The uniquely diverse structures and functions of biomolecules offer many exciting opportunities for creating new materials with advanced properties. Using only a limited set of side chains and auxiliary groups, they have evolved unparalleled abilities to accelerate chemical transformations, facilitate the delivery of genetic cargo to targeted cells, bind specific analytes in complex mixtures, transduce energy, and generate elaborate three-dimensional structures through self-assembly. Over the years, our lab has sought to incorporate these capabilities into new materials for use in drug delivery, diagnostic imaging, solar energy collection, and water purification. To do this, however, we also needed to develop chemical strategies that can functionalize biomolecules with a wide range of synthetic functionalities. This presentation will focus on a powerful set of oxidative coupling reactions that involve o-quinone and o-iminoquinone intermediates. These species can modify proteins with very high chemoselectivity and efficiency, and have been adapted for use in a large number of experimental contexts. Newer versions of these reactions involve the use of oxidative enzymes that can generate o-quinone intermediates from simple phenols and tyrosine residues using molecular oxygen as the stoichiometric oxidant. These mild conditions have proven extraordinarily successful for the coupling of full-size protein domains, allowing facile access to bispecific cell engagers and other protein therapeutics of pharmaceutical interest. They have also been used to attach proteins to a diverse set of material components through well-defined linkages. The chemical development of these reactions will be presented, along with several examples of new protein bioconjugates that have been prepared through their use.

Enzymatic oxidative coupling reactions to make protein therapeutics

ACS Spring 2022

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