Peptides occupy a privileged space in drug development, often exhibiting higher target specificity, lower toxicity and higher binding affinities than small molecule drugs, leading to far fewer side effects. However, the use of peptides as drugs has been limited by their poor bioavailability, in part due to their susceptibility to proteolytic degradation, which decreases the half-life of peptide therapies. Synthesising complex peptide topologies, such as lasso peptides, may serve to overcome proteolytic instability, but has been a challenge using established synthetic chemistry methods. Building upon previous work within the group, we explore the incorporation of a metal-binding domain into a peptide backbone via macrocyclisation. This metal-binding domain presents a promising avenue for the synthesis of mechanically interlocked peptides, thereby expanding the repertoire of accessible structures through synthetic means.

This presentation will detail our work towards the synthesis of these metal binding peptides, as well as optimisation of metal binding conditions and uses of peptide-metal complexes in the synthesis of diverse peptide topologies. Our method utilises a 2,6-pyridinediamide linker, which, along with a labile acetonitrile ligand, is able to bind Pd²⁺ ions in a square planar geometry which positions the metal ion within the centre of the macrocyclic peptide. This gives us a passive-metal template for the synthesis of interlocked structures. The labile acetonitrile ligand may be exchanged with a variety of 2,6-pyridinediol-based ligands to afford a collection of ligands threaded through our macrocyclic ring. These interlocked ‘pseudorotaxanes’ can in principle be transformed into catenanes and rotaxanes, including lasso-peptide like [1]rotaxane structures. We therefore envisage that this metal-binding macrocyclic peptide technology will prove valuable for the development of complex peptide therapeutics and will add to the growing toolbox of late-stage peptide modification strategies.