N-Terminal Protein Modification through a Biomimetic Transamination Reaction

摘要

An important challenge in the field of protein bioconjugation is the development of strategies that can modify a protein once at a single site. Although many bioconjugation reactions can functionalize specific amino acids in aqueous solution,[1] most proteins display multiple copies of the targeted residue on their surface. This commonly results in product mixtures that present the new functionality in multiple locations on the protein surface. As it is one of the rarest amino acids,[2] cysteine is the most commonly targeted residue when site-selective modification is required, but there remain many situations in which the modification of a unique copy of this residue is inconvenient or impossible. To address these limitations, several chemoselective techniques have been developed to target surface-accessible aromatic residues.[3] To complement these methods further, we report herein a biomimetic transamination reaction that can modify the N terminus of proteins and peptides under mild conditions. This technique introduces a uniquely reactive ketone or aldehyde group in a single location, thus allowing further modification through oxime or hydrazone formation. This simple strategy does not require the use of site-directed mutagenesis, and therefore has the potential to introduce virtually any functional group on a wide range of protein substrates.