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Discovery and structures of the cyclotides: novel macrocyclic peptides from plants

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Circular disulfide-rich polypeptides were unknown a decade agobut over recent years a large family of such molecules hasbeen discovered, which we now refer to as the cyclotides. They are typically about 30 amino acids in size, contain an N- to C-cyclised backbone and incorporate three disulfide bondsarranged in a cystine knot motif. In this motif, an embeddedring in the structure formed by two disulfide bonds and theirconnecting backbone segments is penetrated by the thirddisulfide bond. The combination of this knotted and stronglybraced structure with a circular backbone renders thecyclotides impervious to enzymatic breakdown and makes themexceptionally stable. This article describes the discovery ofthe cyclotides in plants from the Rubiaceae and Violaceaefamilies, their chemical synthesis, folding, structuralcharacterisation, and biosynthetic origin. The cyclotides havea diverse range of biological applications, ranging fromuterotonic action, to anti-HIV and neurotensin antagonism.Certain plants from which they are derived have a history ofuses in native medicine, with activity being observed afteroral ingestion of a tea made from the plants. This suggeststhe possibility that the cyclotides may be orallybioavailable. They therefore have a range of potentialapplications as a stable peptide framework.

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Correspondence to David J. Craik.

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Craik, D.J., Anderson, M.A., Barry, D.G. et al. Discovery and structures of the cyclotides: novel macrocyclic peptides from plants. Letters in Peptide Science 8, 119–128 (2001).

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  • circular proteins
  • cystine knot
  • NMRspectroscopy
  • Oldenlandia affinis
  • plant proteins