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| Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix |
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| Author(s): Walensky LD, Kung AL, Escher I, Malia TJ, Barbuto S, Wright RD, Wagner G, Verdine GL, Korsmeyer SJ |
| Source: SCIENCE Volume: 305 Issue: 5689 Pages: 1466-1470 Published: SEP 3 2004 |
| Times Cited: 266 References: 31 |
| 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Verdine, GL (reprint author), Dana Farber Canc Inst, Howard Hughes Med Inst, Boston, MA 02115 USA |
Addresses:
1. Dana Farber Canc Inst, Howard Hughes Med Inst, Boston, MA 02115 USA
2. Dana Farber Canc Inst, Dept Pediat Hematol Oncol, Boston, MA 02115 USA
3. Dana Farber Canc Inst, Childrens Hosp Boston, Boston, MA 02115 USA
4. Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA
5. Harvard Univ, Dept Chem & Biol Chem, Cambridge, MA 02138 USA
6. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA
7. MIT, Dept Chem, Cambridge, MA 02139 USA |
| Publisher: AMER ASSOC ADVANCEMENT SCIENCE, 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA |
| Subject Category: Multidisciplinary Sciences |
| IDS Number: 852NK |
| ISSN: 0036-8075 |
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