Discovery, X-ray structure and CPP-conjugation enabled uptake of p53/MDM2 macrocyclic peptide inhibitors
Anselm F. L. Schneider, Joerg Kallen, Johannes Ottl, Patrick Reid, Sebastien Ripoche, Stephan Ruetz, Therese‐Marie Stachyra, Samuel Hintermann, Christoph E. Dumelin, Christian P. R. Hackenberger, Andreas L. Marzinzik
Abstract
-translated cyclic peptides, we have identified a macrocyclic ligand that shows picomolar potency on MDM2. X-Ray crystallography reveals a novel binding mode utilizing a unique pharmacophore to occupy the Phe/Trp/Leu pockets on MDM2. Conjugation of a cyclic cell-penetrating peptide (cCPP) to the initially non cell-permeable ligand enables cellular uptake and a pharmacodynamic response in SJSA-1 cells. The demonstrated enhanced intracellular availability of cyclic peptides that are identified by a display technology exemplifies a process for the application of intracellular tools for drug discovery projects.