title: A Thiol-Ene Coupling Approach to Native Peptide Stapling and Macrocyclization.
abstract: 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.
authors.affiliation: Department of Biochemistry, University of Utah, 15 N. Medical Drive East 4100, Salt Lake City, UT 84112 (USA).
authors.forename: Yuanxiang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, University of Utah, 15 N. Medical Drive East 4100, Salt Lake City, UT 84112 (USA). dchou@biochem.utah.edu.
authors.forename: Danny Hung-Chieh
authors.initials: DH
authors.lastname: Chou
mesh_terms: D003500:Cyclization; D010455:Peptides / Q000737:chemistry*; D013438:Sulfhydryl Compounds / Q000737:chemistry*
chemical_list: D010455:Peptides; D013438:Sulfhydryl Compounds
keywords: bioconjugation; peptide macrocyclization; peptide stapling; thiol-ene coupling