Bioinspired Synthesis of Allysine for Late-Stage Functionalization of Peptides

Inspired by the enzyme lysyl oxidase, which selectively converts the side chain of lysine into allysine, an aldehyde-containing post-translational modification, we report herein the first chemical method for the synthesis of allysine by selective oxidation of dimethyl lysine. This approach is highly chemoselective for dimethyl lysine on proteins. We highlight the utility of this biomimetic approach for generating aldehydes in a variety of pharmaceutically active linear and cyclic peptides at a late stage for their diversification with various affinity and fluorescent tags. Notably, we utilized this approach for generating small-molecule aldehydes from the corresponding tertiary amines. We further demonstrated the potential of this approach in generating cellular models for studying allysine-associated diseases. A biomimetic approach was developed for the synthesis of allysine by selective oxidation of the side chain of dimethyl lysine. The reaction exhibits broad substrate scope and modifies dimethyl lysine and tertiary amines to form aldehydes in small molecules, peptides, proteins and cells.+ image