Strategie zur Identifizierung zyklischer Peptide als selektive Inhibitoren von RNA-Protein-Wechselwirkungen zur antibakteriellen Therapie

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Structured RNA-elements play an important role in the gene regulation of viruses, bacteria as well as eukrayotes. Bacteria use so called riboswitches in the mRNA to link gene expression to their metabolism. Binding of ligands to the riboswitch induces conformational changes resulting in the inhibition of transcription or translation of the respect gene. Cyclic peptides (ZP) belong to the most effective, high-affinity drug-like agents, which are extremely stable, flexible, variable and exhibit a wide range of biological activities. Recently methods were developed to generate libraries of genetically encoded and expressed cyclopeptides, which allow the direct identification of the active member when combined with an in vivo screening assay. Aim of the here proposed project is to establish an in vivo screening assay to identify ZPs from an expressed library, specifically binding to structured and conserved RNA elements in bacterial mRNAs in order to inhibit growth of pathogenic bacteria. These ZP-RNA interactions will be biochemical, biophysical and structural characterised and their conformational states theoretically and biophysically analysed. Based on these results, chemical modifications influencing the dynamics of the ZPs will be introduced, resulting in an increased binding probability and affinity to the target RNA.