Synthetic Anion Carriers for Biomedical Applications
Lead Research Organisation:
University of Bristol
Department Name: Chemistry
Abstract
Cystic fibrosis (CF) is one of the most common genetic diseases. Like many such illnesses, it is caused by the malfunction of a particular protein, the Cystic Fibrosis Transmembrane Conductance Regulator (or CFTR). In normal people CFTR resides in the membranes of cells and serves as a channel through which anions, such as chloride ions, can enter or leave the cell. Its role is especially important in the lungs, as this flow of anions helps to maintain the system which keeps the lungs clean. If the CFTR is missing, or fails to work properly, the lungs become full of sticky mucous and vulnerable to infection. In the UK, patients with CF usually die from lung disease before the age of 30.A possible approach to CF treatment is channel replacement therapy . In principle, the cell in the lungs could be provided with synthetic compounds which would mimic the action of CFTR, allowing anions to pass through the membranes. The idea has been difficult to try out, because of a lack of suitable compounds. However, we have recently discovered a family of molecules, termed cholapods , which have the necessary properties. Firstly they are made largely of hydrocarbon, and will therefore locate in cell membranes rather than aqueous solution. Secondly they have high affinities for anions such as chloride, which they can extract from water. Thirdly they can move through the membranes, carrying the anions with them. By binding chloride ions on one side and releasing them on the other, they allow the anions to cross the membrane, mimicking the overall action of CFTR. There seems a genuine prospect for developing cholapods, or related anionophores (anion carriers), into treatments for CF. However, further studies are necessary before a full biomedical programme can be considered. We need anionophores which are optimised in key respects (effectiveness as carriers, low toxicity, ease of delivery to cells). We also need to show that they can operate in natural cell membranes, as well as the simpler synthetic models used in most of our experiments. We will begin by completing a full study of the cholapods in the synthetic membranes. In particular, we will use electrical methods to achieve a detailed understanding of the transport process. We are especially interested in finding out which step (anion extraction, movement across membrane etc.) is the slowest, and is therefore rate-determining . We can then work to improve this step. We will also prepare and study a range of new examples, so that we can determine structure-activity relationships. By combining the two approaches we will identify optimal cholapods for biological studies. We will also explore some novel, cholapod-inspired structures. These contain key features of the original design, but are different in ways which might improve performance (e.g. by speeding up movement through the membrane).Once the anionophores have been optimised in synthetic membranes, they will be tested in natural systems. Electrical studies in individual cells will be followed by experiments in cultured epithelia (layers of cells which mimic the lining of the lungs). We will perform preliminary tests for toxicity and other properties relating to druggability (absorption, metabolism etc.). If results are favourable, these studies should provide proof of principal for anionophore-based channel replacement therapy for CF patients.
Organisations
Publications
Wenzel M
(2011)
Thiourea isosteres as anion receptors and transmembrane transporters
in Chemical Communications
Wang Y
(2014)
CFTR potentiators partially restore channel function to A561E-CFTR, a cystic fibrosis mutant with a similar mechanism of dysfunction as F508del-CFTR.
in British journal of pharmacology
Wang Y
(2014)
Understanding how cystic fibrosis mutations disrupt CFTR function: from single molecules to animal models.
in The international journal of biochemistry & cell biology
Valkenier H
(2014)
Preorganized bis-thioureas as powerful anion carriers: chloride transport by single molecules in large unilamellar vesicles.
in Journal of the American Chemical Society
Valkenier H
(2013)
Making a match for Valinomycin: steroidal scaffolds in the design of electroneutral, electrogenic anion carriers.
in Accounts of chemical research
Valkenier H
(2015)
Visualization and quantification of transmembrane ion transport into giant unilamellar vesicles.
in Angewandte Chemie (International ed. in English)
Valkenier H
(2014)
Visualization and Quantification of Transmembrane Ion Transport into Giant Unilamellar Vesicles
in Angewandte Chemie
Valkenier H
(2015)
Sterically geared tris-thioureas; transmembrane chloride transporters with unusual activity and accessibility.
in Chemical communications (Cambridge, England)
Valkenier H
(2014)
Lipophilic balance - a new design principle for transmembrane anion carriers
in Chemical Science
Mora N
(2016)
Targeted anion transporter delivery by coiled-coil driven membrane fusion
in Chemical Science
McNally BA
(2008)
Structure-activity relationships in cholapod anion carriers: enhanced transmembrane chloride transport through substituent tuning.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Lisbjerg M
(2015)
Biotin[6]uril Esters: Chloride-Selective Transmembrane Anion Carriers Employing C-H···Anion Interactions.
in Journal of the American Chemical Society
Li H
(2017)
Bypassing CFTR dysfunction in cystic fibrosis with alternative pathways for anion transport.
in Current opinion in pharmacology
Li H
(2018)
Therapeutic approaches to CFTR dysfunction: From discovery to drug development.
in Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
Li H
(2016)
Efficient, non-toxic anion transport by synthetic carriers in cells and epithelia.
in Nature chemistry
Judd LW
(2010)
From cholapod to cholaphane transmembrane anion carriers: accelerated transport through binding site enclosure.
in Chemical communications (Cambridge, England)
Hussain S
(2011)
Diaxial diureido decalins as compact, efficient, and tunable anion transporters.
in Journal of the American Chemical Society
Hughes LK
(2008)
Potentiation of cystic fibrosis transmembrane conductance regulator (CFTR) Cl- currents by the chemical solvent tetrahydrofuran.
in Molecular membrane biology
Edwards SJ
(2016)
Tilting and Tumbling in Transmembrane Anion Carriers: Activity Tuning through n-Alkyl Substitution.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Edwards SJ
(2015)
High-affinity anion binding by steroidal squaramide receptors.
in Angewandte Chemie (International ed. in English)
Cooper JA
(2014)
A flexible solution to anion transport: powerful anionophores based on a cyclohexane scaffold.
in Angewandte Chemie (International ed. in English)
Cai ZW
(2011)
Targeting F508del-CFTR to develop rational new therapies for cystic fibrosis.
in Acta pharmacologica Sinica
Brotherhood PR
(2010)
Steroid-based anion receptors and transporters.
in Chemical Society reviews
Bose SJ
(2015)
Exploiting species differences to understand the CFTR Cl- channel.
in Biochemical Society transactions
Becq Frederic
(2011)
Pharmacological therapy for cystic fibrosis: From bench to bedside
in JOURNAL OF CYSTIC FIBROSIS
Description | We have shown that organic molecules derived from steroids and related scaffolds can locate in cell membranes and carry anions from one side to another. We have also found ways of raising activities such that only small amounts are required. |
Exploitation Route | We aim for the production of research tools for the promotion of anion transport across cell membranes, and ultimately to use the molecules to treat channelopathies such as cystic fibrosis. |
Sectors | Healthcare |
Description | This programme has continued through a succeeding EPSRC grant and is moving towards the production of research tools for the promotion of anion transport across cell membranes. There is potential for using the molecules to treat channelopathies such as cystic fibrosis, and we should soon find out if this can be realised. |
First Year Of Impact | 2012 |
Sector | Healthcare |
Impact Types | Societal |
Description | EPSRC |
Amount | £676,169 (GBP) |
Funding ID | EP/J00961X/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2012 |
End | 09/2015 |