Stereoretentive Post-Translational Protein Editing

Xia-Ping Fu; Yizhi Yuan; Ajay Jha; Nikita Levin; Andrew M Giltrap; Jack Ren; Dimitrios Mamalis; Shabaz Mohammed; Benjamin G Davis

doi:10.1021/acscentsci.2c00991

Stereoretentive Post-Translational Protein Editing

ACS Cent Sci. 2023 Feb 24;9(3):405-416. doi: 10.1021/acscentsci.2c00991. eCollection 2023 Mar 22.

Authors

Xia-Ping Fu^{1

2}, Yizhi Yuan^{1

2}, Ajay Jha^{1

2}, Nikita Levin¹, Andrew M Giltrap^{1

2}, Jack Ren^{1

3}, Dimitrios Mamalis^{1

3}, Shabaz Mohammed^{1

3}, Benjamin G Davis^{1

2

3}

Affiliations

¹ Rosalind Franklin Institute, Harwell, Oxfordshire OX11 0QX, United Kingdom.
² Department of Pharmacology, University of Oxford, Oxford OX1 3QT, United Kingdom.
³ Department of Chemistry, University of Oxford, Oxford OX1 3TA, United Kingdom.

Abstract

Chemical post-translational methods allow convergent side-chain editing of proteins without needing to resort to genetic intervention. Current approaches that allow the creation of constitutionally native side chains via C-C bond formation, using off-protein carbon-centered C· radicals added to unnatural amino acid radical acceptor (SOMOphile, singly occupied molecular orbital (SOMO)) "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-proteinl-alanyl C_β· radicals, allows C_β-H_γ, C_β-O_γ, C_β-Se_γ, C_β-B_γ, and C_β-C_γ bond formation to flexibly generate site-selectively edited proteins with full retention of native stereochemistry under mild conditions from a natural amino acid precursor. This methodology shows great potential to explore protein side-chain diversity and function and in the construction of useful bioconjugates.