Issue Date: July 18, 2011
One-Pot Protein Synthesis
Chemists aiming to design drugs that target vascular endothelial growth factor (VEGF), a protein responsible for blood vessel growth in tumors, could now have a ready synthetic supply of it for their screening tests, thanks to a study (Angew. Chem. Int. Ed., DOI: 10.1002/anie.201103237). Researchers Kalyaneswar Mandal and Stephen B. H. Kent of the University of Chicago have devised a way of producing in one reaction vessel a 204-residue portion of the VEGF protein that is biologically active. “This is the largest protein molecule prepared by one-pot native chemical ligation,” the researchers write. To generate the truncated protein, which is a homodimer made of two 102-residue polypeptide chains joined by two disulfide bonds, Mandal and Kent started with three peptide segments and added them together sequentially. The segments covalently bind through the reaction of terminal cysteine groups and thioesters, eventually forming one of the 102-residue monomer chains. These chains then fold, forming three intrachain disulfide bonds each, and dimerize to yield the biologically active VEGF. What’s significant about the synthesis, Kent says, is the formation of a total of eight disulfide bonds at near-quantitative yield.
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