Total chemical synthesis of proteins

Chem Soc Rev. 2009 Feb;38(2):338-51. doi: 10.1039/b700141j. Epub 2008 Sep 16.


This tutorial review outlines the modern ligation methods that enable the efficient total chemical synthesis of enzymes and other protein molecules. Key to this success is the chemoselective reaction of unprotected synthetic peptides ('chemical ligation'). Notably, native chemical ligation enables the reaction of two unprotected peptides in aqueous solution at neutral pH to form a single product in near quantitative yield. Full-length synthetic polypeptides are folded to form the defined tertiary structure of the target protein molecule, which is characterized by mass spectrometry, NMR, and X-ray crystallography, in addition to biochemical and/or biological activity.

Publication types

  • Review

MeSH terms

  • Crystallography, X-Ray
  • Cysteine / chemistry
  • Humans
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Protein Conformation
  • Proteins / chemical synthesis*
  • Proteins / chemistry
  • Proteins / classification
  • Proteins / isolation & purification


  • Proteins
  • Cysteine