Electron-rich anilines as cleavable linkers for peptides

Area of Science:

• Organic Chemistry
• Peptide Chemistry
• Bioconjugation

Background:

• Peptide synthesis often requires specialized linkers for cleavage and purification.
• Existing linkers may lack stability or cause decomposition of sensitive amino acid residues.
• Developing robust and orthogonal cleavage strategies is crucial for advanced peptide applications.

Purpose of the Study:

• To develop a novel electron-rich aniline (ERA)-based cleavable linker for peptide synthesis.
• To demonstrate the rapid cleavage and stability of ERA-containing peptides under various oxidative conditions.
• To evaluate the utility of ERA-linkers in peptide library screening and bioconjugation.

Main Methods:

• Incorporation of electron-rich aniline into peptides during solid-phase peptide synthesis (SPPS).
• Cleavage of ERA-containing peptides using oxidants like DDQ, CAN, and NaIO4 at room temperature.
• Compatibility assessment with natural and unnatural amino acids, including tyrosine (Tyr) and tryptophan (Trp).
• Demonstration of capture and release of biotinylated peptides using immobilized streptavidin.

Main Results:

• ERA-linkers are stable during SPPS and rapidly cleaved (30 min) by common oxidants at room temperature.
• Sensitive amino acid residues Tyr and Trp remain stable during DDQ-mediated cleavage, unlike other labile linkers.
• The ERA-linker facilitates efficient capture and release of biotinylated peptides from streptavidin.
• Demonstrated compatibility with a range of natural and unnatural amino acids.

Conclusions:

• Electron-rich aniline (ERA)-based linkers offer a rapid and orthogonal cleavage strategy for peptides.
• ERA-linkers provide superior stability for sensitive amino acid residues during oxidative cleavage.
• ERA-linkers are valuable tools for peptide library screening and bioconjugation applications.