Design, synthesis and functional characteristics of low molecular weight proline-rich motif (PRM) mimetics recognized by PRM binding domains

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A major reason for the difficulty in modulating protein-protein interactions (PPI) by small molecules is that they typically possess flat and rather large binding interfaces, displaying little concavity. These interactions are classified according to their specificity. An important dass of such protein domains exhibits solvent exposed regions that are able to bind the proline-rich motifs (PRM) of their target proteins. Currently, six distinct families of PRM-binding domains (PRO) (Src-homology 3 (SH3) domains, WW domains, EVH1 (Ena/VASP homology 1) domains, GYF domains, UEV (ubiquitin E2 variant) domains and profilin are known. Present in many multi-component signaling complexes, such PRDs recognize characteristic patterns of proline residues by means of stacked aromatic amino acids on their surface. Additionally, the specificity of this interaction is influenced by flanking binding epitopes. The aim of this project is to discover new specific modulators of the human EVH1 domain, the SH3-domain of the src kinase Fyn, and the YAP-WW domain, based on a new polyproline II helix mimetic structure and structural modifications developed and characterized during the previous project phase. These compounds represent a new dass of PRM mimetics and may serve äs starting points for the development of specific, pharmacologically relevant inhibitors of PRM- mediated protein-protein interaction (PPI). Additionally, we search for new lead compounds to modulate the three families of domain by screening the ChemBioNet library and by virtual screening of specifically assembled focused libraries. The project combines rational, structurebased small molecule design, structural biology, stereoselective synthesis of novel scaffolds, peptide synthesis, new scaffold-based ligation strategies, compound screening and functional characterization of the PRO modulators.