Cyclotides are plant-derived peptides of approximately 30 amino acids. They have the characteristic structural features of a head-to-tail cyclized backbone and a cystine knot arrangement of their three conserved disulfide bonds. Their unique structural features lead to exceptional stability. This and their amenability to chemical synthesis have made it possible to use cyclotides as templates in protein engineering and drug design applications.
David J Craik, University of Queensland, Brisbane, Australia, whose laboratory is working over 20 years in the field, summarizes the history of cyclotides. He describes some of the background of their discovery – starting with a Norwegian physician in the Congo region of Africa – and their isolation. He focuses on how their unique structural features lead to exceptional stability as well as on their applications, the determination of their biological activities, and their biophysical characterization, as well as studies on their biosynthesis. The biosynthetic studies have opened up new horizons for the future of cyclotide-based peptides, leading us to pursue the idea of using plants to produce cyclotide-based pharmaceuticals.
In short, it is the story of how what started as pure curiosity-driven research into a family of structurally interesting proteins from an African weed shows potential for applications that might eventually prove useful in human health.
David J Craik believes that cyclic peptides are a under-discovered class of molecules. They are typically not identified in genomics or transcriptomics studies, which provide only linear sequence information and do not usually annotate short sequences of the size typically seen in cyclic peptides. Proteomics studies tend to miss cyclic peptides, which do not fragment very well in mass spectrometric analyses and are impossible to sequence directly without prior treatment with an enzyme to linearize them. Thus, there is a great need for new techniques and approaches for the de novo discovery of cyclic peptides, molecules with ‘endless’ potential, as he says.