Recent Trends in Cyclic Peptides as Therapeutic Agents and Biochemical Tools

Abstract

Notable progress has been made in the therapeutic and research applications of cyclic peptides since our previous review. New drugs based on cyclic peptides are entering the market, such as plecanatide, a cyclic peptide approved by the United States Food and Drug Administration in 2017 for the treatment of chronic idiopathic constipation. In this review, we discuss recent developments in stapled peptides, prepared with the use of chemical linkers, and bicyclic/tricyclic peptides with more than two rings. These have widespread applications for clinical and research purposes: imaging, diagnostics, improvement of oral absorption, enzyme inhibition, development of receptor agonist/antagonist, and the modulation of protein-protein interaction or protein-RNA interaction. Many cyclic peptides are expected to emerge as therapeutics and biochemical tools.

Keywords: Bicyclic peptide; Cyclic peptides; Drug lead; Stapled peptides.

Fig. 1.

Structure of guanylin. (A) Solution structure of guanylin. Alpha carbons are shown as spheres, and the disulfide bonds are shown as sticks. The model was drawn from PDB id 1gnb. (B) Amino acid sequences of guanylin and its analogs linaclotide and plecanatide. Disulfide bonds are indicated.

Fig. 2.

Cyclic peptide libraries. (A) Bicyclic peptide with a chemical linker connecting three cysteine residues. (B) Cyclic peptide in mRNA display with a chemical linker coupling N-terminal Met with the side chain of Lys at position 10. (C) Cyclic peptide in mRNA display with a chemical linker connecting two cysteine residues.

Fig. 3.

Structure of SAH-p53-8, a stapled peptide. The aliphatic staple (yellow) provides conformational stability to the peptide sequence QTF^*NLWRLL^*QN (^*indicates the aliphatic staple). The model was drawn from PDB id 3v3b.