Activation of Apoptosis in Vivo by a Hydrocarbon-Stapled BH3 Helix

Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States
Science (Impact Factor: 33.61). 10/2004; 305(5689):1466-70. DOI: 10.1126/science.1099191
Source: PubMed


BCL-2 family proteins constitute a critical control point for the regulation of apoptosis. Protein interaction between BCL-2
members is a prominent mechanism of control and is mediated through the amphipathic α-helical BH3 segment, an essential death
domain. We used a chemical strategy, termed hydrocarbon stapling, to generate BH3 peptides with improved pharmacologic properties.
The stapled peptides, called “stabilized alpha-helix of BCL-2 domains” (SAHBs), proved to be helical, protease-resistant,
and cell-permeable molecules that bound with increased affinity to multidomain BCL-2 member pockets. A SAHB of the BH3 domain
from the BID protein specifically activated the apoptotic pathway to kill leukemia cells. In addition, SAHB effectively inhibited
the growth of human leukemia xenografts in vivo. Hydrocarbon stapling of native peptides may provide a useful strategy for
experimental and therapeutic modulation of protein-protein interactions in many signaling pathways.

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Available from: Gregory L Verdine, Dec 18, 2013
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    • "Despite the contrasts with the b-arrestin/b-adaptin 2 PPI and with our recommendations , we share the interpretation that the stabilization of a helices is not a requirement for the design of peptide inhibitors (photoswitchable or not) of PPIs mediated by a helix. Regarding this issue, another study questions the effect of stabilization of the helix by stapling in the BimBH3/Bcl-2 PPI (Okamoto et al., 2013), a classic example where stapled peptides were tested previously (Walensky et al., 2004). "
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    Chemistry & Biology 01/2015; 22(1):31-37. DOI:10.1016/j.chembiol.2014.10.022 · 6.65 Impact Factor
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    • "We recently demonstrated that stapled peptide analogues of Nutlin targeting Mdm2 are able to bind and inhibit both wild type and the M62A/Q24R resistant variants in biophysical and cell-based assays [18], [19]. Stapled peptides comprise a covalent linkage bridging adjacent turns of an alpha helical peptide (the “staple”) [20]. By pre-stabilising favourably interacting conformer(s), the staple increases affinity by reducing the entropic penalty of binding. "
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    • "Through this interaction, the anti-apoptotic BCL-2 family members titrate out BH3-only proteins and thus prevent them from driving apoptosis forward [1] [6] [7] [25]. Therefore, small molecules or peptides [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] and proteins [36] used as BH3-only mimetics have recently been developed. Thus, for further progress in this field, accurate structural data of the groove region and the understanding of the structural mechanism governing the function of the anti-apoptotic BCL-2 family members have become indispensable. "
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