cyclotides

Cyclotides are a family of plant-derived cyclic peptides that are typically 28 to 37 amino acids long. They feature a head-to-tail cyclized backbone and a cystine knot formed by three disulfide bonds among six cysteine residues. This topology gives cyclotides exceptional stability to heat, extreme pH, and proteolytic degradation. They are ribosomally synthesized and post-translationally modified peptides (RiPPs).

Cyclotides have been identified in a variety of flowering plants, with notable abundance in the Violaceae and Rubiaceae families. The first cyclotide to be characterized was kalata B1, isolated from Oldenlandia affinis (a Rubiaceae plant), and linked to a traditional Kenyan remedy used by midwives. Since then, many related peptides have been found across different plant species, revealing a diverse and widespread family.

Biosynthesis begins with ribosomal production of a larger precursor protein that includes signal and propeptide regions. The cyclotide domain is released through proteolytic processing and then cyclized, a reaction often catalyzed by asparaginyl endopeptidases (AEPs) or related ligases that mediate head-to-tail transpeptidation to form the cyclic peptide.

Biological activities attributed to cyclotides include insecticidal and antimicrobial effects, along with antifungal, antiviral, and enzyme-inhibitory properties reported in various members of the family. Many findings derive from in vitro studies; observed activities can vary depending on sequence, structure, and context.

Because of their compact size and exceptional stability, cyclotides are explored as scaffolds for peptide engineering, enabling grafting of functional epitopes while maintaining structural integrity. They also attract interest for agricultural applications and as templates in drug development.