Oral Presentation 10th Australian Peptide Conference 2013

In the search for more potent, selective and less toxic drugs, medicinal chemists have turned their interest into peptides as drug candidates instead of small molecules. Nevertheless, the proteolytic instability of peptides still presents a limitation for the widespread utilization of these molecules as therapeutics. One common strategy to improve bioactivity and stability of peptides is to cyclise the linear peptide into a rigid, stable conformation.

Here we report a novel approach for macrocyclisation of peptides based on selenoether crosslinking. Selenoethers, like thioether linkages, are promising surrogates of disulfide bonds with the advantage of being stable to reducing environments. However, thioether macrocyclization of peptides by intramolecular thiolation of cysteine is often difficult, but can be overcome by replacing cysteine with the more reactive isosteric selenocysteine amino acid. This simple synthetic strategy provides an easy way to cyclize peptides with short non-reducible linkages.

The linear peptide is assembled on solid support and equipped with selenocysteine and halogenated residues. Cyclisation is carried out under mild conditions in solution via Se-alkylation of the selenocysteine by the halogenated amino acid. The selenide closure is chemoselective and can be applied to unprotected peptides in aqueous media at room temperature without a catalyst. We have recently applied the new methodology to construct seleno-analogs of naturally occurring lantibiotic peptides in an unprecedented simplified fashion.¹  We now describe biologically active analogues of the neuropeptide oxytocin, where the stable selenoether bridge replaces the native disulfide bond with minimal structural perturbations.