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.

Peptides are regarded as promising next-generation therapeutics. However, an analysis of over 1000 bioactive peptide candidates suggests that many have underdeveloped affinities and could benefit from cyclization using a bridging linker sequence. Until now, the primary focus has been on the use of inert peptide linkers. Here, we show that affinity can be significantly improved by enriching the linker with functional amino acids. We engineered a peptide inhibitor of PCSK9, a target for clinical management of hypercholesterolemia, to demonstrate this concept. Cyclization linker optimization from library screening produced a cyclic peptide with ∼100-fold improved activity over the parent peptide and efficiently restored low-density lipoprotein (LDL) receptor levels and cleared extracellular LDL. The linker forms favorable interactions with PCSK9 as evidenced by thermodynamics, structure−activity relationship (SAR), NMR, and molecular dynamics (MD) studies. This PCSK9 inhibitor is one of many peptides that could benefit from bioactive cyclization, a strategy that is amenable to broad application in pharmaceutical design.

Disulfide bonds typically introduce conformational constraints into peptides and proteins, conferring improved biopharmaceutical properties and greater therapeutic potential. In our opinion, disulfide‐rich microdomains from proteins are potentially a rich and under‐explored source of drug leads. A survey of the UniProt protein database shows that these domains are widely distributed throughout the plant and animal kingdoms, with the EGF‐like domain being the most abundant of these domains. EGF‐like domains exhibit large diversity in their disulfide bond topologies and calcium binding modes, which we classify in detail here. We found that many EGF‐like domains are associated with disease phenotypes, and the interactions they mediate are potential therapeutic targets. Indeed, EGF‐based therapeutic leads have been identified, and we further propose that these domains can be optimized to expand their therapeutic potential using chemical design strategies. This Review highlights the potential of disulfide‐rich microdomains as future peptide therapeutics.