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Synthesis of Protein Bioconjugates via Cysteine-maleimide Chemistry
Published on: July 20, 2016
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Maleimide-thiol adducts stabilized through stretching
Wenmao Huang1, Xin Wu1, Xiang Gao1
1Collaborative Innovation Center of Advanced Microstructures, National Laboratory of Solid State Microstructure, Department of Physics, Nanjing University, Nanjing, China.
Nature Chemistry
|February 6, 2019
Summary
Mechanical force stabilizes unstable maleimide-thiol adducts, crucial for creating robust protein-polymer conjugates for therapeutics. This novel approach enhances stability against degradation, opening new avenues in bioconjugation chemistry.
Area of Science:
- Bioconjugation Chemistry
- Mechanochemistry
- Polymer Science
Background:
- Maleimide-thiol reactions are standard for protein-polymer conjugation in therapeutics.
- Existing maleimide-thiol adducts exhibit instability in vivo due to retro-Michael reactions or thiol exchange.
Purpose of the Study:
- To investigate the stabilizing effect of mechanical force on maleimide-thiol adducts.
- To develop a novel method for producing stable protein-polymer conjugates using mechanochemistry.
Main Methods:
- Single-molecule force spectroscopy to probe adduct stability.
- Kinetic analysis and bulk structural characterizations.
- Mild ultrasonication to apply mechanical force.
Main Results:
- Applying stretching force to the thiosuccinimide linkage significantly stabilizes maleimide-thiol adducts.
- Force-dependent hydrolysis of the succinimide ring was identified as the dominant stabilization pathway.
- Stable polymer-protein conjugates were successfully produced using mechanical force.
Conclusions:
- Mechanical force can be unconventionally employed to stabilize otherwise labile chemical linkages.
- This mechanochemical approach offers a promising strategy for creating stable bioconjugates for therapeutic applications.
- Mechanical force has significant potential for driving productive chemical transformations.
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