Cyclic Peptides as Drugs for Intracellular Targets: The Next Frontier in Peptide Therapeutic Development

• Published in: Chemistry : a European journal 2021-01, Vol.27 (5), p.1487-1513
• Main Authors: Buckton, Laura K., Rahimi, Marwa N., McAlpine, Shelli R.
• Format: Article
• Language: English
• Subjects: Binding; Biological activity; Cell differentiation; Cell Membrane Permeability - drug effects; Cell membranes; Cell permeability; Chemical activity; Chemistry; Conformation; drug delivery; Drug development; Humans; Intracellular; Intracellular Space - drug effects; Intracellular Space - metabolism; medicinal chemistry; Membrane permeability; Methylation; Molecular Targeted Therapy; Peptide synthesis; Peptides; Peptides, Cyclic - metabolism; Peptides, Cyclic - pharmacology; Peptides, Cyclic - therapeutic use; peptidomimetics; Permeability; Physical properties; protein–protein interactions
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201905385

Developing macrocyclic peptides that can reach intracellular targets is a significant challenge. This review discusses the most recent strategies used to develop cell permeable cyclic peptides that maintain binding to their biological target inside the cell. Macrocyclic peptides are unique from small molecules because traditional calculated physical properties are unsuccessful for predicting cell membrane permeability. Peptide synthesis and experimental membrane permeability is the only strategy that effectively differentiates between cell permeable and cell impermeable molecules. Discussed are chemical strategies, including backbone N‐methylation and stereochemical changes, which have produced molecular scaffolds with improved cell permeability. However, these improvements often come at the expense of biological activity as chemical modifications alter the peptide conformation, frequently impacting the compound's ability to bind to the target. Highlighted is the most promising approach, which involves side‐chain alterations that improve cell permeability without impact binding events. This review describes recent strategies used to develop cell permeable cyclic peptides that retain binding to their biological target once inside the cell. Discussed are chemical strategies that have produced molecules with improved cell permeability however negatively impact biological activity. Highlighted is the most promising approach involving side chain alterations.