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Science 305 (5689): 1466-1470

Copyright © 2004 by the American Association for the Advancement of Science

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

Loren D. Walensky,1,2 Andrew L. Kung,2,3 Iris Escher,4 Thomas J. Malia,5,6 Scott Barbuto,1 Renee D. Wright,3 Gerhard Wagner,5 Gregory L. Verdine,4* Stanley J. Korsmeyer1*

Abstract: 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 {alpha}-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.

1 Howard Hughes Medical Institute,
2 Department of Pediatric Hematology/Oncology and Children's Hospital Boston
3 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
4 Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
5 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
6 Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

* To whom correspondence should be addressed. E-mail: stanley_korsmeyer{at}dfci.harvard.edu (S.J.K.) and verdine{at}chemistry.harvard.edu (G.L.V.)

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