Next: SFTI Up: The Cyclotides Previous: Cyclotide Evolution
One of the motivating factors behind research into cyclic peptides is their application as scaffolds for the development of bioactive drugs. As we have seen, the cyclotides exhibit a compact, rigid and stable fold and would appear to be ideal for the engineering of novel bioactive moieties. To accomplish this goal an understanding of the way the CCK fold is affected by variations in loop composition and length will be crucial. For example the haemolytic activity of the cyclotides is an undesirable trait from a drug development perspective and the abolition of this activity is a priority for the development process. However it has been shown that the hydrophobic patch of the cyclotides may stabilise the fold and the engineering of less hydrophobic cyclotides may result in the loss of stability. To explore the limits of the CCK fold two pathways can be followed -- the synthesis of novel peptides or, given the ever expanding rate of cyclotide discovery, the screening of a wide number of plants to discover unusual cyclotides with atypical characteristics.
The evolution of the cyclotides presents a mystery. As discussed the unusual distribution of the cyclotides suggests that the cyclotides are either more prevalent than previously thought or have been lost in the majority of plants. Also of interest is what, if any, evolutionary relationship exists between the cyclotides and the other ICK-containing proteins.
A key research goal in the field of cyclic peptides is the determination of their biosynthesis and the cyclotides are not the only cyclic peptides that are found in the plant kingdom. As the biosynthesis of these peptides is so poorly understood it is not possible to say whether there is a unifying cyclising process or whether cyclisation can occur in a number of different ways. As mentioned previously a recurring theme that will develop through this section is the involvement of proteases in the processing of linear precursors into mature cyclic peptides and the most compelling evidence for this is the existence of the small trypsin inhibitor SFTI-1 from the seeds of the sunflower. In the next section this fascinating peptide will be examined and the key role that proteases have played in cyclising this peptide in vitro reviewed.
Next: SFTI Up: The Cyclotides Previous: Cyclotide Evolution Jason Mulvenna