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Cyclic Peptides as Drugs for Intracellular Targets: The Next Frontier in Peptide Therapeutic Development
Author(s) -
Buckton Laura K.,
Rahimi Marwa N.,
McAlpine Shelli R.
Publication year - 2021
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201905385
Subject(s) - intracellular , cell permeability , peptide , cyclic peptide , membrane permeability , membrane , cell , chemistry , biophysics , cell membrane , small molecule , combinatorial chemistry , biochemistry , microbiology and biotechnology , biology
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.