Development of an o-aminoanilide-mediated native chemical ligation-assisted DADA strategy for the synthesis of disulfide surrogate peptides

The hydrazide-based native chemical ligation-assisted diaminodiacid (DADA) strategy is an efficient method for synthesizing large-span disulfide bridge surrogates. However, it is difficult to synthesize disulfide bond surrogates at Gln–Cys or Asn–Cys ligation sites using this strategy. Herein, we report a peptide o-aminoanilide-mediated NCL-assisted DADA strategy that enables the synthesis of large-span peptide disulfide bridge surrogates containing only Gln–Cys or Asn–Cys ligation sites. Through this strategy, we successfully synthesized disulfide bond surrogates of conotoxin vil14a and κ-hefutoxin 1. This strategy provides a new option to obtain large-span peptide disulfide bridge substitutes for native chemical ligation at Gln–Cys and Asn–Cys sites.