2-Alkyl Furans Undergo Radiolytic Oxidative Protein Cross-Linking

Area of Science:

• Biochemistry
• Chemical Biology
• Radiation Chemistry

Background:

• Covalent cross-linking is vital for studying biological systems.
• Current methods often rely on photochemistry, limiting applications to optically accessible environments.
• Expanding cross-linking triggers beyond light could enable studies in more complex biological settings.

Purpose of the Study:

• To explore ionizing radiation as a novel trigger for covalent cross-linking chemistry.
• To systematically compare different radiolytic cross-linking candidates.
• To establish a foundation for using radiation-initiated covalent chemistry in biological applications.

Main Methods:

• Systematic comparison of rationally designed 2-alkyl furan derivatives.
• Assessment of protein labeling efficiency in a radiation dose-dependent manner.
• Mechanistic studies involving hydroxyl radical-mediated oxidation and adduct formation with lysine residues.

Main Results:

• 2-alkyl furans demonstrated efficient protein labeling upon exposure to ionizing radiation.
• The process involves radiation-induced hydroxyl radical oxidation of furans, forming reactive dicarbonyl intermediates.
• These intermediates form stable adducts with lysine residues on proteins.
• The strategy was successfully applied to covalently capture a reversible small-molecule-protein interaction in cells.

Conclusions:

• Ionizing radiation is an effective and previously unexplored trigger for initiating covalent bond formation.
• This work expands radiolytic chemistry to include bond formation and establishes a new method for cross-linking.
• The findings pave the way for using targeted radiation in target identification and next-generation therapeutics.