Matthew B. Francis

Our lab has developed several chemical strategies to functionalize biomolecules with a wide range of synthetic functional groups, providing well-defined bioconjugates for therapeutic applications. This presentation will focus on a powerful enzymatic oxidative coupling strategy catalyzed by tyrosinase, which generates o-quinones from simple phenols and tyrosine residues using molecular oxygen as the stoichiometric oxidant. These reactive intermediates undergo rapid coupling reactions with select nucleophiles, including anilines, N-terminal proline residues, and cysteine thiolates. The mild conditions, high yields, and high chemoselectivity of this strategy have proven particularly successful for the coupling of full-size protein domains, allowing facile access to protein therapeutics with interdomain geometries that were previously inaccessible. The potential of this chemistry will be highlighted for the generation of bispecific cell engagers and targeted STING agonist delivery platforms for cancer treatment.