In the past, naturally occurring cyclic peptides in plants, animals and bacteria were thought to be produced mainly by non-ribosomal synthesis. However, over the last decade, a large number of ribosomally synthesized cyclic peptides have been discovered, ranging in size from 5-70 amino acids.¹ Typically these cyclic peptides are processed from precursor proteins that contain a leader sequence and often a C-terminal recognition sequence. This presentation will focus on the biosynthesis of cyclic peptides from plants, including the cyclotides, which so far are the largest family of naturally occurring ribosomally synthesized cyclic peptides, and from animals, including the theta-defensins. Studies of the biosynthesis of cyclotides from the Fabacaeae (legume), Solanaceae (Nightshade), and Cucurbitaceae (cucumber) families as well as the Rubiaceae (coffee) and Violaceae (violet) plant families will be described. A common feature of all of the cyclotide precursor proteins is the presence of an asparagine (or aspartic acid) at the C-terminal end of the mature peptide domain, which implicates asparaginyl endopeptidase activity as being responsible for a transpeptidation reaction that produces the cyclic peptide. Synthetic access via native-chemical-ligation-like reactions to both naturally occurring as well as modified cyclotides and theta-defensins has been established, and has demonstrated their amenability to optimization as pharmaceutically active molecules².

1. Craik D J: Seamless proteins tie up their loose ends. Science, 311, 1563-1564 (2006).
2. Henriques S T, Craik D J: Cyclotides as templates in drug design. Drug Discovery Today (2010) 15, 57-64.