Abstract
'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 language | English |
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Pages (from-to) | 428-436 |
Number of pages | 9 |
Journal | Journal of Peptide Science |
Volume | 18 |
Issue number | 7 |
DOIs | |
Publication status | Published - 2012 Jul |
All Science Journal Classification (ASJC) codes
- Structural Biology
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmacology
- Drug Discovery
- Organic Chemistry