Molecular Design of Cyclic Peptides with Cell Membrane Permeability and Development of MDMX-p53 Inhibitor

Cyclic peptides have been expected to be one of the modalities of intracellular protein-protein interaction (PPI) inhibitors, but they are generally known to have low cell membrane permeability. In this study, we focused on the conformation of cyclic peptides in the cell membrane to determine the requirement for their cell membrane permeability through passive diffusion. Utilizing the requirement, we searched for structures with high affinity for MDMX via computational chemistry and acquired cyclic peptide 19 (P_app = 0.80 × 10^-6 cm s^-1, IC₅₀ = 0.07 μM).