Synthetic biopolymer conjugates

Prof. dr. Gijs van der Marel

Nucleic acids, peptides and carbohydrates are biopolymers that play essential roles in a wide array of biological processes. The same holds for naturally occurring conjugates of these molecules. To elucidate the mechanism of action of these molecules at a molecular level and ultimately modulate the biological processes in which they are involved, our group is focused on the development of synthetic approaches to (modified) oligomers and corresponding conjugates of these biopolymers. The development of new glycosylation procedures, phosphorylation methods, conjugation techniques and protective group manipulations are examples of synthetic approaches that are elaborated to attain structurally well-defined target molecules. The biological evaluation is carried out in collaboration with international renowned research groups.

Research

The role of (modified) nucleic acid fragments in biology and medicine is impressive, as exemplified by their use as primers for DNA sequencing and small interfering RNA. Our group explores the use of modified oligonucleotides as immune modulators. For instance, unmethylated CpG oligonucleotides are characteristic for bacterial DNA and can activate the mammalian innate immune system through recognition by TLR-9, a pattern-recognition receptor. Synthetic CpG oligonucleotides, stabilized by the incorporation of phosphorothioate esters, are provided with functionalities that allow both the covalent attachment of a peptide epitope and the introduction of (fluorescent) labels. Evaluation of such nucleic acid-oligopeptide conjugates provides information on fundamental immunological processes and we currently focus our attention in this area on the development of molecularly well-defined synthetic vaccines.

With the same aim, well-defined ligands for the TLR-2 receptor (the lipopeptide Pam3CK4) ligand), TLR-7 (specific unnatural nucleobases), TLR-4 ((modified) lipid A ligands) and the NOD-1 and NOD-2 receptors (fragments of bacterial peptidoglycan), are pursued. An important part of this program entails structure-activity studies to obtain an optimal, well-defined agonist for a specific pattern-recognition receptor. Subsequently conjugates comprising peptide epitopes and one or two selected ligands/agonists of pattern-recognition receptors are designed, assembled and immunologically evaluated. The projected conjugates are synthesized by solution and solid phase approaches and their advanced structures require a tailor-made combination of peptide, nucleic acid and carbohydrate chemistries, the development of new protecting groups, conjugation methods and purification techniques.

Carbohydrates not only play a role in the innate immune system as ligands of pattern-recognition receptors (such as lipid A for TLR-4 and peptidoglycans for NOD-2) but these molecules can also function as epitopes in the adaptive immune system. The same holds for teichoic acids, that are structurally unique poly(glycosyl)alditol phosphates of Gram-positive bacterial origin. To determine the role of carbohydrates and teichoic acid both in the innate and adaptive immune system our research is directed at the development of synthetic procedures to efficiently produce these classes of compounds.  Ideally a coherent set of structurally related structures is made synthetically available. Because the glycosidic linkage is one of the most challenging bonds to stereoselectively introduce a lot of attention is directed to elucidate the exact mechanism of glycosylation reactions and the influence of the reaction partners therein.

Among the posttranslational modifications of proteins, adenosine diphosphate ribosylation (ADP-ribosylation) is one of the least well understood. In order to elucidate the nature and function of this modification both well-defined fragments of poly ADP-ribosylated proteins and inhibitors (and the corresponding probes) of the enzymes involved are designed and synthesized. Because of the presence of cis-configured ribosyl adenosine moieties interconnected by pyrophosphates linkages in poly ADP-ribosylated proteins robust procedures for the synthesis of glycosylated nucleosides and phosphorylation methods allowing repeated introduction of pyrophosphates are being developed.

Projects (together with Dr. Jeroen Codee)
  • Synthesis of mono- and poly-ADP ribosylated oligomers (Hans Kistemaker)
  • Synthesis of activity- based probes for mono- and poly-ADP ribosylation (Sander Engelsma)
  • Design and synthesis of immunomodulation conjugates (Geoffroy Gential)
  • Automated solid phase oligosaccharide synthesis (Anne Geert Volbeda, Jeanine van Mechelen and Qingju Zhang)
  • New tools for complex oligosaccharide synthesis (Anne Geert Volbeda)
  • Conformational behavior of carbohydrate oxocarbenium and iminium ions (Erwin van Rijssel)
  • Glycerol phosphate containing biomolecules: protein post-translational modifications and teichoic acids (Daan van der Es)
  • Synthesis of well-defined wall teichoic acid fragments (Sara Ali)
  • Stereoselective synthesis of complex bacterial oligosaccharides (Bas Hagen)
  • High mannose type oligosaccharides for the selective delivery of inhibitors and immunomodulors (Chung Wong)
  • Automated synthesis of complex bacterial polysaccharides (Qingju Zhang)
  • Alginate biosynthesis inhibitors (Sara Khosravi)
  • Neisseria meningitidis post translational modifications (Jeanine van Mechelen)
  • Molecular immunology: design and synthesis of carbohydrate based immunomodulatory entities (Niels Reintjens)
  • Microreactor technology to harness the stereoselective formation of glycosidic bonds (Stefan van der Vorm)
  • Synthesis of labeled complex glycosphingolipids (Patrick Wisse)
  • Design and synthesis of glycosidase activity based probes (Sybrin Schroder)
  • Design and synthesis Glycosyl transferase inhibitors (Thomas Beenakker)
  1. Kistemaker, H.A.V., L.N. Lameijer, N.J. Meeuwenoord, H.S. Overkleeft, G.A. van der Marel, D.V. Filippov, "Synthesis of Well-Defined Adenosine Diphosphate Ribose Oligomers", Angewandte Chemie International Edition, vol. 54, issue 16, pp. 4915 - 4918, 04/2015. DOI: 10.1002/anie.201412283
  2. Kistemaker, H.A.V., H.S. Overkleeft, G.A. van der Marel, D.V. Filippov, "Branching of poly(ADP-ribose): Synthesis of the Core Motif", Organic Letters, vol. 17, issue 17, pp. 4328 - 4331, 09/2015. DOI: 10.1021/acs.orglett.5b02143
  3. Hogendorf, W.F.J., L.N. Lameijer, T.J.M. Beenakker, H.S. Overkleeft, D.V. Filippov, J.D.C. Codee, G.A. van der Marel, "Fluorous Linker Facilitated Synthesis of Teichoic Acid Fragments", Organic Letters, vol. 14, no. 3, pp. 848-851, Feb 3, 2012. DOI: 10.1021/Ol2033652
  4. Christina, A.E., D. van der Es, J. Dinkelaar, H.S. Overkleeft, G.A. van der Marel, J.D.C. Codee, "beta-Rhamnosides from 6-thio mannosides", Chemical Communications, vol. 48, no. 21, pp. 2686-2688, 2012. DOI: 10.1039/C2cc17623h

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