Chemical Editing of Proteins: From a Specific Residue to Functional Domains

The remarkable complexity of life is supported by proteins, yet their functional diversity is constrained by the limited chemical alphabet of 20 canonical amino acids. Although nature partially overcomes this restriction through nongenetically encoded processes such as post-translational modifications or cofactors, these mechanisms are often difficult to predict, control and engineer. This limitation raises a fundamental question: can we programmably "chemically edit" proteins to generate new functions on demand? To address this challenge, our laboratory has been dedicated to advancing a "protein chemical editing" toolkit by integrating synthetic chemistry with protein engineering. This framework enables precise manipulation of proteins from individual residues to entire functional domains. We pursue two complementary strategies: genetic code expansion, which introduces unnatural amino acids (UAAs) as new chemical building blocks, and directed evolution platforms, which generate programmable protein-editing enzymes capable of rewriting protein sequences. In this Account, we outline a multiscale approach for protein chemical editing, spanning atomic-level control of active sites with photocaged amino acids, refinement of catalytic pockets using noncanonical residues, covalent stabilization of protein-protein interfaces through designer electrophile warheads, and domain-level editing enabled by evolved proteases. Prospectively, through the synergistic integration of chemical design, genetic encoding, and directed evolution, protein chemical editing unlocks a new level of control over biological function. This paradigm, which merges the precision of synthetic chemistry with the complexity of living systems, fundamentally transforms our capabilities from merely observing life to actively programming it, with profound implications for biomedicine and biotechnology.