J. Am. Chem. Soc. 138, 8340–8343 (2016)

Credit: JACS

Macrocyclization can endow peptides with enhanced proteolytic stability and cell permeability. Multiple approaches have been developed to generate macrocyclic peptides, including the use of perfluoroaryl compounds that react with cysteine residues to form peptide staples. Lautrette et al. have developed a method that instead uses lysine residues, which yields compounds with improved stability under basic and oxidative conditions compared to compounds produced by the cysteine-based reaction. This method uses an optimized perfluoroaryl reactant and mild conditions to couple two lysine residues via an SNAr mechanism. Peptides containing a range of spacing between the two lysine residues (from adjacent to 14 residues apart) are generally well tolerated by the reaction, which is specific for lysine over other non-cysteine nucleophilic residues. In addition, unnatural lysine analogs with varying side chain lengths can also be stapled. Using this approach, the authors synthesized a macrocyclic analog of a p53 peptide inhibitor of MDM2. This macrocyclic peptide showed better stability toward proteases, increased cell uptake, and improved MDM2 binding compared to the linear peptide. With macrocycles being attractive targets for drug development, the addition of a facile and versatile stapling approach to the peptide toolbox will enable the generation of new macrocyclic peptide scaffolds with the potential for new bioactivities.