| Multivalency has been recognized as an important strategy to develop semi-synthetic ligands with high affinity and specificity for biological targets. Most research in this field has focussed on synthetic scaffolds bearing carbohydrate binding units, e.g. as inhibitors of cell-virus interactions. Here we propose to apply this strategy to develop semi-synthetic multivalent proteins and peptides, as proteins play a central role in biomolecular recognition processes. We recently developed a general synthetic methodology that allows conjugation of both peptides and recombinant proteins to cysteine-functionalized dendrimers using native chemical ligation. Covalent protein and peptide dendrimers provide a good starting point to gain a molecular understanding of multivalent interactions and to investigate their potential in a variety of biomedical applications. In addition we will explore different possibilities to obtain multivalent protein and peptide systems based on dynamic, noncovalent interactions. This approach allows access to more complex biomolecular constructs that have the unique ability to reorganize into the tightest binding configuration in the presence of the target. Such self-organizing biomolecular constructs are attractive ligands for molecular recognition of complex biological targets and are expected to find applications in drug delivery, molecular imaging and proteomics. Three specific topics have been defined with these challenges in mind: " Affinity maturation of phage-display derived peptides using dendrimer display. Streptavidin will be used as a well-defined model sytem, while collagen will be studied as a biomedically relevant target. " Synthesis and characterization of (non)covalent protein dendrimers. The noncovalent but strong interaction between the S-peptide and S-protein in RNaseS will be used as an efficient method to prepare protein dendrimers. " Multivalent peptides and proteins using alternative supramolecular interactions. Two systems will be explored: protein micelles consisting of PEGylated lipids and G-quadruplexes formed by association of guanine repeats. |
