Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix.
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.
Walensky
Loren D
LD
Howard Hughes Medical Institute, Department of Pediatric Hematology/Oncology and Children's Hospital Boston, Massachusetts, USA.
Kung
Andrew L
AL
Escher
Iris
I
Malia
Thomas J
TJ
Barbuto
Scott
S
Wright
Renee D
RD
Wagner
Gerhard
G
Verdine
Gregory L
GL
Korsmeyer
Stanley J
SJ
D000475:Alkenes; D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002352:Carrier Proteins / Q000737:chemistry; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000473:pathology; D017254:Leukemic Infiltration; D051379:Mice; D016513:Mice, SCID; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D018716:Molecular Mimicry; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000737:chemistry*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D015202:Protein Engineering; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014183:Transplantation, Heterologous
D000475:Alkenes; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; C474007:Bax protein (53-86); C494815:Bid protein, mouse; D001952:Bridged-Ring Compounds; D002352:Carrier Proteins; D010446:Peptide Fragments; D010455:Peptides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D045304:Cytochromes c