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The first general method for the rapid, chemoselective, and modular functionalization of serine residues in native polypeptides is reported. Using a reagent platform based on P(V) oxidation state, this redox-economic approach can be used to append nearly any kind of cargo onto serine generating a stable, benign, and hydrophilic phosphorothioate linkage. The method tolerates all other known nucleophilic functional groups of naturally occurring proteinogenic amino acids. A variety of applications can be envisaged enabled by this expansion of the toolbox of site-selective bioconjugation methods.

This Communication reports the first general method for rapid, chemoselective, and modular functionalization of serine residues in native polypeptides, which uses a reagent platform based on the P(V) oxidation state. This redox-economical approach can be used to append nearly any kind of cargo onto serine, generating a stable, benign, and hydrophilic phosphorothioate linkage. The method tolerates all other known nucleophilic functional groups of naturally occurring proteinogenic amino acids. A variety of applications can be envisaged by this expansion of the toolbox of site-selective bioconjugation methods.

The first general method for the rapid, chemoselective, and modular functionalization of serine residues in native polypeptides is reported. Using a reagent platform based on P(V) oxidation state, this redox-economic approach can be used to append nearly any kind of cargo onto serine generating a stable, benign, and hydrophilic phosphorothioate linkage. The method tolerates all other known nucleophilic functional groups of naturally occurring proteinogenic amino acids. A variety of applications can be envisaged enabled by this expansion of the toolbox of site-selective bioconjugation methods.

Copyright © 2020 American Chemical Society, This Communication reports the first general method for rapid, chemoselective, and modular functionalization of serine residues in native polypeptides, which uses a reagent platform based on the P(V) oxidation state. This redox-economical approach can be used to append nearly any kind of cargo onto serine, generating a stable, benign, and hydrophilic phosphorothioate linkage. The method tolerates all other known nucleophilic functional groups of naturally occurring proteinogenic amino acids. A variety of applications can be envisaged by this expansion of the toolbox of site-selective bioconjugation methods., Financial support for this work was provided by Bristol-Myers Squibb, the NIH (GM-118176), the Marie Skłodowska-CurieGlobal Fellowships (749359-EnanSET to N.M.P) within the European Union’s Research and Innovation Framework Programme (2014−2020), FCT Portugal (IF/00624/2015), and the Royal Society (URF\R\180019). D.F. was supported by the National Center for Advancing Translational Sciences,National Institutes of Health, through Grant UL1 TR002551 and Linked Award TL1 TR002551.