Targeting intracellular protein-protein interactions with macrocyclic peptides

Intracellular protein-protein interactions (PPIs) are challenging targets for traditional drug modalities. Macrocyclic peptides (MPs) prove highly effective PPI inhibitors in vitro and can be rapidly discovered against PPI targets by rational design or screening combinatorial libraries but are generally impermeable to the cell membrane. Recent advances in MP science and technology are allowing for the development of 'drug-like' MPs that potently and specifically modulate intracellular PPI targets in cell culture and animal models. In this review, we highlight recent progress in generating cell-permeable MPs that enter the mammalian cell by passive diffusion, endocytosis followed by endosomal escape, or as-yet unknown mechanisms.