Cyclotides

Abstract

The cyclotides are a recently discovered family of miniproteins that contain a head‐to‐tail cyclized backbone and a knotted arrangement of disulfide bonds. They are approximately 30 amino acids in size and are present in high abundance in plants from the Rubiaceae, Violaceae, and Cucurbitaceae families, with individual plants containing a suite of up to 100 cyclotides. They have a diverse range of bioactivities, including uterotonic, anti‐HIV, antitumor, and antimicrobial activities, although their natural function is believed to be in host defence against pests and pathogens. In addition to their natural activities, cyclotides have been proposed as a stable peptide template for applications in protein engineering and drug design. Their exceptional stability and resistance to thermal, chemical or enzymatic treatments can be attributed to the cyclic cystine knot structural motif that forms their compact molecular core. The backbone loops protruding from this core vary in their amino acid compositions and because of this tolerance to substitutions, cyclotides can be regarded as a natural combinatorial template. To date, most bioactivity studies on cyclotides have involved peptides extracted from plants. Cyclotides are amenable to chemical synthesis but this is expensive and so the development of bioprocesses for the production of cyclotides is an important objective for enabling their future industrial applications. This article gives a brief overview of the structures and properties of cyclotides and discusses new approaches to their production using bioprocesses on an industrial scale.