D/L-PEPTIDE LIBRARY · Antibacterial lead discovery with D/L-peptide libraries

Nowadays, a multitude of examples for targeting enzymes with small molecules is known, whereas the direkt access to macromolecular interaction, such as DNA/protein, RNA/protein and protein/protein within the cell still waits to be solved by generic methods. We intend to create a toolbox for targeting these interactions with D-/L-peptides, a new class of biostable oligomer ligands. Initially we will establish split-and-pool libraries using postsynthetic dimerization of two orthogonal pairing partners which can be expected to form stable folds of the size of interactive protein subdomains. In a second approach, specific target functions and interaction domains will be used to generate new ligands by design and structural analogy. Folding and secondary structure preference of the most potent constructs will be elucidated (CD, NMR, FRET) to deduce preferences for pairing, minimal sequence length, and composition. Macromolecular targets and activity will be further studied using fluorescence microscopy and protein binding assays.