Cyclotides as a basis for drug design

Abstract

The ultra-stable cyclotides are promising templates for drug development applications and are currently being assessed for the potential breadth of their applications. For synthetic versions of cyclotides to enter human clinical trials further studies to examine their biopharmaceutical properties and toxicities are required. However, several promising proof-of-concept studies have established that pharmaceutically relevant bioactive peptide sequences can be grafted into cyclotide frameworks and thereby stabilised, while maintaining biological activity. These studies include examples directed at cancer, cardiovascular disease and infectious diseases. Solid phase peptide synthesis has been the preferred approach for making pharmaceutically modified cyclotides so far, but promising progress is being made in biological approaches to cyclotide production.

Oral activity of a nature-derived cyclic peptide for the treatment of multiple sclerosis

“…Thus, at the very least, they can be anticipated to complement the existing collections of natural products or synthetic molecules that are used in drug discovery. In particular, building on the unique topology of cyclotides (16) may complement efforts in rational design of bioavailable cyclic peptide therapeutics (41).…”

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.…”

Anionic Host Defence Peptides from the Plant Kingdom: Their Anticancer Activity and Mechanisms of Action

“…In this capacity, as shown by this review, AHDPs from cyclotides are by far the most researched and it is becoming increasingly clear that their anticancer potential may be achieved through progress in deriving synthetic versions of these peptides [22]. The high plasticity and tolerance to substitution of the cyclotide scaffold is now well established and several studies have clearly shown that bioactive peptide sequences can be efficiently grafted into these scaffold for a variety of therapeutic purposes, including the production of compounds with anticancer capacity [48,97]. For example, PE shows the potential to serve as a biomarker for many malignancies [98] and it has been proposed that derivatives of PE-binding cyclotides may be suitable for development as agents in tumour imaging and anticancer therapeutics [75,76,81,99,100].…”