Chapter 8: Bicyclic Peptide Inhibitors of Protein–Protein Interactions

Protein–protein interactions (PPIs) are challenging targets for small molecules because their binding sites usually do not contain well-defined pockets for small molecules to bind. Biologic drugs (e.g., monoclonal antibodies) are effective against extracellular PPIs, but not intracellular ones, due to their lack of cell permeability. Bicyclic peptides have demonstrated the capacity for binding to PPI targets with antibody-like affinity and specificity and represent an exciting modality for targeting both extracellular and intracellular PPIs. Powerful combinatorial library technologies have recently been developed to rapidly synthesize and screen large bicyclic peptide libraries for ligands against enzymes and PPI targets. Bicyclic peptide ligands against extracellular targets have already advanced into the clinic, while examples of cell-permeable bicyclic peptide inhibitors against intracellular PPIs have recently emerged. This chapter provides a summary of the recent developments in the synthesis and applications of bicyclic peptides as PPI inhibitors.