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Dr. Roland J. Pieters |
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Department of
Medicinal Chemistry and Chemical Biology Associate Professor
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Utrecht Institute for Pharmaceutical Sciences Department of Medicinal Chemistry and Chemical Biology
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Glycodendrimers are used to explore multivalency effects in receptor-ligand interactions. Carbohydrate ligands are involved in important biological processes, yet typically exhibit limited binding power. Multivalent presentation can dramatically increase affinities. Synthetic methodology, e.g. based on click chemistry and analytical protocols were developed that ensure reliable synthesis and well-defined materials. Cholera toxin, the causative agent of cholera, is a pentavalent protein for which ligands were developed. Successful systems were prepared based on a GM-1 mimic and more recently on natural gangliosides. Large multivalency enhancements (up to 2 million ) were observed.
Anti-infective compounds/Antibiotics
Anti-adhesion: Glycodendrimers were prepared that bind to bacteria so they can no longer infect. The pathogens include P. aeruginosa, Streptococcus suis and E. coli . Specific carbohydrate sequences were obtained through modern glycoside assembly strategies (on solid phase, in solution) or biocatalytic processes. The multivalency effect greatly varied from system to system and important rationalizations were made. For S. suis an octavalent ligand was 3000-fold more potent than its monovalent counterpart, effects translated to our initial animal studies in a mouse model and represents the first study of its kind. A significant part of this work was performed within the EU project POLYCARB.
Vancomycin models: a series of simplified model compounds of the antibiotic of last resort Vancomycin were made. Selected members were shown to be more effective towards Vancomycin-resistant bacteria than Vancomycin itself.
Antimicrobial peptides: Novel multivalent structures based on antimicrobial peptides were successful and able to puncture model membranes at up to 1000-fold lower concentrations than the original peptide.
Galectins
These are galactose-specific lectins that are especially relevant due to their involvement in cancer. Two aspects: 1) Inhibition: Our multivalent lactose systems were highly active galectin inhibitors, and we also discovered peptides with galectin afffinty. 2) Detection/Proteomics: It is important to know the amounts of the various galectins in tissues, particularly cancerous tissues, for diagnosis and prognosis. We developed a chemical photoprobe with galectin selectivity for this purpose. Using novel microwave chemistry, a carbohydrate ligand was outfitted with a photoreactive group, whose position proved a crucial factor. After successful covalent capture of the protein, click chemistry was used to attach a fluorescence tag to allow selective galectin visualization even in complex lysates and of natural galectin-3 in a tumor cell line. A peptide probe was able to do the same but binds to a different part of the protein.
News items:
-Highly accessed article in ChemBioChem
-Coverpage of Bioorg. Med. Chem. Lett. 2005
-Coverpage of ChemBioChem 2005
-Research highligh, Farmacopij (local departmental newsletter, Dutch, 2006)
-Research highlight, NPC highlights (English, Netherlands Proteomics Center, 2005)
-POLYCARB article in Geo Magazine (German)
-POLYCARB press release (German)
Intervention with Bacterial Adhesion by Multivalent Carbohydrates, Pieters, R. J. Med. Res. Rev. 2007 , in press, available on-line, DOI 10.1002/med.20089.
Solid phase carbohydrate synthesis via on-bead protecting group chemistry, Branderhorst H. M., Liskamp, R. M. J.; Pieters, R. J. Tetrahedron 2007 , in press, available on-line, doi:10.1016/j.tet.2007.03.051.
Detection of galectin-3 by novel peptidic photoprobes, van Scherpenzeel, M.; van der Pot, M.; Arnusch, C. J.; Liskamp, R. M. J.; Pieters, R. J. Bioorg. Med. Chem. Lett. 2007 , 17, 376-378.
Inhibition and Detection of Galectins, Pieters, R. J. ChemBioChem , 2006 , 7 , 721-728.
A New Chemical Probe for the Detection of the Cancer-Linked Galectin-3, Ballell, L; van Scherpenzeel, M.; Buchalova, K.; Liskamp, R. M. J.; Pieters, R. J. Org. Biomol. Chem. 2006, 4 , 4387-4394.
Tannic Acid Mimicking Dendrimers as a Small Intestine Submucosa Stabilizing Nanomordant, Kasyanov, V.; Isenburg, J.; Draughn, R. A.; Hazard, S.; Hodde, J.; Ozolanta, I.; Murovska, M.; Halkes, S. B. A.; Vrasidas, I.; Liskamp, R. M. J.; Pieters, R. J.; Simionescu, D.; Markwald, R. R.; Mironov, V. Biomaterials , 2006 , 27 , 745-751 .
Identification of Peptide Ligands for Malignancy and Growth-Regulating Galectins Using Random Phage-Display and Designed Combinatorial Peptide Libraries, Andre, S.; Arnusch, C. J.; Kuwabara, I.; Russwurm, R.; Kaltner, H.; Gabius, H.-J.; Pieters, R. J. Bioorg. & Med. Chem . 2005 , 13 , 563-573.
A New Chemical Probe for Proteomics of Carbohydrate Binding Proteins, Ballell, L.; Alink, K. J.; Slijper, M.; Versluis, C.; Liskamp, R. M. J.; Pieters, R. J. ChemBioChem , 2005 , 6, 291–295.
Novel multivalent mannose compounds and their inhibition of the adhesion of type 1 fimbriated uropathogenic E. coli, Appeldoorn, C. C. M.; Joosten, J. A. F.; Ait el Maate, F.; Dobrindt, U.; Hacker, J.; Liskamp, R. M. J.; Salam Khan, A.; Pieters, R. J. Tetrahedron Asymmetry, 2005 , 16, 361-372.
Identification of laminin-binding motifs of Yersinia pestis plasminogen activator by phage display, Benedek, O; Khan, A. S.; Schneider, G.; Nagy, G.; Autar, R.; Pieters, R. J.; Emödy, L. Int. J. Med. Microbiol. 2005 , 295 , 87-98.
High yielding microwave assisted synthesis of triazole-linked glycodendrimers via copper catalyzed [3+2] cycloaddition, Joosten, J. A. F.; Tholen, N. T. H.; Ait El Maate, F.; Brouwer, A. J.; van Esse, G. W.; Rijkers, D. T. S.; Liskamp, R. M. J.; Pieters, R. J. Eur. J. Org. Chem. 2005 , 3182-3185.
A facile synthesis of the GalNAc-beta1-4Gal target sequence of respiratory pathogens, Autar, R.; Liskamp, R. M. J.; Pieters, R. J. Carbohydr. Res. 2005 , 340 , 2436-2442.
Efficient microwave-assisted synthesis of multivalent dendrimeric peptides using cycloaddition reaction (click) chemistry, Rijkers, D. T. S; van Esse, G. W.; Merkx, R.; Brouwer, A. J.; Jacobs, H. J. F.; Pieters, R. J.; Liskamp, R. M. J. Chem. Commun. 2005 , 4581-4583.
Interference of the Galactose-dependent Binding of Lectins by Novel Pentapeptide Ligands, Arnusch, C. J.; Andre, S.; Valentini, P.; Lensch, M.; Russwurm, R.; Siebert, H.-C.; Fischer, M J. E.; Gabius, H.-J.; Pieters, R. J. Bioorg. Med. Chem. Lett. 2004 , 14 , 1437-1440.
Synthesis of a Novel 14-membered Highly Constrained Cyclic Peptide Scaffold, Arnusch, C. J.; Pieters, R. J. Tetrahedron Lett. 2004 , 45, 4153-4156.
Interference with Lectin Binding and Bacterial Adhesion by Multivalent Carbohydrates and Peptidic Carbohydrate Mimics, Pieters, R. J., Trends in Glycoscience and Glycotechnology 2004 , 16 , 243-254.
Synthesis and Cholera Toxin Binding Properties of Multivalent GM1 Mimics, Arosio, D.; Vrasidas, I.; Valentini, P.; Liskamp, R. M. J.; Pieters, R. J.; Bernardi, A. Org. & Biomol. Chem. 2004, 2 , 2113-2124.
Microwave-Assisted, Tin-Mediated, Regioselective 3- O -alkylation of Galactosides, Ballell, L.; Joosten, J. A. F.; Ait el Maate, F.; Liskamp R. M. J.; Pieters, R. J. Tetrahedron Lett. 2004, 45 , 6685-6687.
Inhibition of Streptococcus Suis Adhesion by Dendritic Galabiose Compounds at Low Nanomolar concentration, Joosten, J. A. F.; Loimaranta, V.; Appeldoorn, C. C. M.; Haataja, S.; Ait El Maate, F.; Liskamp, R. M. J.; Finne, J.; Pieters, R. J. J. Med. Chem. 2004, 47 , 6499-6508.
Rigidified Multivalent Lactose Molecules and Their Interactions With Mammalian Galectins: A Route to Selective Inhibitors, Vrasidas, I; Andre, S.; Valentini, P.;Böck, C.; Lensch, M.; Kaltner H.; Liskamp, R. M. J.; Gabius, H.-J.; Pieters, R. J. Org. & Biomol. Chem. 2003 , 1, 803-810.
Homodimeric galectin-7 (p53-induced gene 1) is a Negative Growth Regulator for Human Neuroblastoma Cells, Kopitz, J.; Andre, S.; von Reitzenstein, C.; Versluis, K.; Kaltner, H.; Pieters, R. J.; Wasano, K.; Kuwabara, I.; Liu, F.-T.; Cantz, M.; Heck, A. J. R.; Gabius, H.-J, Oncogene, 2003 , 22 , 6277-6288.
Solid Phase Synthesis of Vancomycin Mimics, Arnusch, C. J.; Pieters, R. J. Eur. J. Org. Chem. 2003 , 3131-3138.
Adhesion inhibition of F1C fimbriated Escherichia coli and Pseudomonas aeruginosa PAK and PAO by multivalent carbohydrate ligands, Autar, R.; Khan, A. S.; Schad M.; Hacker, J.; Liskamp R. M. J.; Pieters, R. J. ChemBioChem. 2003 , 4 , 1317-1325.
Synthesis and Cholera Toxin Binding Properties of a Lactose-2-Aminothiazoline Conjugate, Vrasidas, I.; Kemmink, J.; Liskamp, R. M. J.; Pieters, R. J. Org. Lett. 2002 , 4, 1807-1808.
Synthesis and Biological Activity of Polygalloyl-Dendrimers as stable Tannic Acid Mimics, Halkes, S. B. A.; Vrasidas, I.; Rooijer, G. R.; Van den Berg, A. J. J.; Liskamp, R. M. J.; Pieters, R. J. Bioorg. Med. Chem. Lett. 2002 , 12 , 1567-1570.
Catalytic Conversions of Diazosugars, Branderhorst, H. M.; Kemmink, J.; Liskamp, R. M. J.; Pieters, R. J. Tetrahedron Lett. 2002 , 43 , 9601-9603.
Wedge-like Glycodendrimers as Inhibitors of Binding of Mammalian Galectins to Various Glycoproteins, Lactose Maxiclusters and Tumor or Blood Cell Surface Glycoconjugates, Andre, S.; Pieters, R. J.; Vrasidas, I.; Kaltner, H.; Kuwabara, I.; Liu, F.-T, Liskamp, R. M. J.; Gabius, H.-J ChemBioChem . 2001 , 2 , 822-830.
Synthesis of Lactose Dendrimers and Multivalency Effects in Binding to the Cholera Toxin B Subunit, Vrasidas, I.; de Mol, N. J.; Liskamp, R. M. J.; Pieters, R. J . Eur. J. Org. Chem. 2001 , 4685-4692.
Synthesis and Binding Studies of Carboxylate Binding Pocket Analogs of Vancomycin, Pieters, R. J. Tetrahedron Lett. 2000 , 41 , 7541-7545.
Publications as a (graduate) student and post-doc