Developing rice as a production system for cyclic therapeutic peptides

H Qu, MA Jackson, EK Gilding and D Craik

Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld 4072, Australia

Plant-produced cyclic peptides range from 14~37 amino acids in length and are characterised by a head-to-tail cyclised backbone that is further strengthened by intramolecular disulphide bonds. They exhibit various bioactivities, including uterotonic, antimicrobial and anti-HIV activities, which are potentially exploitable for therapeutic uses. Moreover, due to their unique stable topological structure and tolerance to residue substitution, cyclic peptides have become promising molecular scaffolds for pharmaceutical protein-engineering applications. Currently, chemical synthesis is a common strategy for producing native and modified cyclic peptides, as well as recombinant synthesis and natural extraction. However, these strategies are limited to large-scale production by the high production cost, complexity of separation and deficient knowledge of the biosynthesis pathway. To address these issues, we are investigating a non-native cyclic peptides producing species, rice, as a plant bioreactor to express cyclic peptides of interest. Rice represents a promising recombinant peptide production platform based on its proven stable accumulation of proteins, low bio-safety risk and cost-effectiveness. So far, no native cyclic peptides have been identified in any monocot species, however, several peptide precursor genes with homology to cyclic peptide genes have been identified, differing only in the absence of residues known to be important for in planta cyclisation. In this study, we aim to test the capacity of rice to produce cyclic peptides through transformation of a variety of precursor peptide genes together with or without helper accessory genes that are believed to aid cyclisation in planta. It is envisioned that engineering rice to be a cyclic peptide bioreactor will enable rapid production of cyclic peptide pharmaceuticals in large quantity.