Genetically encoding latent bioreactive amino acids and the development of covalent protein drugs

As natural proteins generally do not bind targets in a covalent mode, the therapeutic potential of covalent protein drugs remains largely unexplored. Recently, latent bioreactive amino acids have been incorporated into proteins through genetic code expansion, which selectively react with nearby natural residues via proximity-enabled reactivity, generating diverse covalent linkages for proteins in vitro and in cells. These new covalent linkages provide novel avenues for protein research and engineering. In addition, a general platform technology, proximity-enabled reactive therapeutics (PERx), has been established for the development of covalent protein drugs. The first covalent protein drug demonstrates advantageous features in cancer immunotherapy in mice. Selective introduction of covalent bonds into proteins will advance biological studies, synthetic biology, and biotherapeutics with the power of biocompatible covalent chemistries.