Synthesis of Natural and Novel Cyclic Peptides

Naturally occurring cyclic peptides exhibit a wide range of biological activities and are often more resistant to enzymatic hydrolysis than their linear counterparts. Additionally, the restricted conformational flexibility of cyclic peptides allows them to present functional groups in a spatially well-defined manner and this is of use in the study and mimicry of protein folding and in the determination of the active conformations of peptides. However, the head-to-tail cyclisation of linear peptides is often a slow and low-yielding reaction. We have developed a new method for the efficient head-to-tail synthesis of small cyclic peptides and examined its use in a number of model systems. Our methodology has been employed in the synthesis of the naturally occurring cyclic peptides mahafacyclin B and axinellin A and we are currently investigating the scope of our cyclisation method and its application in the synthesis of both naturally occurring and novel cyclic peptides.

Rigidified Cyclic Peptides as Supramolecular Scaffolds

The introduction of aromatic subunits into a cyclic peptide backbone greatly reduces the conformational flexibility of these already constrained molecules and allows functional groups to be arranged in a convergent and preorganised manner suitable for binding of a guest molecule. We have used analogues of the naturally occurring Lissoclinum family of cyclic peptides, which incorporate oxazole subunits in the macrocyclic ring, to provide rigid scaffolds for the positioning of molecular receptor groups. These cyclic peptides are further rigidified by the presence of a network of bifurcated hydrogen bonds and their synthesis from amino acid building blocks allows a wide range of functional groups to be appended to the scaffold. Compounds bearing dipicolylamino zinc(II) complexes have been used to bind biologically relevant anions (e.g. pyrophosphate ions) in aqueous solution with high affinity and good selectivity. We are currently investigating how the selectivity of these receptors for target anions can be improved and looking at the attachment of alternative binding sites to the cyclic peptide scaffolds.

Molecular Self-Assembly

The design of molecules capable of self-assembly to form novel multicomponent supramolecular structures remains a significant challenge for synthetic chemists. Despite intense interest in the field, the assembly of synthetic structures which replicate the complexity and control apparent in the larger self-assembled biological structures is yet to be achieved. An understanding of the interactions between molecules is required to enable molecular building blocks capable of forming such structures to be designed. We are investigating the self-assembly of molecular aggregates (e.g. capsules) using both hydrogen bonding and metal-ligand interactions as the glue to hold our molecular subunits together.