Peptide Ligations by Using Aryloxycarbonyl‐o‐methylaminoanilides: Chemical Synthesis of Palmitoylated Sonic Hedgehog

• Published in: Angewandte Chemie International Edition 2018-12, Vol.57 (49), p.16120-16125
• Main Authors: Palà‐Pujadas, Judith, Albericio, Fernando, Blanco‐Canosa, Juan B.
• Format: Article
• Language: English
• Subjects: acylureas; Chemical synthesis; Embryogenesis; Embryonic growth stage; Hedgehog protein; lipoproteins; native chemical ligation; o-methylaminoanilides; Organic chemistry; Patched protein; Peptides; Protein biosynthesis; Protein synthesis; Proteins; Signal transduction; Sonic Hedgehog; Thioesterification; Tumors
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201810712

A simple procedure for C‐terminal activation of peptides in solution and its application in native chemical ligation and protein synthesis is described. This method involves a mild thioesterification based on the conversion of an aryloxy‐o‐methylaminoanilide to thioester under aqueous conditions and in situ ligation with an N‐terminal cysteine peptide. The versatility is shown in pH‐controlled sequential ligations. To illustrate the usefulness of this methodology, we synthesized the palmitoylated N‐terminal domain of human Sonic Hedgehog, a morphogen protein that binds the transmembrane receptor Patched and activates the Hedgehog signaling pathway, involved in embryonic development and in the proliferation of multiple tumors. This approach extends the chemical toolset of chemical protein synthesis based on o‐aminoanilide and o‐methylaminoanilide peptides. Chemical protein synthesis: C‐terminal aryloxycarbonyl‐o‐methylaminoanilide peptides undergo thioesterification and carry out native chemical ligation. They can participate in sequential ligations in the N‐to‐C direction, thereby facilitating convergent approaches in the chemical synthesis of proteins. Using these mildly activated peptides, the N‐terminal palmitoylated domain of Sonic Hedgehog was efficiently synthesized.