Progress in kalata peptide production via plant cell bioprocessing

Cyclotides are disulfide-rich mini-proteins with the unique structural features of a circular backbone and knotted arrangement of three conserved disulfide bonds. They typically comprise 28–37 amino acids and are produced from linear precursors, and translational modification via oxidative folding, proteolytic processing and N-C cyclization. Because these plant-derived peptides are resistant to degradation and do exhibit a diverse range of biological activities, they have become important agronomic and industrial objectives. Due to its tolerance to sequence variation, the cyclotide backbone is also potentially useful as a molecular scaffold for protein-engineering applications. Several production options are available for bioactive plant metabolites including natural harvesting, total chemical synthesis, and expression of plant pathways in microbial systems. For the cyclotides with low yields in nature, chemical complexity and lack of knowledge of the complete biosynthetic pathway, however, many of these options are precluded. Plant cell-culture technology shows promise towards the goal of producing therapeutically active cyclotides in quality and quantities required for drug development as they are amenable to process optimization, scale-up, and metabolic engineering. It is conceivable that plant-based production systems may ultimately prove to be the preferred route for the production of native or designed cyclotides, and will contribute towards the development of target-specific drugs.