A protein functionalization platform based on selective reactions at methionine residues

Area of Science:

• Chemical Biology
• Synthetic Chemistry
• Biochemistry

Background:

• Proteins undergo post-translational modifications, increasing functional diversity.
• Chemical tools are vital for advancing protein structure and function studies in biology and medicine.
• Existing protein functionalization methods are limited by stringent biological system requirements.

Purpose of the Study:

• To develop a novel chemoselective labeling method for protein functionalization.
• To expand the available bioconjugation strategies by targeting less-explored amino acids.
• To create a versatile platform for secondary bioorthogonal protein functionalization processes.

Main Methods:

• Developed a bespoke hypervalent iodine reagent to target methionine residues.
• Utilized the electrophilic reactivity of the reagent for S-Me group targeting.
• Explored secondary visible-light-mediated bioorthogonal functionalization of the resulting protein conjugate.

Main Results:

• Achieved fast and selective protein functionalization at methionine residues.
• Demonstrated successful bioconjugation under biologically ambient conditions and low-micromolar concentrations.
• Created a reactive protein conjugate intermediate for further functionalization.

Conclusions:

• The developed method offers a new, complementary strategy for protein functionalization.
• This approach significantly expands the protein functionalization toolbox by targeting methionine.
• The platform enables the development of novel transformations for information-rich protein conjugates.