Protein Chemistry

We are developing powerful chemical methods to synthesize and modify proteins. In 2000, we invented the “traceless Staudinger ligation” to couple a peptide with a C-terminal phosphinothioester to one having an N-terminal azido group to form an amide bond. More recently, we introduced the diazo group into chemical biology. We did so by developing a facile reaction to access diazo compounds from azides, demonstrating that the versatility of diazo compounds in 1,3-dipolar cycloadditions (“click chemistry”) greatly exceeds that of azides, showing that diazo compounds endure metabolism and enable chemoselectivity in cellulo, and discovering how to tune diazo compounds for the efficient esterification of protein carboxyl groups in water. Notably, this esterification is reversible by esterases that are endogenous in human cells. We are now using tuned diazo compounds to confer upon biologics the advantages of “prodrugs”, such as cellular permeability, enabling “gene therapy without the genes.“