Through the looking glass--a new world of proteins enabled by chemical synthesis.
'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 50,825 Da, 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.
University of Chicago, Chicago, IL 60637, USA. skent@uchicago.edu
Stephen
S
Kent
Youhei
Y
Sohma
Suhuai
S
Liu
Duhee
D
Bang
Brad
B
Pentelute
Kalyaneswar
K
Mandal
D018360:Crystallography, X-Ray; D008958:Models, Molecular; D015394:Molecular Structure; D011506:Proteins / Q000138:chemical synthesis* / Q000737:chemistry
D011506:Proteins