A protein functionalization platform based on selective reactions at methionine residues

Nature displays a remarkable ability to carry out site-selective post-translational modification of proteins, therefore enabling a dramatic increase in their functional diversity1. Inspired by this, chemical tools have evolved for the synthetic manipulation of protein structure and function, and have become essential to the continued advancement of chemical biology, molecular biology and medicine. However, the number of chemical transformations suitable for effective protein functionalization is limited because the stringent demands inherent to biological systems preclude the applicability of many potential processes2. Put simply, these chemical transformations often need to be selective at a single site on a protein, proceed with very fast reaction rates, operate under biologically ambient conditions and should provide homogeneous products with near perfect conversion2–7. While many elegant bioconjugation methods exist at cysteine, lysine and tyrosine, we reasoned that a method targeting a less explored amino acid would significantly expand the protein functionalization toolbox. Herein, we report the development of a multifaceted-approach to protein functionalization based on chemoselective labelling at methionine residues. By exploiting the unique electrophilic reactivity of a bespoke hypervalent iodine reagent, one can target the S-Me group in the side-chain of methionine. The bioconjugation reaction is fast, selective, operates at low µM concentrations and is complementary to existing bioconjugation strategies. Moreover, the new reaction produces a protein conjugate that is, itself, a high energy intermediate with reactive properties that can serve as a platform for the development of secondary, visible-light mediated bioorthogonal protein functionalization processes. Taken together, the merger of these approaches provides a versatile platform for the development of distinct transformations that can deliver versatile, information-rich protein conjugates directly from the native biomacromolecules.