Naturally occurring peptides offer great potential as leads for drug design.^1,2 Our work focuses on a class of cyclic peptides known as cyclotides,³ which are topologically unique in that they have a head-to-tail cyclised peptide backbone and a cystine knotted arrangement of disulfide bonds. This makes cyclotides exceptionally stable to heat or enzymatic treatments and, indeed, they are amongst nature’s most stable proteins.  Their stability and compact structure favours them as attractive protein frameworks onto which bioactive peptide epitopes can be grafted to stabilise them.  More than two dozen examples have now been reported where biologically active epitopes have been grafted onto cyclic peptide frameworks to produce lead molecules with potential in the treatment of cancer, cardiovascular disease, infectious disease, autoimmune disease (multiple sclerosis) and pain. Until now solid-phase peptide chemistry has been the primary method used to make cyclotides for laboratory evaluations. Scale-up for clinical evaluation of cyclotides and other therapeutic peptides will require more efficient and potentially more sustainable production routes. This presentation will describe the use of plants as bio-factories to produce therapeutic designer cyclotides.⁴

 References:

1. Craik D J: Science, (2006) 311, 1561–1564.
2. Craik D J, Fairlie D P, Liras S, Price D: Chemical Biology & Drug Design (2013) 81, 136–147.
3. De Veer S J, Kan M-W, Craik D J: Cyclotides: From structure to function. Chemical Reviews (2019) 119, 12375-12421.
4. Jackson M A, Xie J, Nguyen L T T, Xiaohan W, Yap K, Harvey P J, Gilding E K, Craik D J: Plant-based production of an orally active cyclotide for the treatment of multiple sclerosis. Transgenic Research (2023) 32, 121-133.

Acknowledgments: Work in our laboratory is supported by the Australian Research Council and the National Health & Medical Research Council