PROTEIN CARBOHYDRATE INTERACTIONS AND DISEASE

The recognition of carbohydrates by proteins is an important phenomenon in living systems and also plays a role in numerous diseases. Interference with these interactions is an important goal towards drug development. Interference is possible by multivalent carbohydrates that greatly enhance inhibitory potency compared to monovalent inhibitors. Bacterial lectins and toxins have been explored with the goal of optimizing inhibition by optimizing the multivalent presentation of the ligands. The optimization process depends on the orientation of the binding sites and different solutions were fond for the pentavalent cholera toxin [1] in comparison with the functionally divalent adhesion lectin LecA of Pseudomonas aeruginosa [2]. Besides lectins, carbohydrates processing proteins are important and we have studied the inhibition of glycosidases by modified iminosugars. These guanidiniums [3] and pseudo-ureas were particularly portent inhibitors of the human beta-glucocerebrosidase with low nanomolar inhibition. Finally, we are involved in the study of O-GlcNAcylation of serine and threonine residues of proteins.  In order to study the addition and removal of GlcNAc moieties we used a peptide microarray and were able to find specific conditions to measure and also inhibit these processes and measure cross-talk with kinases [4]. 

References

[1]  Zomer-van Ommen, D.; Pukin, A.; Fu, O.; Quarles van Ufford, L.; Janssens, H.; Beekman, J.; Pieters, R. J. J. Med. Chem. 2016, 59, 6968-6972.

[2] a) Visini, R.; Jin, X.; Bergmann, M.; Michaud, G.; Pertici, F.; Fu, O.; Pukin, A.; Branson, T. R.; Thies-Weesie, D. M. E.; Kemmink, J.; Gillon, E.; Imberty, A.; Stocker, A.; Darbre, T.; Pieters, R. J.; Reymond, J.-L. ACS Chemical Biology, 2015, 10, 2455-2462 ; b) Pertici, F.; de Mol, N.; Kemmink, J.; Pieters, R. J. Chem. Eur. J.  2013, 19, 16923-16927.

[3] Sevšek, A; Šrot, L.; Rihter, J.; Čelan, M.; Quarles van Ufford, L.; Moret, E. E.; Martin, N. I.; Pieters, R. J ChemMedChem, 2017, 12, 483-486..

[4] Shi, J.; Tomašič, T.; Sharif, S.; Brouwer, A.J.; Anderluh, M.; Ruijtenbeek, R.; Pieters, R.J. FEBS Letters, 2017, 591, 1872-1883.