Title: Building New Fusion Proteins With Enzymatic Oxidative Coupling Reactions
Matt Francis was born in Ohio and received his undergraduate degree in Chemistry from Miami University in Oxford, OH in 1994. From 1994-1999 he attended graduate school at Harvard University, working in the lab of Prof. Eric Jacobsen. His Ph.D. research involved the development of combinatorial strategies for the discovery and optimization of new transition metal catalysts. He then moved to UC Berkeley, where he was a Postdoctoral Fellow in the Miller Institute for Basic Research in Science. He worked under the guidance of Prof. Jean Fréchet, focusing on the development of DNA-based methods for the assembly of polymeric materials and the application of dendrimers for drug delivery. Matt started his independent career in the UC Berkeley Chemistry Department in 2001, and has built a research program involving the development of new organic reactions for protein modification. These new chemical tools have then been used to modify biomolecular assemblies to prepare new materials for diagnostic imaging, wastewater treatment, and solar cell development. For his research accomplishments, Matt has received the Dreyfus Foundation New Faculty Award, an NSF Career Award, a GlaxoSmithKline Young Investigator Award, the 2017 Bioconjugate Chemistry Lectureship Award from the American Chemical Society, and the 2019 Arthur C. Cope Scholar Award from the American Chemical Society. Matt served as the chair of the chemistry department at UC Berkeley from 2018-2023. Matt has also received the UC Berkeley Departmental Teaching Award on four occasions, the Noyce Prize for Excellence in Undergraduate Teaching, and the 2009 University Distinguished Teaching Award.
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.
Keywords: Chemical biology, proteins, bioconjugation, immunotherapy
Host: Prof. Jeff Martell