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.
journal_name
Proc Natl Acad Sci U S Aauthors
Becattini B,Culmsee C,Leone M,Zhai D,Zhang X,Crowell KJ,Rega MF,Landshamer S,Reed JC,Plesnila N,Pellecchia Mdoi
10.1073/pnas.0603460103subject
Has Abstractpub_date
2006-08-15 00:00:00pages
12602-6issue
33eissn
0027-8424issn
1091-6490pii
0603460103journal_volume
103pub_type
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