Side-Chain Anchoring Strategies for the Synthesis of Peptide Thioesters and Selenoesters

Methods Mol Biol. 2022;2530:125-140. doi: 10.1007/978-1-0716-2489-0_9.


Peptides bearing C-terminal thioester and selenoester functionalities are essential precursors for the chemical synthesis of larger proteins using ligation chemistry, including native chemical ligation (NCL) and diselenide-selenoester ligation (DSL). The use of a side-chain anchoring thioesterification or selenoesterification approach offers a robust method to access peptide thioesters or peptide selenoesters in excellent yields and in high purity. Importantly, this methodology overcomes solubility issues and epimerization of the C-terminal amino acid residue that can occur using solution-phase approaches. Detailed methods for the solid-phase synthesis of peptide thioesters and selenoesters using a side-chain anchoring approach are outlined in this article.

Keywords: Chemical protein synthesis; Ligation; Selenoester; Selenoesterification; Side-chain; Side-chain anchored; Synthetic proteins; Thioester; Thioesterification.

MeSH terms

  • Peptides* / chemistry
  • Proteins
  • Solid-Phase Synthesis Techniques* / methods
  • Sulfur Compounds / chemistry


  • Peptides
  • Proteins
  • Sulfur Compounds