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Chemoselective Modification of Viral Surfaces via Bioorthogonal Click Chemistry
Published on: August 19, 2012
Copper-Triggered Bioorthogonal Cleavage Reactions for Reversible Protein and Cell Surface Modifications
Xin Wang1,2, Yanjun Liu1, Xinyuan Fan1
1Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering , Peking University , Beijing 100871 , China.
Researchers developed a new bioorthogonal reaction for reversible protein and cell conjugation. This method allows for traceless release of antibody-drug conjugates and on-demand cell surface modification, expanding bioorthogonal chemistry tools.
Area of Science:
- Bioconjugation Chemistry
- Chemical Biology
- Medicinal Chemistry
Background:
- Temporal and reversible control over protein and cell conjugations is crucial for applications like targeted drug delivery and cell surface engineering.
- Existing methods often lack traceless release or reversibility, limiting their therapeutic potential.
Purpose of the Study:
- To develop a bioorthogonal and traceless releasable reaction for reversible protein and cell conjugation.
- To enable on-demand alteration or removal of targeting elements on cell surfaces.
- To create cleavable antibody-drug conjugates (ADCs) for in situ drug release.
Main Methods:
- Systematic survey of transition metals for catalyzing bioorthogonal cleavage reactions.
- Utilized copper complexes (Cu(I)-BTTAA) with dual-substituted propargyl (dsPra) or propargyloxycarbonyl (dsProc) moieties as a bioorthogonal releasable pair.
- Developed "traceless linker" strategies for cleavable ADCs and "reversible modification" strategies for cell surface engineering.
- Coupled with genetic code expansion for site-specific modulation of ligand-receptor interactions on live cell membranes.
Main Results:
- Identified Cu(I)-BTTAA/dsProc and Cu(I)-BTTAA/dsPra pairs as effective for reversible blockage and rescue of primary amines and phenol alcohols.
- Demonstrated successful construction of cleavable ADCs for in situ cytotoxic compound release on cancer cells.
- Showcased reversible cell surface engineering and site-specific modulation of ligand-receptor interactions on live cells.
Conclusions:
- The developed bioorthogonal reaction provides temporal and reversible conjugation strategies for therapeutic proteins and cells.
- This work expands the transition-metal-mediated bioorthogonal cleavage tool kit beyond terminal decaging to internal-linker breakage.
- Offers a versatile platform for advanced applications in targeted therapy and cell engineering.
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