Macrocyclic Peptides for Intracellular Drug Targets
There has been sustained interest in cyclic peptides as new modalities in medicinal chemistry research. The amino acid composition and greater molecular size of cyclic peptides, compared to conventional small-molecule drugs, has made cyclic peptides viable molecules for interrogating difficult targets such as protein–protein interactions. However, these binding and screening advantages of cyclic peptides also lead to poor pharmacokinetic properties. Cellular permeability and, more importantly, the ability to engage with intracellular targets remains an ongoing challenge. This chapter covers recent developments for passive cellular permeability of cyclic peptides by intramolecular hydrogen bonding, scaffold design, and peptide modifications. Notable examples and strategies in the active transport of cyclic peptides are also discussed.