Zwitterionic oligosaccharides: charging the immune system
How are carbohydrates processed by the immune system? Can carbohydrates be used to trigger T-cells against other conjugated antigens? Can they be used as adjuvants?
- Jeroen Codee
- NWO Vidi
Well defined, synthetic oligosaccharides are invaluable tools to the growing field of glycobiology research. The development of improved synthetic methods to acquire sufficient amounts of (ever more complex) carbohydrates is therefore imperative. This project aims at bringing synthetic carbohydrate chemistry to the necessary higher level. Jeroen Codée aims to advance our fundamental knowledge regarding the key glycosylation process and at the same time develop state-of-the-art synthetic technology. Microreactor technology will be implemented to gain maximum control over glycosidic bond formation and investigate how stereoselectivity develops at temperatures, unfeasible for conventional equipment. Automated synthesis will be set up to efficiently assemble larger oligomers. These innovations will be directed at the assembly of a library of zwitterionic polysaccharide (ZP)-fragments of unprecedented diversity and complexity. ZPs, carbohydrate polymers containing both positively and negatively charged groups, display unique biological activities and act on both the innate and adaptive immune system by interacting with Toll-like receptors and recruiting T-cells. Especially the latter peptide-like behaviour is remarkable, since other carbohydrates are not capable of this type of interaction. It is clear that both the positive and the negative charges on the polysaccharide are important for activity, but insight into the molecular mode of action is lacking. The ZP-library will be probed for TLR activating capacity, T-cell stimulating behaviour and antigenicity. Once active ZP-fragments have been identified detailed studies towards their interaction with biological binding partners can be undertaken.
The compounds will be applied to develop new vaccine strategies and used to answer fundamental immunological questions: How are carbohydrates processed by the immune system? Can carbohydrates be used to trigger T-cells against other conjugated antigens? Can they be used as adjuvants? This will ultimately lead to the use of ZP-fragments in immunomodulatory therapeutics or as a component of tailor-made synthetic vaccines with well-defined properties.