Selective chemical protein modification

The chemical modification of proteins is an important tool for probing natural systems and synthesizing novel conjugates. Here, Spicer and Davis review the merits and limitations of the most useful methods for selective modification at both natural and unnatural amino acids. Chemical modification of proteins is an important tool for probing natural systems, creating therapeutic conjugates and generating novel protein constructs. Site-selective reactions require exquisite control over both chemo- and regioselectivity, under ambient, aqueous conditions. There are now various methods for achieving selective modification of both natural and unnatural amino acids—each with merits and limitations—providing a ‘toolkit’ that until 20 years ago was largely limited to reactions at nucleophilic cysteine and lysine residues. If applied in a biologically benign manner, this chemistry could form the basis of true Synthetic Biology.