Targeting intracellular protein-protein interactions with cell-permeable cyclic peptides

Intracellular protein-protein interactions (PPIs) are challenging targets for conventional drug modalities, because small molecules generally do not bind to their large, flat binding sites with high affinity, whereas monoclonal antibodies cannot cross the cell membrane to reach the targets. Cyclic peptides in the 700-2000 molecular-weight range have the sufficient size and a balanced conformational flexibility/rigidity for binding to flat PPI interfaces with antibody-like affinity and specificity. Several powerful cyclic peptide library technologies were developed over the past decade to rapidly discover potent, specific cyclic peptide ligands against proteins of interest including those involved in PPIs. Methods are also being developed to enhance the membrane permeability of cyclic peptides through both passive diffusion and active transport mechanisms. Integration of the permeability-enhancing elements into cyclic peptide design has led to an increasing number of cell-permeable and biologically active cyclic peptides against intracellular PPIs. In this account, we review the recent developments in the design and synthesis of cell-permeable cyclic peptides.