One current strategy to improve bioactivity and stability of peptides is to cyclise the linear sequence into a rigid biologically active configuration. Nature often applies disulfide bonds to promote such stabilizing cyclization, yet the redox liability of disulfide bridges can be a significant pitfall for the development of disulfide-containing peptide drugs. Thioether linkages are considered potential replacements for disulfide bonds, but peptide chemists have often encountered synthetic complications when preparing thioether cyclic peptides. To solve this problem, we have recently developed a novel approach for peptide macrocyclisation based on selenoether crosslinking. Selenoethers, like thioether linkages, are promising surrogates of disulfide bonds with the advantage of being stable to reducing environments. By replacing cysteine with the more reactive isosteric selenocysteine, we were able to overcome the synthetic limitations associated with unfavorable intramolecular cysteine thiolation observed during classical thioether cyclization.
In this approach, the linear peptide is assembled on solid support and equipped with one or two selenocysteines at the appropriate position. Cyclization is then carried out under mild conditions in solution via Se-alkylation of the selenocysteine by halogenated residues. The selenide closure is chemoselective and can be applied to unprotected peptides in aqueous media at room temperature without a catalyst. Using this methodology, we constructed seleno-analogs of naturally occurring lantibiotic peptides in an unprecedented simplified fashion. We also built biologically active Se-analogues of the neuropeptide oxytocin, where a selenoether bridge replaced the native disulfide bond with minimal structural perturbations. Additionally, we showed that selenoether linking can take place prior to disulfide bonding, allowing regiocontrol over multifaceted bridges configurations. More recently, we have applied Se-alkylation to crosslink peptides into stabilizing alfa-helical configuration, which allowed their cell uptake by cancer cells. Overall, this simple synthetic strategy provides an easy way to cyclize peptides with short non-reducible linkages.