Extraction, isolation, and Biological activity of natural cyclic dipeptides

Cyclic dipeptides (CDPs) are small, highly bioactive peptides produced by plants, animals, and fungi. They consist of two cyclized amino acids forming a four-carbon central diketopiperazine ring with two side chains. Planar and resistant to enzymatic degradation they serve a variety of biological functions. CDPs derived from natural sources exhibit biological activities including cytotoxic, antimicrobial, antimalarial, antitumor, and potential involvement in quorum sensing. For example, Cyclo (Phe-Pro) has been shown to inhibit the growth of certain human cancer cell lines via the formation of reactive oxygen species. The majority of naturally derived CDPs have been isolated from bacteria. Notably, the structures of CDPs can be modified enzymatically, such as by the dehydration of the alpha-beta double bonds on the amino acid residues. This transformation results in Δ-CDPs, which have been shown to have much higher bioactivity than the nonΔ intermediates. Isolation techniques include direct extraction from the bacterial/fungal biomass or filtration of spent bacterial medium. This review will explore chromatographic isolation techniques, prevalence, and biological activity of cyclic and Δ-CDPs.