Erkennen von Proteinoberflächen durch ungewöhnliche Substrat-analoge Inhibitoren am Beispiel der cAMP-abhängigen Proteinkinase A

In the course of this collaborative work with the workgroups GEYER and DEHNEN from Marburg and SCHREINER from Gießen that was financed by the LOEWE-SynChemBio-project we wanted to establish new concepts for the developement of new, selective peptidic ligands for protein kinases and verify these concepts via binding assays, protein cristallization and structural determination via X-Ray diffraction. We tried to insert ribo-amino acids into the peptidic ligand PKI to introduce linker-groups for covalent assembly with boronic acids. Afterwards we tried to use derivatives containing boronic acids of the highly potent literature known inhibitor Fasudil, which binds in the ATP binding pocket of kinases, in the hopes of orienting the phenylboronic acids in the direction of the peptidic ligand binding pocket. This way, we hoped to generate self-assembling complexes between the Ribose from the peptidic ligand and the phenylboronic acid from the Fasudil-derivatives, whose formation was proven by Dr. ROMINA KIRSCHNER via NMR in DMSO in solution in a protein environement and thereby link both binding pockets.