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FAUST: Foldamers As Unnatural Signal Transducers


Project Description

The cell membrane not only defines a cell but also acts as a protective barrier, which means that cells must use specialised transmembrane proteins in their membranes to communicate with the world around them. G-protein-coupled receptors (GPCRs) are one such class of protein. GPCRs transmit a signal when an external messenger molecule (the ‘signal’) binds to their exterior, which induces conformational changes in the protein that then trigger the release of a message within the cell. The creation of completely artificial molecules that can copy GPCR behaviour and transmit messages across membranes (a distance of several nanometres) would lead to many exciting opportunities. For example, they could provide artificial signalling pathways that ‘short-circuit’ natural signalling networks, reprograming cells while providing fundamental scientific insights.
Building on our recent work synthesising and studying compounds that mimic aspects of GPCR behaviour (published in Science and Nature Chemistry), we wish to initiate a new project at the interface of synthetic, supramolecular and biological chemistry; the “catch-and-release” of oxygen by membrane-spanning α-aminoisobutyric acid (Aib) foldamers in membranes.
This project will start with the chemical synthesis of Aib oligomers that can bind to haemoglobin. These folded oligomers (“foldamers”) will be designed to bind a messenger molecule, which causes them to change shape. This shape change will be transmitted along the multi-nanometre length of the foldamer, to perturb haemoglobin conformation and thereby turn oxygen binding on or off. These foldamers will then be used for the “catch-and-release” of oxygen in ‘artificial cells’ (vesicles) that contain haemoglobin. Finally these foldamers would be inserted into erythrocyte membranes and messenger binding relayed into the cell interior, leading to changed oxygen binding by internal haemoglobin. This unique system would be the first synthetic signal transduction system applied to a natural cell, a huge advance towards truly synthetic biology.

Applicants should have or expect a good 2:i or 1st class honours degree (or an equivalent degree) in Chemistry or a related discipline. Prior experience of organic synthesis and/or supramolecular chemistry is advantageous but not essential.

Contact for further Information:
Informal enquiries should be directed to Dr Simon Webb,
A formal application must be submitted to be considered for this project. Please select PhD Organic Chemistry in the online application form.
Webb group: http://www.webblab.org
Burthem group: https://www.research.manchester.ac.uk/portal/j.burthem.html

Funding Notes

This is a 3.5 year funded studentship covering all fees and stipend (£14.777 in September 2018).

Due to funding restrictions this is open to UK/EU applicants only.

The start date for this PhD programme will be September 2019.

References

[1] R. A. Brown, V. Diemer, S. J. Webb, J. Clayden, Nature Chem. 2013, 5, 853.
[2] M. De Poli, W. Zawodny, O. Quinonero, M. Lorch, S.J. Webb, J. Clayden, Science 2016, 352, 575.
[3] F. G. A. Lister, B. A. F. Le Bailly, S. J. Webb, J. Clayden, Nature Chem. 2017, 9, 420.
[4] Lister, F. G. A.; Eccles, N.; Pike, S. J.; Brown, R. A.; Whitehead, G. F. S.; Raftery, J.; Webb, S. J.; Clayden, J. Chem. Sci. 2018, 9, 6860.

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