Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix.
Science
; 305(5689): 1466-70, 2004 Sep 03.
Article
em En
| MEDLINE
| ID: mdl-15353804
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
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Peptídeos
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Hidrocarbonetos Aromáticos com Pontes
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Leucemia Experimental
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Proteínas Proto-Oncogênicas
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Apoptose
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Mimetismo Molecular
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Alcenos
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2004
Tipo de documento:
Article