The cyclic peptide is a protein-like molecule with a ring structure that is formed by linking one end to another by various chemical bonds, including amide, lactone, ether, and thioether. Its ring structure makes it resistant to cleavage by proteases, and also prevents conformational changes in the binding pocket, thus improving the affinity and specificity of the peptide-target interaction.
Several peptides with cyclic structures have been discovered as new drugs. These include natural peptide hormones such as calcitonin, oxytocin, octreotide and vasopressin; antibiotics such as vancomycin, daptomycin and polymyxin B; and immunosuppressants such as ciclosporine. In fact, more than 40 kinds of cyclic peptides are currently in clinical use. The success of these peptide drugs is due to their unique characteristics, such as high binding affinity and specificity and low cytotoxicity.
In recent years, both genetic and synthetic approaches have been used to develop cyclic peptide compounds. The genetic approach uses mRNA display, which is a method for screening peptides covalently linked to mRNA that encode the target, to select cyclic peptides. The cyclic peptides are then fused to a cross-linker to form the peptide-target binding domain. One example is the disulfide-containing cyclic peptide CTT (CTTHWGFTLC) that was developed as a matrix metalloproteinase inhibitor.
The synthetic approach involves using a modified intein to generate lariat peptides, which are cyclized in solution. This method is called the SICLOPPS system, which allows the selection of cyclic peptides with a range of sizes and is easily scaled up for large-scale screening. Screening of a SICLOPPS cyclic hexapeptide library for the prolactin receptor resulted in compounds with dissociation constants in the micromolar range. More cyclic peptides are expected to emerge as therapeutic agents and biochemical tools as the exploitation of these libraries advances.