Cyclic proteins

Naturally occurring circular proteins (in which the N- and C-termini are linked by a peptide bond) offer enhanced stability over their linear counterparts. Of particular interest is a plant-derived group of cyclic peptides called cyclotides, which are further stabilised by three disulphide bonds that form a conserved cysteine knot motif. Cyclotides exhibit a range of intrinsic bioactivities, such as insecticidal, anti-HIV and neurotensin binding, and their exceptional stability marks them as promising scaffolds for the grafting of other bioactive sequences for pharmaceutical applications. Achieving efficient backbone-cyclisation in vitro has hindered the realisation of this potential.

Native cyclotides are produced as precursors that are enzymatically processed to their mature, cyclic form. Our lab has identified a vacuolar processing enzyme (VPE) from a cyclotide producing plant that is capable of performing the final processing step: removal of the C-terminal prodomain and circularisation of the peptide backbone. We are now focussing on harnessing the potential of this enzyme for large scale production of both naturally and non-naturally occurring cyclic peptides using in vitro and in vivo systems.