Design, synthesis and functional characteristics of low molecular weight proline-rich motif (PRM) mimetics recognized by PRM binding domains
Final Report Abstract
Protein-protein interactions (PPI) are often mediated by specialized domains that represent difficult targets for ligand design. A particularly prominent group of such domains like ena/VASP homology 1 (EVH1), src-homology 3 (SH3), WW and GYF domains specifically recognize short proline-rich motifs (PRM) adopting a left-handed polyproline II helix (PPII) conformation. PRM-mediated PPI are widely utilized by nature and are involved in several relevant biological processes such as tyrosine kinase receptor signalling, endocytosis, cytoskeletal rearrangements, transcription, and splicing. Competitive small organic compounds are, so far, not known. Within the project, we developed a toolkit of rationally designed new chemical entities mimicking diproline and xP fragments in PPII conformation. Based on these building blocks we developed highly effective non-peptidic inhibitors of ena/VASP family EVH1 domains. We could show that these new inhibitors modulate the actin filament synthesis in invasive cancer cell lines. To prove that our toolkit of building blocks offers many applications, we synthesized peptide chimeras based on known Fyn-SH3, YAP-WW, and GYF peptides where PRMs are replaced by the new building blocks. We could demonstrate that these compounds bind to the specific PRM-binding regions of these domains.
Publications
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(2010) Practical One-pot Double Functionalizations of Proline, Synthesis, 6, 954-960
Huy, P., Schmalz, H.-G.
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(2010). Addressing protein protein interactions by small molecules: A designed Pro-Pro dipeptide mimic with a PPII helix conformation as a module for the synthesis of PRD-binding ligands. Angewandte Chemie, Int. Ed., 49, 7111-7115
Zaminer, J., Brockmann, C., Huy, P., Opitz, R., Reuter, C., Beyermann, M., Freund, C., Müller, M., Oschkinat, H., Kühne, R., and Schmalz, H.-G.
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(2011). A Practical Synthesis of Trans-3-Substituted Proline Derivatives through 1, 4-Addition, Org. Lett.,13, 216-219
Huy, P.; Neudörfl, J.-M.; Schmalz, H.-G.
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(2011). Exercises in Pyrrolidine Chemistry: Gram Scale Synthesis of a Pro-Pro Dipeptide Mimetic with a PPII Helix Conformation. Chem. Eur. J. 17, 12037-12044
Reuter, C., Huy, P., Neudörfl, J.-M., Kühne, R., Schmalz, H.-G.
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(2013). Efficient α-helix induction in a linear peptide chain by N-capping with a bridged-tricyclic diproline analogue. Angew Chem. Int Ed Engl. 52, 9539-9543
Hack V., Reuter C., Opitz R., Schmieder P., Beyermann M., Neudörfl J.M., Kühne R., Schmalz H.-G.
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(2014). Stereoselective Synthesis of Proline-Derived Dipeptide Scaffolds (ProM-3 and ProM-7) Rigidified in a PPII Helix Conformation. Eur. J. Org. Chem.
Reuter, C.; Kleczka, M.; de Mazancourt, S.; Neudörfl, J.-M.; Kühne, R.; Schmalz, H.-G.
