Chemistry and Biology of Cyclotides: Circular Plant Peptides Outside the Box

Abstract

Cyclotides stand out as the largest family of circular proteins of plant origin hitherto known, with more than 280 sequences isolated at peptide level and many more predicted from gene sequences. Their unusual stability resulting from the signature cyclic cystine knot (CCK) motif has triggered a broad interest in these molecules for potential therapeutic and agricultural applications. Since the time of the first cyclotide discovery, our laboratory in Uppsala has been engaged in cyclotide discovery as well as the development of protocols to isolate and characterize these seamless peptides. We have also developed methods to chemically synthesize cyclotides by Fmoc-SPPS, which are useful in protein grafting applications. In this review, experience in cyclotide research over two decades and the recent literature related to their structures, synthesis, and folding as well the recent proof-of-concept findings on their use as "epitope" stabilizing scaffolds are summarized.

Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications

“…One special group of naturally occurring peptides are called cysteine knot miniproteins 162 or cyclotides. [163][164][165][166] These are cyclic peptides with three crosslinked disulfide bridges. The disulfide bridges provide the cyclotide with extraordinary thermal stability and resistance against protolytic degradation.…”

The role of C-terminal amidation in the membrane interactions of the anionic antimicrobial peptide, maximin H5

“…This form of structural stabilisation is also important for the therapeutic development of AMPs as seen with the cysteine knot architectures of cyclotides from plants [2,16]. The exceptional stability of these peptides coupled to their high tolerance of residue substitutions [17] makes them potential candidates to serve as lead compounds in scenarios ranging from tumour imaging [18] to preventing the sexual transmission of HIV [19].…”

Micropropagation of Viola uliginosa (Violaceae) for endangered species conservation and for somaclonal variation-enhanced cyclotide biosynthesis

“…Plants of the Violaceae family are known for their expression of cyclotides (Burman et al 2014). The chemistry and biology of this unique family of ribosomally produced plant peptides are of interest to numerous researchers (Arnison et al 2013).…”

“…Cyclotides have a headto-tail cyclic peptide backbone and three disulfide bonds arranged in a cystine knot (Craik et al 1999;Rosengren et al 2003). They are expressed as complex peptide mixtures in apparently all species of Violaceae; outside of that plant family, cyclotides or cyclotide-like proteins or genes have been found in Rubiaceae, Cucurbitaceae, Fabaceae, Solanaceae and Poaceae (Burman et al 2014;Gerlach et al 2013;Nguyen et al 2013;Poth et al 2012). Numerous biological activities have been reported for cyclotides, including uterotonic, hemolytic, inhibition of neurotensin action, anti-HIV and cytotoxic (Burman et al 2014).…”

“…They are expressed as complex peptide mixtures in apparently all species of Violaceae; outside of that plant family, cyclotides or cyclotide-like proteins or genes have been found in Rubiaceae, Cucurbitaceae, Fabaceae, Solanaceae and Poaceae (Burman et al 2014;Gerlach et al 2013;Nguyen et al 2013;Poth et al 2012). Numerous biological activities have been reported for cyclotides, including uterotonic, hemolytic, inhibition of neurotensin action, anti-HIV and cytotoxic (Burman et al 2014). They are active against different bacteria and insect larvae (Jennings et al 2005Pränting et al 2010.…”