Cyclic peptide is an organic molecule consisting of amino acids linked together in circular or lariat shapes. They are an attractive drug design tool as they can target intracellular protein-protein interactions that are difficult to target by small molecule drugs or antibodies. Furthermore, they can be rapidly prepared and screened in a genetic or synthetic context. This makes cyclic peptides an exciting candidate for the next generation of drug discovery and design tools.
One of the greatest hurdles for cyclic peptide drug development is achieving the proper balance between affinity and membrane permeability. To overcome this obstacle, scientists have used mRNA display to prepare libraries of cyclic peptides that are covalently coupled to mRNA. The libraries can be screened for binding to target proteins with high efficiency. When the cyclic peptides are selected, they can be further optimized by spatial screening to improve the ligand structure.
Another advantage of cyclic peptides is that they are able to cross cell membranes more efficiently than their linear counterparts. This is because cyclic peptides have an additional hydrophobic group on the cationic face, which helps to interact with the lipid head groups of cellular membrane.
This feature has also been exploited to generate a variety of cyclic peptide mimetics of natural molecules. A cyclic peptide mimetic of the monoclonal antibody specific for p185HER2/neu receptor, for example, has been shown to be capable of inhibiting the receptor both in vitro and in vivo (Park et al., 2000).