Discovery and applications of the plant cyclotides

The cyclotides are a family of plant-derived proteins that occur in plants from the Violaceae (violet), Rubiaceae (coffee) and Cucurbitaceae (cucurbit) families and have a diverse range of biological activities, including uterotonic, anti-HIV, antimicrobial, and insecticidal activities; the latter suggests their natural function lies in plant defense. Individual plants express suites of 10-100 cyclotides. Cyclotides comprise ∼30 amino acids, contain a head-to-tail cyclised backbone, and incorporate three disulfide bonds arranged in a cystine knot topology. The combination of a knotted and strongly braced structure with a circular backbone renders the cyclotides impervious to enzymatic breakdown and makes them exceptionally stable. The cyclotides are the largest of several groups of naturally occurring circular proteins that have been discovered in bacteria, plants and animals over recent years. This article describes the discovery of the cyclotides in plants, their structural characterisation, evolutionary relationships and their applications in drug design.