Targeting intracellular protein–protein interactions with macrocyclic peptides

MPs are an emerging class of drug modality for PPI inhibition. Rational design and library screening are established to generate lead peptides. Membrane permeability can be attained by passive diffusion or endocytosis. Integration of membrane permeability and target binding is essential. 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. 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. a mutagenesis method during which an amino acid is mutated to alanine to determine its contribution to a given function. programmed cell death used by multicellular organisms. large collection of structurally diverse compounds prepared from a small set of building blocks. ratio of intracellular over extracellular concentration of a biomolecule (e.g., a CPP). energy-independent process by which a molecule enters the cytosol by directly traversing the plasma membrane. energy-dependent process occurring at the cell surface and involving generation of small vesicles that transport cargo molecules into the cell. process by which a molecule exits the endosome after endocytic uptake. technology that enables in vitro selection and directed evolution of peptides/proteins that are covalently linked to their coding mRNAs. short peptide sequence (e.g., PKKKRKV) that mediates direct import of proteins (or other cargo) into the nucleus. fraction of an orally administered drug that reaches systemic circulation; usually positively correlated with membrane permeability. energy-independent process by which a molecule can cross the plasma membrane. compound that mimics the mode of action of a bioactive peptide but contains various modifications that improve its metabolic stability, bioavailability, and/or target binding affinity. oligomer of N-alkylated glycines. physical interaction between two or more proteins that execute and/or regulate various biological processes. in vitro system that combines mRNA display with flexible in vitro translation (FIT) to generate and screen large peptide libraries.