In addition to the inherent structural properties of peptides, cyclic peptides are metabolically stable and have low cytotoxicity, making them excellent therapeutic agents. Moreover, the cyclic structure limits the conformational flexibility of a peptide to enhance binding affinity and specificity against a target protein. The combination of these advantages makes cyclic peptides one of the most promising drug discovery tool for inhibiting PPIs.
A number of cyclic peptides have already been developed as drugs and are in clinical trials. These peptides have been developed by both genetic and synthetic approaches. For example, cyclosporin A is a cyclic peptide derivative of the naturally occurring cyclosporine molecule extracted from the cells of horseshoe crabs. Its pharmacological effects include inhibition of proteasome activity and cell cycle progression. Cyclosporin A is also a potent antagonist of CXCR4 chemokine G protein-coupled receptor (GPCR), which plays a role in the metastasis of cancer, as well as infection by viruses such as HIV.
There are two general methods for preparing cyclic peptides: head-to-tail cyclization and side-chain cyclization. The former involves the formation of amide bonds between the amino acids in a peptide chain. The latter involves the formation of a Cys-Cys bond between the side chains of amino acids in the peptide chain.
The cyclic RGD peptide, for example, is a natural peptide sequence with a high affinity toward the integrin family of receptors in blood vessels and other tissues, making it a valuable therapeutic tool in antiangiogenic therapy. The synthesis of cyclic peptides has been accelerated by the development of combinatorial libraries and powerful phage display techniques.