We have developed a glycan-nanoparticle (NP, e.g. QD or gold nanoparticle, GNP) based multimodal readout strategy which dissected the different binding mode and affinity enhancing mechanism for DC-SIGN/R successfully. We find that DC-SIGN bind simultaneously with one glycan-NP and give impressive affinity enhancement (5-6 orders of magnitude over monovalent binding); whereas DC-SIGNR inter-crosslink with glycan-NPs and give much lower affinity enhancement. This result agrees with our proposed CRD orientation difference in DC-SIGN/R. We find that the glycan-NPs’ viral inhibition potency depends on not only the binding affinity but also binding mode with target lectins: only those showing simultaneous-, but not cross-link-, binding mode can to produce robust virus inhibition (Figure 1). Finally, we find that linking glycan-NPs together via rigid DNA linker can significantly enhance their binding affinity with DC-SIGNR, but not with DC-SIGN, suggesting that the glycan-NP assemblies may bind simultaneous with DC-SIGNR and can act as potent inhibitors against DC-SIGNR mediate viral infection. However, the planned dendritic cell immune response and virus inhibition studies were not possible due to the Covid-19 lockdown.
The fellow has received extensive trainings in ligand synthesis, protein production, labelling and FRET assays, as well as project management and grant writing skills. The fellow has also participated in supervising MChem and MSc students and received significant support from technical staff and other lab members. The fellow has collaborated with other group members to produce two research papers as co-author. The fellow prepared drafts, figures for publications, and participated weekly group meetings and monthly discussions.
Research Publications
(1) Wang, W., Kong, Y., Jiang, J., Tian, X., Li, S., Akshath, U.S. Tiede, C., Hondow, N., Yu, A., Guo, Y. and Zhou, D. Nanoscale, 2020,12(16), pp.8647-8655.
(2) Budhadev, D., Poole, E., Nehlmeier, I., Liu, Y., Hooper, J., Kalverda, E., Akshath, U.S. Hondow, N., Turnbull, W.B. Pöhlmann, S., Guo, Y., and Zhou, D. J. Am. Chem. Soc. 2020, 142(42), 18022-18034.
Conference presentation:
(1) U.S. Akshath, D. Budhadev, E. Kalverda, N. Hondow, W. B. Turnbull, Y. Guo and D. Zhou. Probing multivalent lectin-glycan interactions using multifunctional glycan-nanoparticles, Poster-Nanolithography of Biointerfaces Faraday Discussion, London, UK, 3-5/7/2019
(2) D. Budhadev, E. Poole, I. Nehlmeier, Y. Liu, E. Kalverda, J. Hooper, U. S. Akshath, W. B. Turnbull, S. Pöhlmann, Y. Guo and D. Zhou. Polyvalent Glycan-Nanoparticles as Multifunctional Structural Probes for Viral Receptors, DC-SIGN and DC-SIGNR. Poster- European Symposium on Biological and Organic Chemistry, 53rd ESBOC Symposium, Gregynog, UK, 17-19/5/2019.
(3) D. Budhadev, E. Poole, I. Nehlmeier, Y. Liu, E. Kalverda, J. Hooper, U. S. Akshath, W. B. Turnbull, S. Pöhlmann, Y. Guo and D. Zhou. Probing and Blocking DC-SIGN/R-glycan Interaction Mediated Virus Infection Using Polyvalent Multifunctional Glycan Gold Nanoparticles. Oral presentation- RSC Carbohydrate Early Career Researcher Webinar Series, Oral, 2/7/2020.
