Chloride Transport Across Vesicle and Cell Membranes by Steroid‐Based Receptors

Koulov, Atanas V.; Lambert, Timothy N.; Shukla, R. C.; Jain, Mahim; Boon, J. Middleton; Smith, Bradley D.; Li, Hongyu; Sheppard, David N.; Joos, Jean‐Baptiste; Clare, John P.; Davis, Anthony P.

doi:10.1002/anie.200351957

Cited by 186 publications

(148 citation statements)

References 21 publications

Supporting

Mentioning

146

Contrasting

Order By: Relevance

“…The application of anionophores in CF treatment requires that they should be effective in epithelia (for example the bronchial epithelia in the lungs of CF patients). 13 As a further test of their potential, we investigated whether the anionophores could mediate Cl − currents in epithelia using the Ussing chamber technique 18 . YFP-FRT epithelial cells were grown on permeable filter supports to form polarised epithelia with a high electrical resistance.…”

Section: (Figure 3)mentioning

confidence: 99%

“…On the positive side, a few systems have been tested in whole cells, epithelia or (in one case) genetically modified mice 14 , using electrophysiological methods such as patch-clamp and Ussing chamber, and shown to induce anion conduction without obvious toxic effects. These anionophores include synthetic peptides conceptually related to natural anion channels 11,[15][16][17] , as well as the steroid-based system 1 from the authors' laboratory 18 , and other small organic molecules 14,19,20 .…”

mentioning

confidence: 99%

“…We have developed a range of anionophores based on powerful anion binding sites created from hydrogen bond donor groups mounted on alicyclic scaffolds (see for example Figure 4 1) 10,27 . Scaffolds include steroids 18,28,29 , trans-decalins 30,31 and substituted cyclohexanes 32 , and the common design motif is the positioning of axially-directed H-bond donors in 1,5-relationships. Conformational factors promote the convergence of NH groups to create binding sites with high affinities for inorganic anions 10,32,29 .…”

mentioning

confidence: 99%

“…Thus far the only biological testing of these "1,5-diaxial" systems has been the early study on 1, referred to above 18 . The assay involved the application of 1 to the apical membrane of oriented Madin Darby canine kidney cell (MDCK) epithelia, mounted in an Ussing chamber, and measurement of the resulting electrical current caused by Cl − transport.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Efficient, non-toxic anion transport by synthetic carriers in cells and epithelia

Valkenier

Judd³

et al. 2015

Nature Chem

Self Cite

156

160

View full text Add to dashboard Cite

The transport of anions across cell membranes has become an important goal for supramolecular chemistry [1][2][3][4] . It is well-known that cation carriers (cationophores) can serve as antibiotics and toxins 5,6 , and it seems likely that anion carriers might also show useful biological activity. However, suitable anionophores have only recently become available 7-10 , and the nature of their biological effects is still in question. A particular hope is that anionophores might be used to replace the activity of endogenous anion channels which are missing or defective 11,2 . Such deficiencies underlie a number of medical conditions including Best disease, Startle disease, Bartter's syndrome and, most notably, the widespread lifeshortening genetic disease cystic fibrosis (CF) 12,13 .If anionophores are to be used to treat these "channelopathies", it must be shown that they can be delivered to cells in sufficient quantities to produce substantial effects, of the same order of magnitude as endogenous anion channels, and that these quantities are not toxic to the cells. However, while a wide variety of anionophores have been studied in synthetic membranes (principally large unilamellar vesicles, or LUVs), the range of systems subjected to biological investigations is still quite limited. Moreover, from the point of view of CF treatment, the results thus far have been mixed. On the positive side, a few systems have been tested in whole cells, epithelia or (in one case) genetically modified mice 14 , using electrophysiological methods such as patch-clamp and Ussing chamber, and shown to induce anion conduction without obvious toxic effects. These anionophores include synthetic 3 peptides conceptually related to natural anion channels 11,[15][16][17] , as well as the steroid-based system 1 from the authors' laboratory 18 , and other small organic molecules 14,19,20 .Less encouragingly, a number of molecules showing anion transport in LUVs have tested positive for anti-cancer cytotoxicity (potentially valuable, but incompatible with CF treatment) 8,[21][22][23][24][25] . Many of these systems, including the well-studied prodigiosin 2 26 , transport protons as well as anions 8,[21][22][23] . Intracellular acidification can lead to apoptosis 26 , so in these cases proton transport could underlie toxicity. On the other hand, a recent study on calixpyrroles 3 suggested that anion transport as such could be cytotoxic 25 . As the transport activity of 3 was only weak, this raises the concern that powerful anionophores might be highly toxic and thus unsuitable for CF treatment. Thus far the only biological testing of these "1,5-diaxial" systems has been the early study on 1, referred to above 18 . The assay involved the application of 1 to the apical membrane of oriented Madin Darby canine kidney cell (MDCK) epithelia, mounted in an Ussing chamber, and measurement of the resulting electrical current caused by Cl − transport. The methodology is well-established, but not so convenient for screening large numbers of compounds.Mor...

show abstract

Section: (Figure 3)mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Efficient, non-toxic anion transport by synthetic carriers in cells and epithelia

Valkenier

Judd³

et al. 2015

Nature Chem

Self Cite

156

160

View full text Add to dashboard Cite

show abstract

“…A sample of calixpyrrole 2 (4% molar carrier to 95 lipid) was added as a DMSO solution and the resultant Cl -efflux monitored using a chloride selective electrode. 10 After five minutes the vesicles were lysed by addition of detergent and the final reading of the electrode used to calibrate 100% release of chloride. The results show that compound 2 ( Figure 5), in contrast to compound 1, 10 is capable of transporting chloride from sodium, potassium and rubidium chloride containing vesicles with fastest 110 release of the larger group 1 metal cation salts.…”

mentioning

confidence: 99%

1,2,3-Triazole-strapped calix[4]pyrrole: a new membrane transporter for chloride

et al. 2009

View full text Add to dashboard Cite

Supramolecular Chemistry

Cragg¹

2006

Kirk-Othmer Encyclopedia of Chemical Technology

View full text Add to dashboard Cite

Supramolecular chemistry has its origins in the supermolecule, a term used by Nobel Laureate Jean‐Marie Lehn from the early 1970s when referring to a well‐defined chemical species comprising several components. The realization that supermolecules could in turn form larger molecular assemblies led to the shift in emphasis from super‐ to supramolecular in the literature to more accurately describe the complexity of systems involved. Supramolecular chemistry has since advanced to include complexes between molecules with complementary binding sites (molecular recognition), multicomponent complexes (supramolecular assemblies), the programmed interactions between large molecular assemblies (molecular tectonics), and even the directed assembly of three‐dimensional solids (crystal engineering). This article sets out the concepts and aims of supramolecular chemistry, illustrates some of the early development in the field, considers the synthesis and structures of individual supramolecular synthons as well as supramolecular assemblies, and concludes with an assessment of current and anticipated applications in materials science, medicine, the interface with biology, molecular computing, nanomaterials, and nanomachines.

show abstract

Chloride Transport Across Vesicle and Cell Membranes by Steroid‐Based Receptors

Cited by 186 publications

References 21 publications

Efficient, non-toxic anion transport by synthetic carriers in cells and epithelia

Efficient, non-toxic anion transport by synthetic carriers in cells and epithelia

1,2,3-Triazole-strapped calix[4]pyrrole: a new membrane transporter for chloride

Supramolecular Chemistry

Contact Info

Product

Resources

About