Synthesis of Histidine-Containing Oligopeptides via Histidine-Promoted Peptide Ligation

Abstract

Histidine-containing peptides are valuable therapeutic agents for a treatment of neurodegenerative diseases. However, the synthesis of histidine-containing peptides is not trivial due to the potential of imidazole sidechain of histidine to act as a nucleophile if unprotected. A peptide ligation method utilizing the imidazole sidechain of histidine has been developed. The key imidazolate intermediate that acts as an internal acyl transfer catalyst during ligation is generated by deprotonation. Transesterification with amino acids or peptides tethered with C-terminal thioester followed by N→N acyl shifts led to the final ligated products. A range of histidine-containing dipeptides could be synthesized in moderate to good yields via this method without protecting the imidazole sidechain. The protocol was further extended to tripeptide synthesis via a long-range N→N acyl transfer, and tetrapeptide synthesis.

Keywords: acyl transfer; chemical ligation; copper-binding peptides; histidine; peptide synthesis.