Abstract

To genetically introduce new chemical reactivity into live systems, we engineered the genetic code to encode a new class of unnatural amino acids (Uaas), the latent bioreactive Uaas. These Uaas, after being incorporated into proteins, specifically react with target natural amino acid residues via proximity-enabled reactivity, enabling the selective formation of new covalent linkages within and between proteins both in vitro and in live systems. These diverse reactivities, inaccessible to natural proteins, open doors to novel protein engineering, biological research, and therapeutic applications. I will present specific examples of using the proximity-enabled reactivity to probe ligand-receptor binding, to identify elusive protein-protein interactions, and to develop covalent protein drugs for cancer immunotherapy.