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REVIEW
Contents Vol 70(2)

Synthesis and Protein Engineering Applications of Cyclotides

Haiou Qu A , Bronwyn J. Smithies A , Thomas Durek A and David J. Craik A B
+ Author Affiliations
- Author Affiliations

A Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld 4072, Australia.

B Corresponding author. Email: d.craik@imb.uq.edu.au




Haiou Qu is a second year Ph.D. student under the supervision of Professor D. Craik at the Institute for Molecular Bioscience, The University of Queensland. She received her B.Sc. (2012) from Northeast Forestry University and an M.Sc. in biology (2015) from Shanghai Jiao Tong University. Her research interests are in cyclotide expression in plants, and her current project is focused on the application of rice as a bioreactor to express cyclotides.


Bronwyn Smithies received her bachelor's degree in biotechnology and medical research (Hons) from the University of Tasmania in 2013. In 2016, she commenced her Ph.D. studies at the Institute for Molecular Bioscience, The University of Queensland, in Professor David Craik's laboratory. Her research focuses on taking synthetic designer peptides and expressing them recombinantly in biological systems, especially plants.


Thomas Durek obtained his Ph.D. degree from the Max-Planck Institute for Molecular Physiology, Dortmund, Germany. After a post-doctoral stay with Stephen Kent at the University of Chicago, he moved to The University of Queensland. His research interests are in peptide and protein chemistry, biophysics, structural biology (NMR and X-ray) as well as ion channel and GPCR pharmacology.


David Craik is an ARC Australian Laureate Fellow at the Institute for Molecular Bioscience, The University of Queensland. He completed his Ph.D. degree in organic chemistry at La Trobe University in 1981 and after two years of post-doctoral work in the USA, he returned to Australia to a faculty position at the Victorian College of Pharmacy. He moved to UQ in 1995 to set up a new biomolecular NMR laboratory. His research focuses on the discovery and applications of peptides in drug design.

Australian Journal of Chemistry 70(2) 152-161 https://doi.org/10.1071/CH16589
Submitted: 17 October 2016  Accepted: 1 November 2016   Published: 24 November 2016

Abstract

Cyclotides are a group of plant-derived peptides with a head-to-tail cyclized backbone that is stabilized by three knotted disulfide bonds. Their exceptional stability and tolerance for residue substitutions have led to interest in their application as drug design scaffolds. To date, chemical synthesis has been the dominant methodology for producing cyclotides and their analogues. Native chemical ligation is the most common strategy to generate the cyclic backbone and has been highly successful at producing a wide range of cyclotides for studies of structure–activity relationships. Both this and other chemical approaches require a specific linker at the C-terminus and typically involve a non-directed folding (disulfide oxidation) regimen, which can sometimes be a limiting factor in final yields. Following the recent discovery of enzymes involved in peptide cyclization in planta, site-specific and highly efficient enzymatic ligations have been used for synthetic cyclotide backbone cyclization. In this review, chemical synthesis strategies and approaches involving cyclization via enzymes for the production of cyclotides are described.


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