The volume of peptide molecule is between small molecule drug and large molecule, occupying an important "middle molecules" chemical and biological space. Natural peptides often need structural modification to become better drug molecules. In chemical modification technology, the strategy of peptide stapling has shown its unique efficacy in the regulation of peptide structure and properties and the development of peptide drugs.

Recently, Professor Gong Chen 's group has developed a very simple and practical strategy to construct peptide stapling through Lysine-Formaldehyde-Tyrosine (KaY) or Lysine-Formaldehyde-Arginine (KaR) three component reaction. The selective modification is mainly regulated in two stages: formaldehyde is scanned by forming a reversible imine structure on the side chain of Lysine (Lys, K); subsequently, the Tyrosine (Try) or Arginine (Arg) side chains around the imine "locked" into the final stable product by intramolecular nucleophilic attack. The unique kinetic and thermodynamic characteristics of the reaction process enable the three-components to achieve the position selective control in a “cooperative stapling” which is difficult to achieve based on the two-component reaction. This work was recently published in Angew. Chem. Int. Ed., 2020. (DOI: 10.1002/anie.202016267)