Peptide/Protein Functionalization and Macrocyclization via Alkyne Umpolung with Hypervalent Iodine Reagents

Area of Science:

• Organic Chemistry
• Bioconjugation Chemistry
• Medicinal Chemistry

Background:

• Alkynes are fundamental in organic synthesis and bioconjugation due to their versatile chemistry and rigid structure.
• Traditional alkyne introduction methods often require harsh conditions (strong bases, metal catalysts), limiting biomolecule applications.
• An "umpolung" approach using hypervalent iodine compounds offers an alternative for electrophilic alkyne transfer.

Purpose of the Study:

• To highlight the development of novel electrophilic benziodoxol(on)es (EBx/X/Z) reagents for selective peptide and protein modification.
• To showcase advancements in residue-selective alkynylation, alkenylation, peptide stapling, and macrocyclization since 2021.
• To demonstrate the broad applicability of these reagents, including their use in synthesizing cyclic peptides and antibody cross-linking.

Main Methods:

• Development of novel EBx/X/Z reagents with modified iodine cores (e.g., sulfonate, perfluoroaryl) to enhance reactivity and solubility.
• Application of these reagents for selective alkynylation/alkenylation of cysteine, tyrosine residues, and antibody cross-linking.
• Design of EBx(X) reagents for peptide stapling (Cys-Cys, Cys-Lys) and macrocyclization, including the synthesis of EBx-containing amino acids for SPPS and SPS.

Main Results:

• Achieved enhanced lipophilic alkynylation in aqueous environments using sulfonate-modified reagents.
• Enabled sequential Cys-Cys cross-linking of antibodies with superior reactivity using perfluoroaryl-modified reagents.
• Demonstrated successful peptide stapling, macrocyclization for improved protein-protein interaction inhibition (MDM2, KEAP1), and generation of fluorescent cyclic peptides for imaging.

Conclusions:

• EBx/X/Z reagents provide a versatile and tunable platform for residue-selective modification of peptides and proteins under mild conditions.
• The developed strategies facilitate peptide stapling and macrocyclization, leading to enhanced biological activity and novel applications like live-cell imaging.
• The incorporation of EBx-containing amino acids broadens the scope for constructing diverse cyclic peptide libraries.