Through the looking glass - a new world of proteins enabled by chemical synthesis

Stephen Kent, Youhei Sohma, Suhuai Liu, Duhee Bang, Brad Pentelute, Kalyaneswar Mandal

Research output: Contribution to journalReview articlepeer-review

32 Citations (Scopus)


'Chemical ligation' - the regioselective and chemoselective covalent condensation of unprotected peptide segments - has enabled the synthesis of polypeptide chains of more than 200 amino acids. An efficient total chemical synthesis of the insulin molecule has been devised on the basis of a key ester-linked intermediate that is chemically converted to fully active human insulin. Enzyme molecules of defined covalent structure and with full enzymatic activity have been prepared and characterized by high-resolution X-ray crystallography. A 'glycoprotein mimetic' of defined chemical structure and with a mass of 50,825Da, has been prepared and shown to have full biological activity and improved pharmacokinetic properties. d-Protein molecules that are the mirror images of proteins found in the natural world have been prepared by total chemical synthesis. Racemic protein mixtures, consisting of the d-enantiomers and l-enantiomers of a protein molecule, form highly ordered centrosymmetric crystals with great ease; this has enabled the determination of the crystal structures of recalcitrant protein molecules. A protein with a novel linear-loop covalent topology of the peptide chain has been designed and synthesized and its structure determined by facile crystallization as the quasi-racemate with the d-form of the native protein molecule. We have developed an optimized total chemical synthesis of biologically active vascular endothelial growth factor-A; total synthesis of the mirror-image protein will be used to systematically develop d-protein antagonists of this important growth factor. The total chemical synthesis of proteins is now a practical reality and enables access to a new world of protein molecules.

Original languageEnglish
Pages (from-to)428-436
Number of pages9
JournalJournal of Peptide Science
Issue number7
Publication statusPublished - 2012 Jul

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry


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