Peptide-Hypervalent Iodine Reagent Chimeras: Enabling Peptide Functionalization and Macrocyclization.

Area of Science:

• Organic Chemistry
• Chemical Biology
• Medicinal Chemistry

Background:

• Peptide modification is crucial for developing novel therapeutics and chemical probes.
• Existing methods for peptide coupling and macrocyclization can be limited in scope and efficiency.

Purpose of the Study:

• To develop a novel strategy for peptide modification using ethynylbenziodoxolones (EBXs).
• To explore the utility of EBXs in peptide coupling and photocatalytic macrocyclization.
• To investigate the potential of modified peptides as protein-protein interaction inhibitors.

Main Methods:

• Synthesis of peptide-ethynylbenziodoxolones (peptide-EBXs) via solution- and solid-phase peptide synthesis (SPPS).
• Peptide coupling reactions with cysteine residues in organic solvents and aqueous buffers.
• Photocatalytic decarboxylative coupling for intramolecular macrocyclization.
• Design and synthesis of a rigid linear aryl alkyne linker.

Main Results:

• Peptide-EBXs were successfully synthesized and demonstrated versatile reactivity.
• Efficient peptide-peptide and peptide-protein coupling was achieved through reaction with cysteine.
• A novel photocatalytic method enabled intramolecular macrocyclization, forming cyclic peptides.
• A specific peptide-linker conjugate showed high affinity for Keap1 at the Nrf2 binding site.

Conclusions:

• Ethynylbenziodoxolones provide a powerful new tool for peptide modification and conjugation.
• The developed methods allow for efficient synthesis of linear and macrocyclic peptides.
• These findings open avenues for designing peptide-based inhibitors of protein-protein interactions, such as those involving Nrf2 and Keap1.