O-arylation and O-alkylation
Researchers at the University of Chicago recently developed a one-pot protein synthesis involving a 204-residue covalent-dimer vascular endothelial growth factor (VEGF). VEGF is a protein involved in vasculogenesis and angiogenesis and is studied in reference to pharmaceutical compounds, particularly anticancer compounds. The researchers reported that they prepared a 204-residue covalent dimmer VEGF with full mitogenic activity from three unprotected peptide segments by one-pot native chemical ligations. The covalent structure of the synthetic VEGF was confirmed through mass measurements, and the three-dimensional structure of the synthetic protein was determined by high-resolution X-ray crystallography (2, 3).
Chemical protein synthesis is one research area of University of Chicago professor Stephen B.H. Kent, a co-author of the recently published research on the VEGF synthesis. One area of focus is the preparation of long polypeptide chains of protein molecules by the chemoselective reaction (i.e. chemical ligation) of unprotected protein segments containing mutually reactive functional groups. An example of these ligation chemistries is thioester-mediated, amide-forming ligation or native ligation. The resulting polypeptide chains are folded with good efficiency to produce high-purity synthetic proteins. The covalent structure of the molecule is confirmed by mass spectrometry, and the three-dimensional fold structure of the synthetic protein is determined by X-ray crystallography. Another area of research focus is kinetically controlled ligation, a chemistry used for the full convergent synthesis of large protein molecules. The research group is examining insertion reactions for creating molecular diversity in preformed molecular scaffolds and the use of polymer-supported ligation.