Disulfide rich peptides provide promising leads for drug development. However, they are limited by the metabolic and chemical instability of the disulfide bridge in vivo. The replacement of naturally occurring disulfide (-S-S-) bridges with non-reducible isosteres can improve the pharmacokinetic properties of these peptides. An additional challenge is forming interlocked isosteric bridges so that the active topoisomer is selectively formed. Our group is developing the chemistry to enable a selective, successive metathesis route to non-reducible dicarba (-C-C-) bridges in peptides. This strategy enables us to access interlocked dicarba bridges.
We have demonstrated that allylglycine and butynylglycine can be used in tandem to produce a c[2-8]-alkyne-c[3-16]-alkene conotoxin Vc1.1. Using prenylglycine this approach can be extended to generate an interlocked tris-dicarba peptide, such as conotoxin MVIIA.