New Organic Catalysis and Applications

The controlled chemical modification of proteins is of crucial importance in basic biological research and protein-based pharmaceutical application development. The major challenge in this field is to achieve site-specificity. This project seeks to develop biocompatible chemical methods for the site-specific modification of proteins via cooperative organic catalysis. A working hypothesis is to use the distinct local environment surrounding the target residue to achieve site-specificity. For example, functional groups (such as acid groups from glutamic and aspartic residues) present in the protein will be used as catalytic or cocatalytic moieties to direct the modification reaction to a target residue. Selective modification of the target residue will be achieved through its close proximity and proper orientation with these directing groups. As an important step to realize site-specific protein modifications, the first stage of this program involves the development of new synthetic methodology for the functionalization of the side chains of natural amino acids under mild aqueous conditions. Carboxylic acid and hydrogen bond-donor catalysts that resemble the directing groups in proteins will be used as catalysts or cocatalysts in these model reactions. Subsequent research will apply these reactions to develop site-specific methods for in vitro chemical modification of proteins. Further research will use the protein modification methods as crucial tools in addressing challenges in chemical biology and developing protein-based pharmaceutical agents. An immediate impact of this research lies in the use of these methods to produce protein conjugates (such as protein-polymer conjugate) to extend circulatory half-life and reduce immunogenicity of protein therapeutics. Meanwhile, these methods will be used to elucidate important biological processes (such as cancer-relevant protein-protein interactions), leading to medicines of the next generation. Apart from its impact in chemical biology, this research should improve fundamental understanding of catalysis involving complicated systems, and therefore likely stimulating new strategies in catalysis and synthesis.