Developing multivalent ligands to understand specific DC-SIGN-carbohydrate recognition for immune regulation


Contact Dr Yuan Guo to discuss this project further informally.

Project description

Immune cell surface receptors recognise antigens such as pathogens (virus or bacteria) to initiate defence reaction, therefore, understanding the recognition mechanism will allow to construct ligands to target these receptors for immune cells activation to treat diseases such as cancer and allergy. DC-SIGN is one of such receptors found on dendritic cell (DC) surfaces. It specifically recognizes glycosylated antigens for regulating immune response. However, such interactions can also be hijacked by pathogens with glycosylated protein on surface to enhance their infection. DC-SIGN forms tetramers on DC surface, but how its four carbohydrate binding sites are spatially arranged and oriented remain unknown, making it difficult to target DC-SIGN for therapeutic development.

In this project, we will develop novel organic molecule templated tetravalent carbohydrate ligands with systematically tuneable inter-carbohydrate spacing and orientation to probe DC-SIGN’s binding site arrangement. We hypothesise that a perfect spatial and orientation match between the 4 carbohydrates in tetravalent ligand and DC-SIGN binding sites will produce simultaneous multivalent binding, leading to greatly enhanced binding affinity. As a result, we can deduce DC-SIGN’s glycan binding site arrangement from its matched tetravalent carbohydrate ligands.

Moreover, binding of a rigid, spatially perfectly matched tetravalent ligand will restrict DC-SIGN flexibility, allowing us to investigate the molecular structural details of DC-SIGN by X-ray crystallography and/or NMR. Furthermore, the high affinity tetravalent ligands will be used as potent inhibitors to block DC-SIGN mediated virus (e.g. HIV, Ebola) cells entry to prevent infection.

This project includes following objectives:

(1) To synthesis and characterise novel tetravalent carbohydrate ligands using tetravalent organic scaffold and rigid DNA or peptide linkers for well-controlled sugar presentation and systematically tuneable inter-carbohydrate distance. Different carbohydrates will also be used for conjugation to test the effects of different binding affinity on simultaneous binding.

(2) To express and purify DC-SIGN and study its binding affinity and specificity with the above tetravalent carbohydrate ligands by using fluorescence spectroscopy, dynamic light scattering and calorimetry.

(3) To perform protein structural studies by using x-ray crystallography and/or NMR studies.

(4) To perform virus inhibition studies of the carbohydrate ligands against pseudo-virus infection of DC-SIGN expressing cells, and to correlate the binding affinity with inhibition potency.

References: (1) Guo Y, et al. (2004) Nat. Struct. Mol. Biol. 11, 591-598. (2) Guo, Y., et al. (2016) Angew. Chem. Int. Ed. 55, 4738-4742. (3) Guo, Y., et al. (2017) J. Am. Chem. Soc. 139, 11833-11844.

Entry requirements

Applications are invited from candidates with, or expecting, a minimum of the equivalent of a UK upper second class honours degree (2:1) in a relevant discipline, a Master's degree in a relevant discipline, or both.

Additional staff contact

Dr Dejian Zhou

How to apply

Formal applications for research degree study should be made online through the university's website. Please state clearly in the research information second that the PhD you wish to be considered for is 'Developing multivalent ligands to understand specific DC-SIGN-carbohydrate recognition for immune regulation' as well as Dr Yuan Guo as your proposed supervisor.

If English is not your first language, you must provide evidence that you meet the University's minimum English Language requirements.

We welcome scholarship applications from all suitably-qualified candidates, but UK black and minority ethnic (BME) researchers are currently under-represented in our Postgraduate Research community, and we would therefore particularly encourage applications from UK BME candidates. All scholarships will be awarded on the basis of merit.