A Thiol-Ene Coupling Approach to Native Peptide Stapling and Macrocyclization

• Published in: Angewandte Chemie International Edition 2015-09, Vol.54 (37), p.10931-10934
• Main Authors: Wang, Yuanxiang, Chou, Danny Hung-Chieh
• Format: Article
• Language: English
• Subjects: bioconjugation; Blocking; Cyclization; Cysteine; Helicity; Hydrocarbons; Joining; Macrocyclic compounds; peptide macrocyclization; peptide stapling; Peptides; Peptides - chemistry; Residues; Stabilization; Sulfhydryl Compounds - chemistry; thiol-ene coupling
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201503975

We report the discovery of a peptide stapling and macrocyclization method using thiol–ene reactions between two cysteine residues and an α,ω‐diene in high yields. This new approach enabled us to selectively modify cysteine residues in native, unprotected peptides with a variety of stapling modifications for helix stabilization or general macrocyclization. We synthesized stapled Axin mimetic analogues and demonstrated increased alpha helicity upon peptide stapling. We then synthesized stapled p53 mimetic analogues using pure hydrocarbon linkers and demonstrated their abilities to block the p53‐MDM2 interaction and selectively kill p53 wild‐type colorectal carcinoma HCT‐116 cells but not p53 null cells. In summary, we demonstrated a robust and versatile peptide stapling method that could be potentially applied to both synthetic and expressed peptides. The selective modification of cysteine residues in native, unprotected peptides with a variety of stapling modifications for helix stabilization or general macrocyclization is achieved by a new peptide stapling and macrocyclization method. This method uses thiol–ene reactions between two cysteine residues and a diene and gives high yields.