The central focus of the research herein is the development of new, highly site-selective reactions that can expand and complement the current state of the art in protein modification. A multidisciplinary approach has been developed that combines protein expression, purification, and characterization with the physical organic chemistry and organic synthesis techniques required for new reaction development. In particular, the reactions under study are designed to be orthogonal to existing lysine- and cysteine-based strategies, and thus can be used in concert with these tried-and-true methods. By targeting underutilized functional groups and by enhancing reaction selectivity between similar functionality, it is also anticipated that many entirely new avenues for protein labeling, protein immobilization, and de novo protein synthesis will emerge from these studies. Specifically, two powerful new strategies will be developed for the facile modification of tyrosine residues on protein surfaces. The first uses diazonium-coupling reactions to activate tyrosine residues, followed by a hetero-Diels-Alder reaction for further conjugation. Start to finish, this procedure takes as little as three hours to carry out, and can be used to couple alkenes and alkynes to tyrosines with absolute selectivity. The second strategy is a new three-component Mannich-based coupling reaction that can modify tyrosine residues with exquisite selectivity and simultaneously install two new functional groups. This reaction will be explored for as a new strategy for protein ligation. Transition-metal catalyzed reactions will also be explored, as they offer many opportunities for highly selective reactions and the activation of currently unmodifiable functional groups. In particular, the development of a metal carbene-based strategy for disulfide bonds will be explored as a means to modify antibody fragments and N-terminal methionine residues.
| ElSohly, Adel M; Francis, Matthew B (2015) Development of oxidative coupling strategies for site-selective protein modification. Acc Chem Res 48:1971-8 |
| Seim, Kristen L; Obermeyer, Allie C; Francis, Matthew B (2011) Oxidative modification of native protein residues using cerium(IV) ammonium nitrate. J Am Chem Soc 133:16970-6 |
| Dedeo, Michel T; Finley, Daniel T; Francis, Matthew B (2011) Viral capsids as self-assembling templates for new materials. Prog Mol Biol Transl Sci 103:353-92 |
| Witus, Leah S; Francis, Matthew B (2011) Using synthetically modified proteins to make new materials. Acc Chem Res 44:774-83 |
| Stephanopoulos, Nicholas; Francis, Matthew B (2011) Choosing an effective protein bioconjugation strategy. Nat Chem Biol 7:876-84 |
| Witus, Leah S; Francis, Matthew (2010) Site-Specific Protein Bioconjugation via a Pyridoxal 5'-Phosphate-Mediated N-Terminal Transamination Reaction. Curr Protoc Chem Biol 2:125-34 |
| Witus, Leah S; Moore, Troy; Thuronyi, Benjamin W et al. (2010) Identification of highly reactive sequences for PLP-mediated bioconjugation using a combinatorial peptide library. J Am Chem Soc 132:16812-7 |
| Wu, Wesley; Hsiao, Sonny C; Carrico, Zachary M et al. (2009) Genome-free viral capsids as multivalent carriers for taxol delivery. Angew Chem Int Ed Engl 48:9493-7 |
| Tong, Gary J; Hsiao, Sonny C; Carrico, Zachary M et al. (2009) Viral capsid DNA aptamer conjugates as multivalent cell-targeting vehicles. J Am Chem Soc 131:11174-8 |
| Antos, John M; McFarland, Jesse M; Iavarone, Anthony T et al. (2009) Chemoselective tryptophan labeling with rhodium carbenoids at mild pH. J Am Chem Soc 131:6301-8 |
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