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Development of Oxidative Bioconjugation Methodology for the Site-Selective Modification of the Electron Rich Aromatic Amino Acids

  • Author(s): Seim, Kristen Lee
  • Advisor(s): Francis, Matthew B
  • et al.
Abstract

As applications of protein-based materials become increasingly complex, there is a growing need for an expanded set of bioconjugation reactions that can attach synthetic components to defined locations on protein substrates. Although the introduction of artificial amino acids is a useful method for achieving site-selective protein modification, there are advantages to targeting native amino acids that can be introduced without specialized expression systems. This work describes the discovery, development, and application of new oxidation-based bioconjugation methods that target the native electron-rich aromatic amino acids, tyrosine and tryptophan. These methods include a peptide modification strategy that uses synthetic reagents to site-selectively introduce and modify oxidized tryptophan residues, as well as series of protein modification strategies that use cerium(IV) ammonium nitrate (CAN) to oxidatively couple tyrosine and tryptophan residues to electron rich aniline derivatives. One of these reactions, a CAN-mediated oxidative coupling between anisidine derivatives and tyrosine residues, has been applied towards the synthesis of a novel protein-based material and the site-selectivity of this reaction has been explored using combinatorial peptides libraries. Overall, these unprecedented modification strategies target these under-utilized amino acids with excellent chemoselectivity, greatly augmenting the important and growing list of useful bioconjugation techniques.

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