Hypervalent Iodine-Mediated Late-Stage Peptide and Protein Functionalization.

Hypervalent iodine compounds are powerful reagents for the development of novel transformations. As they exhibit low toxicity, high functional group tolerance, and stability in biocompatible media, they have been used for the functionalization of biomolecules. Herein, we report recent advances up to June 2021 in peptide and protein modification using hypervalent iodine reagents. Their use as group transfer or oxidizing reagents is discussed in this Minireview, including methods targeting polar, aromatic, or aliphatic amino acids and peptide termini.

Cys-Cys and Cys-Lys Stapling of Unprotected Peptides Enabled by Hypervalent Iodine Reagents.

Easy access to a wide range of structurally diverse stapled peptides is crucial for the development of inhibitors of protein-protein interactions. Herein, we report bis-functional hypervalent iodine reagents for two-component cysteine-cysteine and cysteine-lysine stapling yielding structurally diverse thioalkyne linkers. This stapling method works with unprotected natural amino acid residues and does not require pre-functionalization or metal catalysis. The products are stable to purification and isolation. Post-stapling modification can be accessed via amidation of an activated ester, or via cycloaddition onto the formed thioalkyne group. Increased helicity and binding affinity to MDM2 was obtained for a i,i+7 stapled peptide.