title: Structure-activity relationships by interligand NOE-based design and synthesis of antiapoptotic compounds targeting Bid.
abstract: Bcl-2 family proteins play a crucial role in tissue homeostasis and apoptosis (programmed cell death). Bid is a proapoptotic member of the Bcl-2 family, promoting cell death when activated by caspase-8. Following an NMR-based approach (structure-activity relationships by interligand NOE) we were able to identify two chemical fragments that bind on the surface of Bid. Covalent linkage of the two fragments led to high-affinity bidentate derivatives. In vitro and in-cell assays demonstrate that the compounds prevent tBid translocation to the mitochondrial membrane and the subsequent release of proapoptotic stimuli and inhibit neuronal apoptosis in the low micromolar range. Therefore, by using a rational chemical-biology approach, we derived antiapoptotic compounds that may have a therapeutic potential for disorders associated with Bid activation, e.g., neurodegenerative diseases, cerebral ischemia, or brain trauma.
authors.affiliation: Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Becattini
authors.forename: Carsten
authors.initials: C
authors.lastname: Culmsee
authors.forename: Marilisa
authors.initials: M
authors.lastname: Leone
authors.forename: Dayong
authors.initials: D
authors.lastname: Zhai
authors.forename: Xiyun
authors.initials: X
authors.lastname: Zhang
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Crowell
authors.forename: Michele F
authors.initials: MF
authors.lastname: Rega
authors.forename: Stefan
authors.initials: S
authors.lastname: Landshamer
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Plesnila
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051023:BH3 Interacting Domain Death Agonist Protein / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D008024:Ligands; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D008024:Ligands