Cyclotides as novel plant-derived scaffolds for orally active cyclic peptide therapeutics

Cyclotides are a group of plant-derived small peptides, characterized by a head-to-tail cyclic backbone and 3 conserved cysteine knots. The unique structure endows cyclotides with exceptional chemical stability and intrinsic cell-penetrating capacities, allowing them to serve as orally active agents for host defense. These properties also position cyclotides as ideal scaffolds for the design of novel edible drugs. This review provides a comprehensive overview of the discovery, distribution, and evolutionary divergence of cyclotides in flowering plants, while also discussing their classification and applications in structure-based engineering for various purposes. Additionally, recent advancements in the biological and pharmaceutical activities of both naturally occurring and synthetic "designer" cyclotides are summarized. The complexities of the cyclotide biosynthetic pathway have posed challenges for their synthesis in non-native organisms. Thus, the article concludes by exploring the latest strategies for large-scale cyclotide production in plants, highlighting Viola species as rich sources for future cyclotide engineering.