Cyclic peptides have many features that make them attractive lead compounds for drug development as well as biochemical tools. For example, cyclic peptides are more resistant to protease enzymes, have longer in vivo stability and enhanced target selectivity. In addition, cyclic peptides are often used as binding partners for ligands and imaging agents that target protein-protein interaction (PPI) targets.
The discovery of cyclic peptides for drug development has traditionally involved genetic approaches. This method is usually limited to ribosomal 20 amino acids, but is also effective for hit discovery and affinity maturation [20].
In contrast, synthetic synthesis provides more versatile cyclic peptide compounds. These are usually derived from natural products such as antibacterial agents or derivatives of human hormones and have been successfully applied to clinical trials.
Peptide-ligand complexes, or PDCSs, have been shown to induce tumor growth inhibition and elimination by interaction with a wide range of cell surfaces including lipid head groups, membrane proteins and DNA. In addition, PDCSs can be conjugated with chemotherapeutic or cytotoxic agents for cancer treatment.
To develop PDCs, two technologies are required: one for identifying a target receptor protein and another to synthesize a peptide-ligand complex. The first approach is called phage display, and it involves displaying a library of polypeptides on a phage by genetic rearrangement. The resulting peptide-protein-receptor complex is screened for binding to target protein (Fig. 2 left).
A second technique, called mRNA display, enables screening of a peptide-protein-receptor library that is chemically covalently linked to a coding RNA via puromycin (Fig. 2 right). This method was developed originally for linear polypeptide libraries, but recently has been applied to cyclic peptides [48].