Facile Synthesis of Hydrocarbon-Stapled Peptides
The intracellular protein-protein interactions that govern many biological pathways are frequently mediated by α-helix structure of protein. Theoretically, helical peptides also can interfere with or stabilize protein-protein interactions, but native helical peptides have major shortcomings as experimental or therapeutic agents because of low potency, instability, and inefficient delivery to cells. Verdine's group [1, 2] has shown that these problems could be overcome by a chemical modification of α-helical peptides they termed hydrocarbon stapling. They used (S)-α-(2′-pentenyl)alanine containing olefin-bearing tethers to generate an all-hydrocarbon “staple” by ruthenium-catalyzed olefin metathesis. The (S)-α-(2-pentenyl)alanine peptides were made to flank three (substitution positions l and l + 4) or six (l and l+ 7) amino acids within the peptide, so that reactive olefinic residues would reside on the same face of α-helix. The modified hydrocarbon-stapled peptides are...
KeywordsSchiff Base Asymmetric Synthesis Olefin Metathesis Normal Amino Acid Helical Peptide