Friday, 22 May 2026 · 9:00 a.m.–9:45 a.m. Keynote

Display Technologies for Expanding Pharmaceutical Applications of Cyclotides

David Craik
Institute for Molecular Bioscience
Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science
The University of Queensland, Brisbane, 4072, QLD Australia

Naturally occurring macrocyclic peptides offer great potential as leads for drug design [1,2]. Our work focuses on a class of macrocyclic peptides known as cyclotides that are exceptionally stable and are resistant to enzymatic or thermal degradation by virtue of their cyclic cystine knot structural motif. They are excellent scaffolds for the incorporation of bioactive peptide epitopes 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 drug lead molecules with potential in the treatment of cancer, cardiovascular disease, infectious disease, autoimmune disease (multiple sclerosis) and pain. This presentation will describe our work on the discovery, structural characterisation and applications of cyclotides in medicine, with recent examples using display technologies to combinatorially vary backbone loops in the cyclotide scaffold [3]. The approach will be illustrated by the development of a potent inhibitor of factor XII to minimise clotting in extracorporeal membrane oxygenation (ECMO) procedures without bleeding complications [4].

Talk figure: Display Technologies for Expanding Pharmaceutical Applications of Cyclotides
Fig. 1. Use of mRNA display to combinatorially vary loops in a cyclotide scaffold. Illustrated by the development of a potent factor XII inhibitor. Reproduced from ref 3.

References

  1. De Veer SJ, Kan M-W, Craik DJ. Cyclotides: From structure to function. Chemical Reviews 119, 12375-12421 (2019).
  2. Wang CK, Craik DJ. A designer’s guide to the making of macrocycles. Nature Chemical Biology 14, 417-427 (2018).
  3. Liu W, de Veer S, Huang Y-H, Sengoku T, Okada C, Ogata K, Zdenek CN, Fry BG, Swedberg JE, Passioura T, Craik DJ, Suga H. An ultrapotent and selective cyclic peptide inhibitor of human β-factor XIIa in a cyclotide scaffold. Journal of the American Chemical Society 143, 18481-18489 (2021).
  4. Gandini L, de Veer SJ, Chan CHH, Passmore MR, Liu K, Lundon B, Rachakonda R, White N, Rhodes M, Shanahan E, Yap K, See Hoe LE, Semezin C, Zhang Y, Li Bassi G, Fraser JF, Craik DJ, Suen JY. Anticoagulation during extracorporeal membrane oxygenation (ECMO): a selective inhibitor of activated factor XII compared to heparin in an ex vivo model. ACS Pharmacology and Translational Science 8, 1260-1269 (2025).
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