.affiliation: School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, UK.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Brotherhood
authors.affiliation: School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, UK.
authors.forename: Sabir
authors.initials: S
authors.lastname: Hussain
authors.affiliation: School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Cooper
authors.affiliation: School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, UK.|Department of Chemistry, University of Jyväskylä, PO Box 35, Jyväskylä FI-40014, Finland.
authors.forename: Ondřej
authors.initials: O
authors.lastname: Jurček
authors.affiliation: School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, UK.
authors.forename: Hazel A
authors.initials: HA
authors.lastname: Sparkes
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Biomedical Sciences Building, University Walk, Bristol BS8 1TD, UK.
authors.forename: David N
authors.initials: DN
authors.lastname: Sheppard
authors.affiliation: School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, UK.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Davis
mesh_terms: D000818:Animals; D000838:Anions / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002713:Chlorine / Q000378:metabolism; D003510:Cyclohexanes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D004337:Drug Carriers / Q000737:chemistry; D015195:Drug Design; D055724:Electrophysiological Phenomena; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D006860:Hydrogen Bonding; D017136:Ion Transport; D008164:Luminescent Proteins / Q000235:genetics; D061985:Madin Darby Canine Kidney Cells; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D010713:Phosphatidylcholines / Q000737:chemistry; D011916:Rats, Inbred F344; D013256:Steroids / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: D000838:Anions; D001426:Bacterial Proteins; D003510:Cyclohexanes; D004337:Drug Carriers; D008164:Luminescent Proteins; D009281:Naphthalenes; D010713:Phosphatidylcholines; D013256:Steroids; C054562:yellow fluorescent protein, Bacteria; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D002713:Chlorine; C007229:decalin; C028694:1-palmitoyl-2-oleoylphosphatidylcholine