Multivalent ligands for adaptive intracellular protein receptors (B09*)

• Subject Area: Biological and Biomimetic Chemistry
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 32049920

In project B9 flexible multivalent protein ligands will be developed as inhibitors of flexible multvalent protein-protein interactions and investigated in intracellular applications. As target proteins we will study two types of bivalent protein receptors, the tandem-WW-domain of FBP21 and the tandem SH2 domains of SYK- and ZAP70 kinases. Cell-permeable multivalent peptide polymers will be prepared by modular coupling of functional peptides, transport peptides, and fluorophores onto carrier polymers. Parameters for the design of peptide polymers will be derived from a comparison of the binding properties of several different biocompatible polymers. Relevant recorded parameters include the enthalpic and entropic contributions to the free energy of binding, the stoichiometry of the interaction and the aggregation behavior of the multivalent ligand-protein complexes. Conclusions for the construction of optimized multivalent polymeric ligands will be derived from molecular dynamics simulations conducted in C2 (Weber) and will be subsequently challenged in functional biological experiments.

• DFG Programme: Collaborative Research Centres
• Subproject of: SFB 765: Multivalency as Chemical Organisation and Action Principle: New Architectures, Functions and Applications
• Applicant Institution: Freie Universität Berlin
• Project Head: Professor Dr. Jörg Rademann