In the last two decades, phosphorus-mediated chemoselective ligation reactions acquired the “gold” status for in vivo labeling of biomolecules. However, some drawbacks of phosphines, such as directing non-canonical amino acids (e.g. azides) as their reaction partners limits the scope of these reactions. Thus, for chemical approaches, targeting canonical amino acids on proteins as targets for site-specific conjugation are of prime importance. Indeed, protein chemists developed several methods using canonical amino acids as selective conjugation sites. For example, cysteine residues are often chosen for residue-specific introduction of different molecules via maleimide conjugation. Furthermore, residues that are rarely modified or are not of great structural importance, e.g. histidine, can be targeted for such conjugation. Until now, only a few publications reported a combination of canonical amino acid and phosphorus based bioconjugation methods. In this contribution, I will comment on two recent approaches using phosphorus chemistry enabling residue-specific bioconjugation on histidine ( Jia et al. J. Am. Chem. Soc. 2019, 141, 7294−7301) as well as cysteine (Kaspar et al. Angew. Chem. Int. Ed. Engl., 2019, ASAP) and discuss their value as elegant, new bioconjugation methodologies.

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Contributed by Can Araman

Can Araman completed his PhD degree under the supervision of Prof. Christian Becker at the University of Vienna. During this period, he worked on the semisynthesis of prion protein variants carrying glycan mimics and investigated their biophysical/biochemical properties in vitro. Currently, he is working as a postdoctoral researcher at the Leiden Institute of Chemistry (Netherlands), Bioorganic Synthesis Division under the guidance of Dr. Sander van Kasteren. His research interests are directed towards to the study kinetics of antigen processing & presentation using bioorthogonal chemistry as well as semisynthesis of posttranslationally modified antigens.