Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 57, Issue 22, Pages 6459-6463Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201800860
Keywords
bioconjugation; bioorthogonal chemistry; cysteine-cyclooctyne reaction; dibenzocyclooctyne; protein modification
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Funding
- NIH [GM110535]
- DARPA [023504-001]
- George Buchi Summer Research Fellowship
- Koch Graduate Fellowship in Cancer Research from MIT
- Bristol-Myers Squibb Fellowship in Synthetic Organic Chemistry
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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-dibenzocy-clooctyne (DBCO) reagents. Compared to a cysteine peptide control, the DBCO-tag increases the rate of the thiolyne reaction 220-fold, thereby 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 the antibody trastuzumab. This study demonsiraies that short peptide tags can aid in accelerating bond-forming, reactions that are often slow to non-existentin water.
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