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

Abstract

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.

1,2,3-Triazoles as Biomimetics in Peptide Science

“…Cyclic head-to-tail peptides occur in a wide variety of natural products, with an impressive range of biological activities [ 56 , 57 ]. These cyclic peptides generally improve metabolic stability and may improve structural rigidity due to the geometric preorganization into a suitable conformation for binding.…”

Macrocycle-Antibiotic Hybrids: A Path to Clinical Candidates

“…A recent study demonstrated modulation of scaffold rigidity to engineer favorable ADME properties in macrocyclic peptides (Furukawa et al, 2020). Finally, drug design strategies, such as N-methylation or replacing NH with sulfur (or vice versa), were found to improve pharmacological activity, solubility, and/or permeability of macrocycles (Mallinson and Collins, 2012;Liras and McClure, 2019;Stadelmann et al, 2020;Buckton et al, 2021). Extending studies of this nature to macrocyclic hybrids is expected to improve their oral bioavailability for systemic uses.…”

Discovery, X-ray structure and CPP-conjugation enabled uptake of p53/MDM2 macrocyclic peptide inhibitors

“… 15 Alternative approaches for creating cell-permeable peptides to disrupt p53/MDMX interactions using cyclic peptide scaffolds, 16 polycationic tags or medchem optimization strategies have been extensively studied. 17,18 …”