1. Copper-Triggered Bioorthogonal Cleavage Reactions for Reversible Protein and Cell Surface Modifications
- Author
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Xin Wang, William Shu Ching Ngai, Yanjun Liu, Gong Zhang, Peng Chen, Jian Lin, Heng Zhang, Xinyuan Fan, Jiaofeng Li, and Jie Wang
- 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 - 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.
- Published
- 2019