Probing Viral Receptor-Glycan Interactions using Polyvalent Multifunctional Glycan-Nanoparticle

Summary

Multivalent viral receptor-glycan interactions are central to viral infection and immune response regulation. However, the underpinning structural mechanisms are often poorly understood, due to a lack of effective probes for such complex, multimeric and flexible proteins. Herein we will develop polyvalent glycan-nanoparticles (NPs) with tuneable glycan valency and flexibility as novel structural probes for two closely related, almost identical tetrameric receptors, DC-SIGN/R, which bind to the HIV/Ebola virus surface sugars to enhance viral infection.[1]

However, how their four carbohydrate-recognition-domains (CRDs) are spatially arranged remain unclear. This information is key to their specific binding to viral surface glycans and viral trans-infection. We hypothesis that a perfect spatial match between the NP surface multiple glycans and protein binding sites will result in high affinity multivalent binding, allowing us to derive the CRD arrangement.[2]

This project includes four objectives:

1) synthesise & characterise dihydrolipoic acid-PEG-sugar based multifunctional ligands;
2) produce site-specifically labelled DC-SIGN/R;
3) prepare & characterise polyvalent sugar coated NPs and study their binding affinity and specificity with DC-SIGN/R by FRET[3], and
4) investigate their inhibition of virus infection of DC-SIGN/R expressing host cells and correlate their binding affinity with viral inhibition potency. This study will not only yield important structural information about these vial receptors but also lead the development of potent multivalent glycan-nanoparticle inhibitors that can block the viral entry to target cells, thereby preventing deadly viral infections.

Reference [1] Geijtenbeek, T. B. H., et al. (2000) Cell 100, 587; Guo Y, et al. (2004) Nature Struct. Mol. Biol. 11, 591. [2] Guo, Y., et al. (2016) Angew. Chem. Int. Ed. 55, 4738. [3] Guo, Y., et al. (2017) J. Am. Chem. Soc. 139, 11833. [4] Budhadev et al. (2020) J. Am. Chem. Soc. 142, 18022.

Applicants to research degree programmes should normally have at least a first class or an upper second class British Bachelors Honours degree (or equivalent) in an appropriate discipline. The criteria for entry for some research degrees may be higher, for example, several faculties, also require a Masters degree. Applicants are advised to check with the relevant School prior to making an application. Applicants who are uncertain about the requirements for a particular research degree are advised to contact the School or Graduate School prior to making an application.

The minimum English language entry requirement for research postgraduate research study is an IELTS of 6.0 overall with at least 5.5 in each component (reading, writing, listening and speaking) or equivalent. The test must be dated within two years of the start date of the course in order to be valid. Some schools and faculties have a higher requirement.