Site‐Selective Installation of N^ϵ‐Modified Sidechains into Peptide and Protein Scaffolds via Visible‐Light‐Mediated Desulfurative C–C Bond Formation

Abstract

Post-translational modifications (PTMs) enhance the repertoire of protein function and mediate or influence the activity of many cellular processes. The preparation of sitespecifically and homogeneously modified proteins, to apply as tools to understand the biological role of PTMs, is a challenging task. Herein, we describe a visible-light-mediated desulfurative C(sp 3 )-C(sp 3 ) bond forming reaction that enables the siteselective installation of N e -modified sidechains into peptides and proteins of interest. Rapid, operationally simple, and tolerant to ambient atmosphere, we demonstrate the installation of a range of lysine (Lys) PTMs into model peptide systems and showcase the potential of this technology by siteselectively installing an N e Ac sidechain into recombinantly expressed ubiquitin (Ub).

Site-selective photocatalytic functionalization of peptides and proteins at selenocysteine

“…To overcome the drawbacks of the above reaction manifolds, new synthetic methods have been developed for the late-stage functionalization of a specific amino acid side chain within proteins, albeit with varying degrees of chemoselectivity 3,22 . For example, cysteine (Cys) has been functionalized using a broad array of chemistries, including but not limited to the reaction with thiosulfonates [28][29][30] , hypervalent iodine reagents [31][32][33] , alkynyl phosphonoamidates 34 , strained cyclic systems 35 , desulfurative radical addition chemistry 36 , and transition-metal catalyzed arylation chemistry [37][38][39][40] . Indirect functionalization of Cys has also been performed through elimination of the sulfhydryl side chain to form dehydroalanine, with subsequent elaboration by radical or Michael addition [41][42][43] .…”

Kinetic Resolution of Epimeric Proteins Enables Stereoselective Chemical Mutagenesis

“…A chemical challenge, especially in the context of PTM research, is the requirement for minimal perturbation of linkages between the protein and new functional groups. Creative solutions for this problem are Cys alkylation, frequently used to install methyllysine analogues, and recent desulfurative − strategies to incorporate useful functional groups such as spin labels, PTMs, and their analogues.…”

Kinetic Resolution of Epimeric Proteins enables Stereoselective Chemical Mutagenesis

“…A chemical challenge, especially in the context of PTM research, is the requirement for precise, minimally perturbing linkages between the protein and new functional groups. Creative solutions for this problem are Cys alkylation, frequently used to install methyllysine analogs, 39 and recent desulfurative [40][41][42][43] strategies to incorporate useful functional groups such as spin labels, PTMs, and their analogues.…”