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

Becattini B,Culmsee C,Leone M,Zhai D,Zhang X,Crowell KJ,Rega MF,Landshamer S,Reed JC,Plesnila N,Pellecchia M

doi

10.1073/pnas.0603460103

subject

Has Abstract

pub_date

2006-08-15 00:00:00

pages

12602-6

issue

33

eissn

0027-8424

issn

1091-6490

pii

0603460103

journal_volume

103

pub_type

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