Cyclic peptides as therapeutic agents and biochemical tools

Abstract

There are many cyclic peptides with diverse biological activities, such as antibacterial activity, immunosuppressive activity, and anti-tumor activity, and so on. Encouraged by natural cyclic peptides with biological activity, efforts have been made to develop cyclic peptides with both genetic and synthetic methods. The genetic methods include phage display, intein-based cyclic peptides, and mRNA display. The synthetic methods involve individual synthesis, parallel synthesis, as well as split-and-pool synthesis. Recent development of cyclic peptide library based on split-and-pool synthesis allows on-bead screening, in-solution screening, and microarray screening of cyclic peptides for biological activity. Cyclic peptides will be useful as receptor agonist/antagonist, RNA binding molecule, enzyme inhibitor and so on, and more cyclic peptides will emerge as therapeutic agents and biochemical tools.

Keywords: Cyclic peptides; Drug lead; On-bead screening; Split-and-pool synthesis.

Fig. 1.. Structure of Cyclic peptides used in clinic. Left top:Tyrocidine A, cyclo (Val-Orn-Leu-D-Phe-Pro-Phe-Phe-Asn-Gln-Tyr). Left bottom: Gramicidin S, cyclo (Val-Orn-Leu-D-Phe-Pro)2. Right:Cyclo-RGD Peptide EMD 66203, cyclo (Arg-Gly-Asp-D-Phe-Val).

Fig. 2.. Structures of cyclic peptides from the genetic libraries. Left top: disulfide-containing cyclic peptide in phage display. Left bottom: intein-based cyclic peptide, X=Ser, or Cys. Right: cyclic peptide in mRNA display, a chemical linker is used to couple the N-terminal Met with the side chain of Lys at position 10.

Fig. 3.. Structures of cyclic peptide libraries based on split-and-pool synthesis. Top: Cyclic peptide for on-bead screening. Bottom: Cyclic peptide for in-solution screening. Cyclic peptides can be released from the bead by hydrolysis of ester linkage, and then the remaining linear peptides are used for sequence determination.