Stereoretentive Post-Translational Protein Editing

Abstract

AbstractChemical post-translational methods now allow convergent side-chain editing of proteins as a form of direct chemical mutagenesis without needing to resort to genetic intervention. Current approaches that allow the creation of constitutionally native side-chains via C–C formation using off-protein carbon-centred C• radicals added to unnatural amino acid radical acceptor SOMOphile ‘tags’ such as dehydroalanine are benign and wide-ranging. However, they also typically create epimeric mixtures of D-/L-residues. Here we describe a light-mediated desulfurative method that, through the creation and reaction of stereoretained on-protein L-alanyl Cβ• radicals, allows Cβ–Hγ, Cβ–Oγ, Cβ–Seγ, Cβ–Bγ and Cβ–Cγ bond formation to flexibly generate site-selectively edited proteins with full retention of native stereochemistry under mild conditions from a natural amino acid. This methodology shows great potential to explore protein side-chain diversity and construct useful bioconjugates.Table of Contents Image