New covalent bonding ability for proteins

Protein Sci. 2022 Feb;31(2):312-322. doi: 10.1002/pro.4228. Epub 2021 Nov 16.


To expand protein's covalent bonding ability, latent bioreactive unnatural amino acids have been designed and genetically encoded into proteins, which react with specific natural amino acid residues through proximity-enabled bioreactivity. The resultant new covalent bonds can be selectively created within and between proteins in vitro, in cells, and in vivo. Offering diverse properties previously unattainable, these covalent linkages have been harnessed to enhance protein properties, to modulate protein function, to probe ligand-receptor binding, to identify elusive protein interactions, and to develop covalent protein drugs. Selective introduction of covalent bonds into proteins is affording novel avenues for biological studies, synthetic biology, and biotherapeutics.

Keywords: covalent drug; genetic code expansion; latent bioreactive unnatural amino acid; protein therapeutics; protein-protein interaction; proximity-enabled bioreactivity.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Amino Acids / chemistry
  • Ligands
  • Protein Binding
  • Protein Engineering*
  • Proteins* / chemistry


  • Amino Acids
  • Ligands
  • Proteins