Objective

The target portfolio of pharmaceutical industry is continuously expanding into unchartered target space. Many biologically attractive targets possess large, shallow, or weakly defined areas for ligand interaction (e.g. PPIs) and are not deemed readily suitable for commonly applied small molecule discovery approaches. Correspondingly, the identification of potent ligands for such targets either as tools to probe the biological function or as starting point for medicinal chemistry has been found to be very challenging. Macrocyclic peptides are considered an appropriate chemical format to address such difficult targets. Traditional methods for the discovery of macrocyclic ligands such as synthesis and screening of small libraries or display technologies based on the twenty natural amino acids demonstrated limited success thus far. More recently developed in-vitro display technologies allow the incorporation of unnatural amino acids to expand the chemical space of the identified hits. We internalized such a platform from Peptidream which allows the incorporation of a large variety of unnatural amino acids into stably cyclized peptide libraries containing trillions of molecules. In this talk, we will discuss the application of such encoded peptide libraries for the identification of MDM2 inhibitors