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.