Pentelute Lab MIT | Site‐Selective Cysteine–Cyclooctyne Conjugation
The Pentelute Lab aims to invent new chemistry for the efficient and selective modification of proteins, to ‘hijack’ these biological machines for efficient drug delivery into cells and to create new machines to rapidly and efficiently manufacture peptides and proteins.
Pentelute Lab, Chemistry, MIT, Chemistry Department, Boston, Cambridge, Biology, Peptides, Peptide, Proteins, Science, Rapid, Brad Pentelute, Brad,
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Site‐Selective Cysteine–Cyclooctyne Conjugation

Site‐Selective Cysteine–Cyclooctyne Conjugation

Volume57, Issue22 May 28, 2018 Pages 6459-6463 Issue Online 22 May 2018 Version of Record online: 26 April 2018 Accepted manuscript online: 25 March 2018 Manuscript revised: 07 March 2018 Dr. Chi Zhang Dr. Peng Dai Dr. Alexander A. Vinogradov Dr. Zachary P. Gates Prof. Dr. Bradley L. Pentelute

Abstract

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 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 demonstrates that short peptide tags can aid in accelerating bond‐forming reactions that are often slow to non‐existent in water.

Category
2018, Publications