Site-specific labelling of native peptides and proteins: chemical and enzymatic strategies

• Antonio Angelastro,
• Jonathan Bargh,
• Subhajit Guria,
• Victor Laserna and
• Louis Luk

Beilstein J. Org. Chem. 2026, 22, 857–881, doi:10.3762/bjoc.22.67

• highlight opportunities for innovation in next-generation native-sequence protein modification technologies. Keywords: affinity-guided chemistry; disulfide-rebridging; enzyme catalysis; glycan modifications; native-sequence; protein labelling; small-molecule modifications; terminal; Introduction Protein

• -molecule modifications provide powerful strategies for site-selective modification of otherwise intractable residues, as summarised in a comprehensive review [109]. However, most new conjugation reagents are not yet commercially available, requiring in-house synthesis, and the resulting conjugates often

• site-specific histidine modification of the Fc region, albeit at a modest yield (37%). Another related and noteworthy technology is the cysteine-to-lysine transfer reaction, which operates via a mechanism analogous to native chemical ligation in Fab fragments [108]. Together the advances of small