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Copper-Triggered Bioorthogonal Cleavage Reactions for Reversible Protein and Cell Surface Modifications
- Source :
- Journal of the American Chemical Society. 141(43)
- Publication Year :
- 2019
-
Abstract
- Temporal and reversible control over protein and cell conjugations holds great potential for traceless release of antibody-drug conjugates (ADCs) on tumor sites as well as on-demand altering or removal of targeting elements on cell surface. We herein developed a bioorthogonal and traceless releasable reaction on proteins and intact cells to fulfill such purposes. A systematic survey of transition metals in catalyzing the bioorthogonal cleavage reactions revealed that copper complexes such as Cu(I)-BTTAA and dual-substituted propargyl (dsPra) or propargyloxycarbonyl (dsProc) moieties offered a bioorthogonal releasable pair for reversible blockage and rescue of primary amines and phenol alcohols on small molecule drugs, protein side chains, as well as intact cell surface. For proof-of-concept, we employed such Cu(I)-BTTAA/dsProc and Cu(I)-BTTAA/dsPra pairs as a "traceless linker" strategy to construct cleavable ADCs to unleash cytotoxic compounds on cancer cells in situ and as a "reversible modification" strategy for cell surface engineering. Furthermore, by coupling with the genetic code expansion strategy, we site-specifically modulated ligand-receptor interactions on live cell membranes. Together, our work expanded the transition-metal-mediated bioorthogonal cleavage tool kit from terminal decaging to internal-linker breakage, which offered a temporal and reversible conjugation strategy on therapeutic proteins and cells.
- Subjects :
- Lysine-tRNA Ligase
Immunoconjugates
Receptor, ErbB-2
Green Fluorescent Proteins
010402 general chemistry
Cleavage (embryo)
Ligands
01 natural sciences
Biochemistry
Proof of Concept Study
Catalysis
Colloid and Surface Chemistry
Phenols
Coumarins
Side chain
Organometallic Compounds
Humans
Prodrugs
Protein Interaction Maps
Amines
Etoposide
Chemistry
Cell Membrane
General Chemistry
Combinatorial chemistry
Small molecule
0104 chemical sciences
Drug Liberation
Membrane
Doxorubicin
Mutagenesis
Cancer cell
Bioorthogonal chemistry
Linker
Copper
Conjugate
HeLa Cells
Subjects
Details
- ISSN :
- 15205126
- Volume :
- 141
- Issue :
- 43
- Database :
- OpenAIRE
- Journal :
- Journal of the American Chemical Society
- Accession number :
- edsair.doi.dedup.....b8c85b8c73667aec72778832d8fa5f43