Peptide macrocyclization through amide-to-amide transpeptidation

Cyclic cysteine peptides are peptide macrocycles endowed with enhanced metabolic stability and potentially, with membrane permeability. They have attracted attention in drug design and interest in their synthesis. The chemical approach for macrocyclization through transpeptidation bears striking similarity to the biological approach using an intein. Both use a similar design of thioester precursors and an amide-to-amide transpeptidation scheme, employing a series of acyl shifts to break and make amide bonds. Here we describe the synthesis of two cyclic cysteine peptides, hedyotide B1 and sunflower trypsin inhibitor-1, highlighting the similarities between the intein-based and chemical amide-to-amide schemes. In our intein-based and chemical schemes, we employed an intein Mxe or a thioethylbutylamido linkage at the C-terminus of their linear precursors, respectively. Our results demonstrated that the chemical approach provides a useful alternative to the intein approach with high efficiency.