Ribosomally-synthesised cyclic peptides from plants as drug leads and pharmaceutical scaffolds

Abstract

Owing to their exceptional stability and favourable pharmacokinetic properties, plant-derived cyclic peptides have recently attracted significant attention in the field of peptide-based drug design. This article describes the three major classes of ribosomally-synthesised plant peptides - the cyclotides, the PawS-derived peptides and the orbitides - and reviews their applications as leads or scaffolds in drug design. These ribosomally-produced peptides have a range of biological activities, including anti-HIV, cytotoxic and immunomodulatory activity. In addition, recent interest has focused on their use as scaffolds to stabilise bioactive peptide sequences, thereby enhancing their biopharmaceutical properties. There are now more than 30 published papers on such 'grafting' applications, most of which have been reported only in the last few years, and several such studies have reported in vivo activity of orally delivered cyclic peptides. In this article, we describe approaches to the synthesis of cyclic peptides and their pharmaceutically-grafted derivatives as well as outlining their biosynthetic routes. Finally, we describe possible bioproduction routes for pharmaceutically active cyclic peptides, involving plants and plant suspension cultures.

Gene-guided discovery and engineering of branched cyclic peptides in plants

“…This discovery sets the stage for geneguided discovery of peptide chemistry in the plant kingdom and therapeutic and agrochemical applications of lyciumins. the plant cell by protein disulfide isomerases (19,22). The modified cyclotide precursor peptide is then cleaved proteolytically Nterminal of the cyclotide core peptide, and, finally, the C terminus of the core peptide is cleaved and cyclized with the N terminus by an asparagine-specific endopeptidase in the plant vacuole (19,23,24).…”

“…the plant cell by protein disulfide isomerases (19,22). The modified cyclotide precursor peptide is then cleaved proteolytically Nterminal of the cyclotide core peptide, and, finally, the C terminus of the core peptide is cleaved and cyclized with the N terminus by an asparagine-specific endopeptidase in the plant vacuole (19,23,24). Similarly, orbitides are derived from precursor peptides by endoproteolytic cleavage N-terminal of the orbitide core peptide followed by subsequent C-terminal proteolysis and cyclization catalyzed by serine proteases (19,25,26).…”

“…The modified cyclotide precursor peptide is then cleaved proteolytically Nterminal of the cyclotide core peptide, and, finally, the C terminus of the core peptide is cleaved and cyclized with the N terminus by an asparagine-specific endopeptidase in the plant vacuole (19,23,24). Similarly, orbitides are derived from precursor peptides by endoproteolytic cleavage N-terminal of the orbitide core peptide followed by subsequent C-terminal proteolysis and cyclization catalyzed by serine proteases (19,25,26). Beyond head-to-tail cyclic peptides, the phytochemical repertoire of cyclic peptides suggests that the plant kingdom contains a largely undiscovered diversity of branched cyclic peptide chemistry with tremendous pharmacological potential and unknown biosynthetic mechanisms (27).…”

“…Most RiPPs discovered to date are from bacteria and fungi, whereas a few examples were also found in plants. The two biosynthetically defined families of plant RiPPs are cyclotides and orbitides, which are "head-to-tail" cyclic peptides with or without disulfide bonds, respectively (17)(18)(19)(20)(21). The cyclic plant peptides with disulfide bonds are further grouped into cyclotides, which have three disulfide bonds, and PawS-derived peptides, which have one disulfide bond (18)(19)(20).…”

Papain-like cysteine proteases prepare plant cyclic peptide precursors for cyclization

“…These structural attributes engender cyclotides with exceptional chemical and proteolytic stability (9). The inherent insecticidal, nematicidal, and molluscicidal activities of cyclotides suggest a natural role in plant host defense, highlighting their potential for agricultural applications (10-12), and their exceptional stability has seen cyclotides used for the stabilization of pharmaceutically relevant epitopes (13,14).Efforts to cost-effectively produce natural or modified cyclotides in transgenic plants require a detailed understanding of their biosynthesis (15). Cyclotides are produced as gene-encoded precursors comprising an N-terminal signal peptide and propeptides that flank one or multiple cyclotide domains (15) (Fig.…”