The chemical synthesis of complex phosphosaccharides

Research

My laboratory has an extensive interest in the chemical preparation of biologically important complex carbohydrates. The area of research involves the chemical synthesis of novel oligosaccharides and glycoconjugates (and their structural analogues), which are fragments of immunologically active surface polysaccharides and phosphoglycans from protozoan parasites, bacteria and yeasts, and application of these synthetic compounds for biochemical studies, immunological studies and the preparation of artificial antigens.

At present, we are engaged in a study of natural phosphoglycans containing glycosyl phosphate or oligoglycosyl phosphate repeat units. These phosphoglycans are immunologically active polymers of the cell wall or capsule of numerous microorganisms and often responsible for the microorganism infectivity and survival. In contrast to many polysaccharides, both the biosynthesis of the phosphoglycans and the chemical synthesis of their fragments were not properly investigated. We have recently developed a highly efficient glycosyl hydrogenphosphonate (H-phosphonate) method for the chemical synthesis of glycosyl phosphosaccharides (Sug-PO3H-Sug) and synthetic phosphoglycans (Sug-PO3H-[Sug-PO3H]n-Sug), which are not accessible by other chemical methods. The H-phosphonate method was used for the preparation of the glycosyl phosphosaccharides and synthetic phosphoglycans, which are fragments of capsular antigens of Escherichia coli K51 and K52, Neisseria meningitidis A and X, of the lipophosphophoglycans from the Leishmania donovani, Leishmania mexicana and Leishmania major parasites and of the exophosphomannan from Hansenula capsulata Y-1842. Most of these compounds and their structural analogues were designed for biosynthetic and immunological studies and the preparation of artificial antigens.

I collaborate closely with Prof. Mike Ferguson's group on study and characterization of Leishmania biosynthetic enzymes (using synthetic substrate analogues) and chemical preparation of the LPG biosynthesis inhibitors as drug leads. I also collaborate with Prof. F. Y. Liew (University of Glasgow), who studies regulation of NO synthase expression and interleukin-12 biosynthesis in macrophages using chemically synthesized phosphoglycans from Leishmania, and Dr. J. G. Raynes (London School of Hygiene and Tropical Medicine) on study of binding some serum proteins to phosphorylated carbohydrates. My general goal is elaboration of novel chemical synthetic methods for the preparation of carbohydrate containing compounds, which are used as tools to achieve new biological knowledge.

Teaching

Publications

1. Glycosylphosphatidylinositol (GPI) anchors and related glycoconjugates: synthetic approaches to the complex molecules (a book chapter). Nikolaev, A.V., Al-Maharik, N., and Tee, J.A. In Progress in the Synthesis of Complex Carbohydrate Chains of Plant and Microbial Polysaccharides, N.E. Nifantiev (Ed.), Research Signpost and Transworld Research Network publishers, 2009, pp. 199-277.
2. Chemical synthesis of parasitic glycoconjugates and phosphoglycans (a book chapter). Al-Maharik, N., Tee, J.A., and Nikolaev, A.V. In Microbial Glycobiology – Structures, Relevance and Applications, A.P. Moran, P.J. Brennan, O. Holst, and M. von Itzstein (Eds.), Academic Press, 2009, pp. 477-548 (in press).
3. GPIomics: global analysis of glycosylphosphatidylinositol-anchored molecules of Trypanosoma cruzi. E.S.Nakayasu, D.V.Yashunsky, L.L.Nohara, A.C.T.Torrecilhas, A.V.Nikolaev and I.C.Almeida. Molecular Systems Biology, 5 (2009) article 261.
4. The glycogen-binding domain on the AMPK  β subunit allows the kinase to act as a glycogen sensor. A.McBride, S.Ghilagaber, A.V.Nikolaev and D.G.Hardie. Cell Metabolism, 9 (2009) 23-34.
5. Probing enzymes late in the trypanosomal glycosylphosphatidylinositol biosynthetic pathway with synthetic glycosylphosphatidylinositol analogues. M.D.Urbaniak, D.V.Yashunsky, A.Crossman, A.V.Nikolaev and M.A.J.Ferguson. ACS Chemical Biology, 3 (2008) 625-634.
6. The chemical synthesis of glycosylphosphatidylinositol anchors from Trypanosoma cruzi trypomastigote mucins: exploration of ester and acetal type permanent protecting groups. D.V.Yashunsky, V.S.Borodkin, P.G.McGivern, M.A.J.Ferguson and A.V.Nikolaev. Frontiers in Modern Carbohydrate Chemistry. ACS Symp. Ser., vol. 960 (2007), pp. 285-306.
7. Natural phosphoglycans containing glycosyl phosphate units: structural diversity and chemical synthesis. A.V.Nikolaev, I.V.Botvinko and A.J.Ross. Carbohydrate Res., 342 (2007) 297-344.
8. Palladium-catalized P-arylation of hydrophosphporyl derivatives of protected monosaccharides. I.P.Beletskaya, N.B.Karlstedt, E.E.Nifant’ev, D.V.Khodarev, T.S.Kukhareva, A.V.Nikolaev and A.J.Ross. Rus. J. Org. Chem., 42 (2006) 1780-1785.
9. Synthetic glycovaccine protects against the bite of Leishmania-infected sand flies. M.E.Rogers, O.V.Sizova, M.A.J.Ferguson, A.V.Nikolaev and P.A.Bates. The Journal of Infectious Diseases, 194 (2006) 512-518.
10. Parasite glycoconjugates. Part 16. Synthesis of a disaccharide and phosphorylated di- and tri-saccharides from Leishmania lipophosphoglycan. A.J.Ross, O.V.Sizova and A.V.Nikolaev. Carbohydrate Res., 341 (2006) 1954-1964.
11. The chemical synthesis of bioactive glycosylphosphatidylinositols from Trypanosoma cruzi containing an unsaturated fatty acid in the lipid. D.V.Yashunsky, V.S.Borodkin, M.A.J.Ferguson and A.V.Nikolaev. Angew. Chem. Int. Ed., 45 (2006) 468-474.
12. The chemical synthesis of bioactive glycosylphosphatidylinositols from Trypanosoma cruzi containing an unsaturated fatty acid in the lipid. D.V.Yashunsky, V.S.Borodkin, M.A.J.Ferguson and A.V.Nikolaev. Angew. Chem., 118 (2006) 482-488.
13. Parasite glycoconjugates. Part 15. Synthetic fragments of antigenic lipophosphoglycans from Leishmania major and Leishmania mexicana and their use for characterization of the Leishmania elongating α-D-mannopyranosylphosphate transferase. A.P.Higson, A.J.Ross, Y.E.Tsvetkov, F.H.Routier, O.V.Sizova, M.A.J.Ferguson and A.V.Nikolaev. Chem. Eur. J., 11 (2005) 2019-2030.
14. Transmission of cutaneous leishmaniasis by sand flies is enhanced by regurgitation of fPPG. M.E.Rogers, T.Ilg, A.V.Nikolaev, M.A.J.Ferguson and P.A.Bates. Nature, 430 (2004) 463-467.
15. Synthesis of potential bisubstrate inhibitors of Leishmania elongating α-D-mannosyl phosphate transferase. V.S.Borodkin, M.A.J.Ferguson and A.V.Nikolaev. Tetrahedron Lett., 45 (2004) 857-862.