title: Tailor-made designer helical peptides that induce mitochondrion-mediated cell death without necrosis.
abstract: Managing protein-protein interactions is essential for resolving unknown biological events at the molecular level and developing drugs. We have designed and synthesized a side-chain-crosslinked helical peptides based on the binding domain of a pro-apoptotic protein (Bad) that induces programmed cell death. The peptide showed high helical content and bound to its target, Bcl-XL, more strongly than its non-crosslinked counterparts. When HeLa cells were incubated with the crosslinked peptide, the peptide entered the cytosol across the plasma membrane. The peptide formed a stable complex with Bcl-XL localized at the outer mitochondrial membrane, and this binding event caused the release of cytochrome c from the intermembrane space of mitochondria into the cytosol. This activated the caspase cascade: 70% of HeLa cells died by the apoptosis pathway (without evidence of necrosis).
authors.affiliation: Graduate School of Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama, 930-0194 (Japan).
authors.forename: Kagayaki
authors.initials: K
authors.lastname: Nogami
authors.forename: Kentaro
authors.initials: K
authors.lastname: Takahama
authors.forename: Ayako
authors.initials: A
authors.lastname: Okushima
authors.forename: Takanori
authors.initials: T
authors.lastname: Oyoshi
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Fujimoto
authors.forename: Masahiko
authors.initials: M
authors.lastname: Inouye
mesh_terms: D016923:Cell Death / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D009336:Necrosis; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D010455:Peptides
keywords: alpha-helix; apoptosis; protein-protein interactions; side-chain crosslinking; solid-phase synthesis