Beilstein J Org Chem. 2026 Jun 3;22:857-881. doi: 10.3762/bjoc.22.67. eCollection 2026.

ABSTRACT

Site-specific modifications of native-sequence proteins are technologies that underpin progresses in chemical biology, diagnostics and next-generation biotherapeutics. However, the pursuit of site-specificity has often come at the expense of scalability and usability, ultimately limiting translational potential of a modification tool. This review critically compares current key strategies, including terminal, disulfide-rebridging, small-molecule, glycan and enzyme-based modifications. Finally, we present a decision tree for method selection and highlight opportunities for innovation in next-generation native-sequence protein modification technologies.

PMID:42266596 | PMC:PMC13245474 | DOI:10.3762/bjoc.22.67