Heterogeneous Catalysis Expands the Toolbox for Chemoselective Peptide Derivatization and Labeling

Area of Science:

• Chemical Biology
• Catalysis
• Organic Chemistry

Background:

• Chemoselective modification of peptides is crucial for bioconjugation and peptide pharmaceuticals.
• Transition-metal catalysis is widely used but typically under homogeneous conditions.

Purpose of the Study:

• To develop a first-in-class heterogeneous catalytic approach for site-selective peptide functionalization.
• To functionalize histidine-containing peptides with various moieties using a novel catalytic system.

Main Methods:

• Employed a copper(II) hexacyanometallate catalyst for heterogeneous Chan-Lam reactions.
• Utilized boronic acids to introduce aryl and alkenyl moieties onto peptides.
• Investigated the correlation between catalyst properties and catalytic activity.

Main Results:

• Achieved site-selective functionalization of histidine-containing peptides at the backbone or histidine imidazole.
• Demonstrated successful introduction of fluorescent tags, affinity tags, lipids, and conjugation handles.
• Observed novel reactivity distinct from homogeneous copper(II) acetate-mediated coupling.

Conclusions:

• Developed a novel heterogeneous catalytic strategy for late-stage peptide derivatization and labeling.
• Unlocked the reactivity of the histidine side chain for broader applications.
• Expanded the utility of heterogeneous catalysis in drug discovery and development.