Rational Activity Improvement of Cyclic Peptides through Stabilization and Rigidification of Main Chain Using φ/ψ Plots of Amino Acids

Medium-sized cyclic peptides that target challenging protein-protein interactions are promising as a new therapeutic modality. To enhance activity, rigidifying the bioactive conformation of these peptides has a great opportunity due to their higher number of rotatable bonds compared with small molecules. In this study, we classified 36 types of α-amino acids (natural and non-natural) and calculated their φ/ψ free energy maps and main chain torsional entropy, a measure of rigidity, for each category. By comparing the φ/ψ torsional angles from the X-ray structure of the hit peptide AP0343 with the computed φ/ψ maps, we demonstrated that the main chain structure could be rationally rigidified. We validated this approach for the derivatization of AP0343 to the clinical KRAS inhibitor LUNA18 and confirmed its utility in an actual drug discovery project. This method is effective for optimizing main chain structures and advancing orally available medium-sized cyclic peptides.