Adapting the Glaser Reaction for Bioconjugation: Robust Access to Structurally Simple, Rigid Linkers

Area of Science:

• Organic Chemistry
• Bioconjugation Chemistry
• Catalysis

Background:

• Copper-mediated Glaser coupling forms rigid 1,3-diyne linkages.
• Simultaneous Cu(I) and oxidant requirements limit its use with sensitive molecules in water.

Purpose of the Study:

• To develop a robust Glaser coupling method for unprotected peptides in aqueous solution.
• To overcome Cu(II)-mediated oxidative degradation of complex substrates.

Main Methods:

• Utilized a specific bpy-diol ligand to protect unprotected peptides.
• Formed an insoluble Cu(II) gel to prevent substrate damage.
• Applied the method for conjugating labels to a GLP-1R agonist.

Main Results:

• The bpy-diol ligand effectively protected peptides from oxidative damage.
• The insoluble Cu(II) gel formation prevented degradation of sensitive substrates.
• Successful conjugation of diverse labels onto an unprotected GLP-1R agonist was achieved.

Conclusions:

• Developed a novel, protective strategy for copper-catalyzed Glaser coupling in aqueous media.
• Enabled bioconjugation of complex peptides and labeling of a GLP-1R agonist.
• Expanded the utility of Glaser coupling for functional molecules and drug discovery.