Synthetic Medicinal Chemistry
- Design and synthesis of high-affinity multivalent carbohydrate ligands
- Molecular recognition of phosphopeptides and peptidomimetics by SH2 domains
- Interference with protein-protein aggregation and formation of amyloid fibrils
- Covalent control of shape and folding in peptides among others by Ring Closing Metathesis
- Synthetic receptors and synthetic antibodies
Several advancements have been made towards design, synthesis and evaluation of biomolecular constructs capable of modulating peptide-protein, protein-protein and carbohydrate-protein interactions. Diphosphorylated peptide-peptidomimetics were capable of competing with crucial protein-protein interactions in signal transduction involved in e.g. allergy. Peptide-peptidomimetic constructs were designed and synthesized capable of interfering with aggregation and fibril formation of islet amyloid in diabetes. Since carbohydrate-protein interactions are relatively weak, multivalency is a powerful approach to increase binding affinity. Different generations of amino acid based dendrimers of varying rigidity and diversity ("combimers") were designed and synthesized and served as multivalent scaffolds for carbohydrates. Large effects were observed on the binding of carbohydrate binding proteins (ga)lectins and cholera toxin. Dendrimers were also used in the multivalent presentation of tannic acid derivatives for improvement of long-term burn wound healing characteristics. A new selectively deprotectable triazacyclophanescaffold was introduced for the construction of artificial receptors. This led to the synthesis and screening of libraries of synthetic tripodal receptor molecules with three different amino acid or peptide arms. Cyclotriveratrylene scaffolds have been successfully used in the organization of large peptide sequences i.e. enhancing the triple-helix formation of collagen peptides. Other large peptides and peptidomimetics which became accessible are azido peptides and b-peptidosulfonamide-b-peptide hybrids.