Disulfide-rich macrocyclic peptides as templates in drug design

•Cyclic disulfide-rich peptides have exceptional stability and rigid frameworks.•Pharmaceutically interesting peptide epitopes can be grafted into these frameworks.•Grafted frameworks show increased stability relative to native bioactive epitopes.•Cyclic disulfide-rich peptides are excellent prospects for drug design.•Grafted peptides can be used to probe challenging pharmaceutical targets.

Recently disulfide-rich head-to-tail cyclic peptides have attracted the interest of medicinal chemists owing to their exceptional thermal, chemical and enzymatic stability brought about by their constrained structures. Here we review current trends in the field of peptide-based pharmaceuticals and describe naturally occurring cyclic disulfide-rich peptide scaffolds, discussing their pharmaceutically attractive properties and benefits. We describe how we can utilise these stable frameworks to graft and/or engineer pharmaceutically interesting epitopes to increase their selectivity and bioactivity, opening up new possibilities for addressing ‘difficult’ pharmaceutical targets.

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