Thursday, March 29, 2018

Site‐Selective Cysteine‐Cyclooctyne Conjugation

Bradley Pentelute  chi zhang  peng dai  Alexander Vinogradov  zak gates

Angew. Chem. Int. Ed. 2018

doi: 10.1002/anie.201800860

We report a site‐selective cysteine‐cyclooctyne conjugation reaction between a seven‐residue peptide tag (DBCO‐tag, Leu‐Cys‐Tyr‐Pro‐Trp‐Val‐Tyr), at the N or C‐terminus of a peptide or protein, and various aza‐dibenzocyclooctyne (DBCO) reagents. Compared to a cysteine peptide control, the DBCO‐tag increases the rate of the thiol‐yne reaction by 220‐fold, enabling selective conjugation of DBCO‐tag to DBCO‐linked fluorescent probes, affinity tags, and cytotoxic drug molecules. Fusion of DBCO‐tag with the protein of interest enables regioselective cysteine modification on proteins that contain multiple endogenous cysteines; these examples include green fluorescent protein and trastuzumab antibody. This study demonstrates short peptide tags could aid in accelerating bond forming reactions that are often slow to non‐existent in water.

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