Late-Stage Aromatic C-H Bond Functionalization for Cysteine/Selenocysteine Bioconjugation

Area of Science:

• Bioconjugation Chemistry
• Organic Chemistry
• Chemical Biology

Background:

• Peptide and protein bioconjugation are vital for biological research and drug discovery.
• Existing methods often require specific functional groups or harsh conditions.

Purpose of the Study:

• To develop a novel, efficient, and biocompatible method for cysteine/selenocysteine-specific bioconjugation.
• To enable late-stage functionalization of complex molecules for creating peptide/protein conjugates.

Main Methods:

• Copper-mediated direct C-H functionalization of electron-rich arenes.
• Bioconjugation with cysteine/selenocysteine-containing peptides and proteins.
• Utilizing biocompatible reaction conditions.

Main Results:

• Successful conjugation of various electron-rich arenes, including natural products and drugs, to peptides/proteins.
• Demonstrated efficient peptide stapling and cross-linking of different peptides to a single arene.
• Achieved selective modification of selenocysteine over cysteine by tuning electron density.
• Mechanistic studies indicated a proton-coupled electron transfer (PCET) process.

Conclusions:

• The developed method offers an efficient strategy for synthesizing peptide/protein conjugates.
• This approach facilitates late-stage functionalization of complex small molecules.
• The technique holds promise for advancing bioconjugation applications in drug development and biological research.