Synthetic carbohydrate chemistry for glycobiology

Dr. Jeroen Codée

Carbohydrates are the most diverse and complex class of biomolecules from both a structural and biological activity point of view. Our research focuses on the development of synthetic tools and strategies, including automated solid phase procedures, to efficiently assemble well-defined oligosaccharides and glycoconjugates to unravel their mode of action at the molecular level. State-of-the-art synthetic chemistry is used to generate synthetic vaccine modalities (directed at bacterial infections and cancer) and in the design and synthesis of inhibitors and probes to study carbohydrate metabolism.

Research

The complexity of oligosaccharides and glycoconjugates - and their biological mode of action - originates from the often subtle but immensely diverse structural variety in carbohydrate monomers and the way that they are interconnected. The subtle structural differences of the carbohydrate mono- and oligomers have a major impact on their chemistry and biology, which is still too little understood. Although we are now capable of synthesizing very complex oligosaccharides, a thorough understanding on the stereoselective construction of glycosidic bonds is still lacking and this is one of the focal points of our research. We aim to develop robust stereoselective glycosylation procedures and unravel their mechanistic pathways. To this end we employ both experimental procedures as well as theoretical approaches. The synthetic insights obtained are used in the construction of libraries of oligosaccharides and we are one of the two labs worldwide to operate an automated solid phase oligosaccharide synthesizer to speed up the assembly process. The generated oligosaccharides are being used in biochemical studies to unravel their mode of action at the molecular level. An area of intense current interest is molecular immunology where we try to understand how various carbohydrate-based molecules interact with our immune system. We generate well-defined single molecules to use them as synthetic antigens, to be used by the adaptive immunesystem, or adjuvants (molecules that boost our immune system) to interact with specific players of the innate immune system. With this knowledge we generate synthetic vaccines with tailor made properties.

Interfering with carbohydrate metabolism and catabolism is another attractive way to combat pathogens or treat diseases. To this end we design and synthesize probes and inhibitors that target glycosidases (enzymes that break-down oligosaccharides and glycoconjugates), glycosyl transferases (enzymes that build-up oligosaccharides), and inhibitors for enzymes that modify oligosaccharides (acetyl transferases and epimerases for example). The synthesis of these probes/inhibitors often involves intricate multi-step routes of synthesis and it requires a through appreciation of synthetic carbohohydrate chemistry.

Projects (together with Prof. Gijs van der Marel)
  • Synthesis of mono- and poly-ADP ribosylated oligomers (Hans Kistemaker)
  • Synthesis of activity- based probes for mono- and poly-ADP ribosylation (Sander Engelsma)
  • Design and synthesis of immunomodulation conjugates (Geoffroy Gential)
  • Automated solid phase oligosaccharide synthesis (Anne Geert Volbeda, Jeanine van Mechelen and Qingju Zhang)
  • New tools for complex oligosaccharide synthesis (Anne Geert Volbeda)
  • Conformational behavior of carbohydrate oxocarbenium and iminium ions (Erwin van Rijssel)
  • Glycerol phosphate containing biomolecules: protein post-translational modifications and teichoic acids (Daan van der Es)
  • Synthesis of well-defined wall teichoic acid fragments (Sara Ali)
  • Stereoselective synthesis of complex bacterial oligosaccharides (Bas Hagen)
  • High mannose type oligosaccharides for the selective delivery of inhibitors and immunomodulors (Chung Wong)
  • Automated synthesis of complex bacterial polysaccharides (Qingju Zhang)
  • Alginate biosynthesis inhibitors (Sara Khosravi)
  • Neisseria meningitidis post translational modifications (Jeanine van Mechelen)
  • Molecular immunology: design and synthesis of carbohydrate based immunomodulatory entities (Niels Reintjens)
  • Microreactor technology to harness the stereoselective formation of glycosidic bonds (Stefan van der Vorm)
  • Synthesis of labeled complex glycosphingolipids (Patrick Wisse)
  • Design and synthesis of glycosidase activity based probes (Sybrin Schroder)
  • Design and synthesis Glycosyl transferase inhibitors (Thomas Beenakker)
  1. Zhang, Q., E.R. van Rijssel, M.T.C. Walvoort, H.S. Overkleeft, G.A. van der Marel, J.D.C. Codée, "Acceptor Reactivity in the Total Synthesis of Alginate Fragments Containing α-", Angewandte Chemie International Edition, vol. 54, issue 26, pp. 7670 - 7673, 06/2015. DOI: 10.1002/anie.201502581
  2. van Rijssel, E.R., P. van Delft, G. Lodder, H.S. Overkleeft, G.A. van der Marel, D.V. Filippov, J.D.C. Codée, "Furanosyl Oxocarbenium Ion Stability and Stereoselectivity", Angewandte Chemie International Edition, vol. 53, issue 39, pp. 10381 - 10385, 09/2014. DOI: 10.1002/anie.201405477
  3. Laverde, D., D. Wobser, F. Romero-Saavedra, W. Hogendorf, G. van der Marel, M. Berthold, A. Kropec, J. Codee, et al., "Synthetic Teichoic Acid Conjugate Vaccine against Nosocomial Gram-Positive Bacteria", PLoS ONE, vol. 9, issue 10, pp. e110953, 10/2014. DOI: 10.1371/journal.pone.0110953
  4. Walvoort, M.T.C., H. van den Elst, O.J. Plante, L. Krock, P.H. Seeberger, H.S. Overkleeft, G.A. van der Marel, J.D.C. Codee, "Automated Solid-Phase Synthesis of beta-Mannuronic Acid Alginates", Angewandte Chemie-International Edition, vol. 51, no. 18, pp. 4393-4396, 2012.
  5. Barroso, S., R. Castelli, M.P. Baggelaar, D. Geerdink, B. ter Horst, E. Casas-Arce, H.S. Overkleeft, G.A. van der Marel, et al., "Total Synthesis of the Triglycosyl Phenolic Glycolipid PGL-tb1 from Mycobacterium tuberculosis", Angewandte Chemie-International Edition, vol. 51, no. 47, pp. 11774-11777, 2012.

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