We have developed a system to systematically determine the reactivity of acceptor glycosides in the glycosylation reaction. This has provided key insight in how the reactivity of the acceptor influences the outcome of the glycosylation reaction. We have used this methodology to, for the first time, systematically investigate how the different groups on carbohydrate building blocks influence their reactivity and with that the outcome of the glycosylation reaction. To understand the stability and reactivity of reactive intermediates formed during the reactions, we have developed computational methods that systematically map the effect the ring substituents have on the shape and stability of these species. Our computational work has been combined with state-of-the-art spectroscopy techniques to measure these intermediates.
To modulate the reactivity of the glycosylation reactions and match the reactivity of the two coupling partners (the “donor” and “acceptor”) we have introduced different reactivity modulators and we have shown how to employ these to achieve highly stereoselective glycosylations.
Using the mechanistic insight gained by our computational and experimental investigations, we have been able to develop highly effective glycosylation reactions that have been used to effectively assemble complex biologically relevant oligosaccharides. Glycans of pathogenic worms (schistosomes) have been synthesized and used for diagnostic purposes. With the synthesized glycans we have been able to detect antibodies directed at the glycans of the worms and we have been able to correlate these to recent infections. These preliminary results show that the glycans can be used in future diagnostic tools to help eradicate these impactful infections. So-called galactosaminogalactans have been synthesized and used in studies to unravel the biosynthesis of these molecules, which occur in pathogenic bacteria (such as Pseudomonas aeruginosa) and pathogenic fungi (Aspergillus fumigatus). Using our synthetic glycans the mode of action of several biosynthesis enzymes has been unraveled and this paves the way to interfere with this machinery opening up new avenues for the development of antibiotics. In addition, we have been able through detailed structural studies to discover a new type of molecular interaction that stabilizes the overall structure of the oligosaccharides. We have been able to generate well-defined fragments of polysaccharides of Staphylococcus aureus, a “super bug” that has acquired resistance to almost all available antibiotics. The synthesized structures can be used in innovative synthetic vaccines to combat this successful bacterium. The stereoselective glycosylation methodology that we developed has also allowed us to generate synthetically challenging glycomimetics (“sugar lookalikes”) that can be used to discover and inhibit carbohydrate processing enzymes.
The results of these studies have been published in various publications, that have been published in high tier journals, reaching a large and diverse audience. The results have been presented in many lectures, given at conferences and at universities and research institutes.
