Periodic Reporting for period 4 - GLYCONTROL (Understanding and Controlling Glycosylation Reactions)
Okres sprawozdawczy: 2021-11-01 do 2022-10-31
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.
The computational methods we have developed have been used to understand the reactivity of “families of compounds” as opposed to studies that focus on a single substrate. This has allowed us to understand how all functional groups present on the carbohydrate rings influence the reactivity of these as stand-alone entities but also in the context of the substituents present. The insight gained has gone far beyond the state-of-the-art as no tools were available to systematically dissect the stereo-electronic effects of these groups.
With our developed methodology we have been able to generate biologically relevant glycans that have never been synthesized before and that therefore have never been available for biological follow-up studies. We have thus been able, by use of the library our synthetic glycans, to unravel the mode of action of different biosynthesis enzymes, the activity of which was previously ill-understood. This will open up possibilities to interfere with these enzymes and in doing so develop new antibiotics.
The insight gained into the glycosylation reaction has made it possible to generate complex bacterial glycans, previously beyond reach, that are now available for the development of synthetic vaccines.