Structure-activity relationships by interligand NOE-based design and synthesis of antiapoptotic compounds targeting Bid.
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.
Becattini
Barbara
B
Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Culmsee
Carsten
C
Leone
Marilisa
M
Zhai
Dayong
D
Zhang
Xiyun
X
Crowell
Kevin J
KJ
Rega
Michele F
MF
Landshamer
Stefan
S
Reed
John C
JC
Plesnila
Nikolaus
N
Pellecchia
Maurizio
M
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
D051023:BH3 Interacting Domain Death Agonist Protein; D008024:Ligands