The bountiful biological activities of cyclotides

Cyclotides are exceptionally stable circular peptides (28-37 amino acid residues) with a unique cyclic cystine knot (CCK) motif that were originally discovered through ethnobotanical investigations and bioassay-directed natural products screenings. They have been isolated from four angiosperm families (Violaceae, Rubiaceae, Curcurbitaceae, and Fabaceae), and they exhibit a wide range of bioactivities including antibacterial/antimicrobial, nematocidal, molluscicidal, antifouling, insecticidal, antineurotensin, trypsin inhibiting, hemolytic, cytotoxic, antitumor, and anti-HIV properties. Reports indicate that the mechanism of cyclotide bioactivity is the ability to target and interact with lipid membranes via the development of pores. Additionally, the nature of their surface-exposed hydrophobic patch and CCK play integral roles in the potency of cyclotides. Their extraordinary stability and flexibility have recently allowed for the successful grafting of analogs with therapeutic properties onto their CCK framework. This achievement, coupled with the myriad of useful naturally occurring bioactivities displayed by cyclotides, makes them appealing candidates in drug design and crop management.