Pharmaceutical applications of cyclotides

Cyclotides are macrocyclic peptides from plants that are notable for their exceptional stability and broad range of biological applications as well as their uses in indigenous medicines. They comprise a head-to-tail cyclic backbone of around 30 amino acids with a cystine knot arrangement of three disulfide bonds. Together these structural elements make cyclotides impervious to proteolytic breakdown and also exceptionally stable to high temperature and harsh solution conditions. These properties make cyclotides valuable templates in drug design applications. So far, approximately a dozen examples have been reported in which foreign bioactive peptide sequences have been grafted into one of the loops of a cyclotide framework to enhance the stability of the peptide epitope while maintaining the biological activity of that epitope. Applications have included cancer, cardiovascular disease, wound healing, pain, infectious disease, and autoimmune disease, amongst others [1]. This talk will describe the principles of the grafting of cyclotides as well as examining the biophysical [2] and biopharmaceutical properties of cyclotides that underpin their applications as drugs.

[1] Poth A G, Chan L Y, Craik D J: Cyclotides as grafting frameworks for protein engineering and drug design applications. Biopolymers Peptide Science (2013) 100, 480 – 491.

[2] Wang C K, Northfield S E, Swedberg J E, Harvey P J, Mathiowetz A M, Price D A, Liras S Craik D J: Translational diffusion of cyclic peptides measured using pulsed-field gradient NMR. J Phys Chem B (2014) 118, 11129 – 11136.