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Development and Application of Oxidative Coupling Bioconjugation Reactions with ortho-Aminophenols

  • Author(s): Obermeyer, Allie
  • Advisor(s): Francis, Matthew B
  • et al.
Abstract

The synthetic modification of proteins plays an important role in the fields of chemical biology and biomaterials science. As applications of protein-based materials continue to become more complex, improved methods for the covalent modification of proteins are needed. Although many methods for the modification of native and artificial amino acids exist, they often require long reaction times or lengthy syntheses of reactive substrates. This work describes the development and application of a suite of bioconjugation reactions that utilize ortho-aminophenols. The oxidative coupling of aniline residues with o-aminophenol substrates was optimized. Potassium ferricyanide was identified as an alternative, mild oxidant for this coupling. These new conditions enabled the use of the oxidative coupling reaction in the presence of free cysteines and glycoslated substrates. Aminophenols were also discovered to react with native residues on protein substrates in addition to artificial aniline moieties. Cysteine and the N-terminus were identified as the reactive residues. The oxidative coupling of o-aminophenols with the N-terminus was optimized to achieve high levels of modification on peptide and protein substrates. The oxidative coupling of anilines and o-aminophenols was applied to the synthesis of a targeted, virus-like particle and to the detection of protein tyrosine-nitration. Overall, these updated and novel oxidative coupling methods expand the utility ortho-aminophenols for the modification of proteins.

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