The synthetic modification of proteins plays an essential role in the fields of biomaterials science and chemical biology. Conjugation of synthetic molecules to proteins enables the incredible diversity of protein structure and function to be harnessed in new protein-based materials. Protein bioconjugates have been used for a wide array of applications from the investigation of biological function to use in new biomaterials such as targeted therapeutics and biocatalysts. The synthesis of these materials requires well-defined protein modification reactions. However, a significant challenge is that these reactions must take place in water, at ambient temperature, near neutral pH and in the presence of a wide array of functional groups. While many methods for the modification of native and artificial amino acids exist, they often require long reaction times, lengthy syntheses of reactive substrates, or lack specificity and selectivity. To address these issues, a suite of bioconjugation reactions that utilize ortho-aminophenols was developed. The oxidative coupling of non-canonical aniline residues with o-aminophenol substrates was developed to enable use with a wide range of protein substrates, including those containing free cysteines and glycosylation. In the course of these studies, it was discovered that under certain conditions aminophenols were reactive with native residues on protein substrates in addition to artificial aniline moieties. The reactive native residues were identified and oxidative coupling of o-aminophenols with the N-terminus was optimized to achieve high levels of modification on peptide and protein substrates. This new reactivity dramatically expands the bioconjugation reaction toolkit, enabling fast, site-selective modification in a single step using low concentrations of reagent.

Synthetic modifications of proteins to make new biomaterials

251st National Meeting (2016)

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