Cited by 1,349Cell death mechanisms and regulationChemical Synthesis and AnalysisProtein Degradation and Inhibitors

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

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Walensky, Loren D., Kung, Andrew L., Escher, Iris, Malia, Thomas J., Barbuto, Scott, Wright, Renee D., Wagner, Gerhard, Verdine, Gregory L., Korsmeyer, Stanley J.·2004·Science

DOI 10.1126/science.1099191PMC PMC1360987

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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 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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Authors: Walensky, L. D., Kung, A. L., Escher, I., Malia, T. J., Barbuto, S., Wright, R. D., Wagner, G., Verdine, G. L., & Korsmeyer, S. J.
Affiliations: Boston Children's Hospital (US)
Corresponding author: Verdine, Gregory L.
Korsmeyer, Stanley J.
ORCID: Walensky, Loren D.
Kung, Andrew L.
Barbuto, Scott
Wagner, Gerhard
Verdine, Gregory L.
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2004-09-03
Volume: 305
Issue: 5689
Pages: 1466-1470
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.1099191
PMC: PMC1360987
OpenAlex: W2008845432
Cited by: 1,349
References: 31
Citations by year: 2026: 27 · 2025: 43 · 2024: 48 · 2023: 45 · 2022: 43 · 2021: 49 · 2020: 55 · 2019: 67 · 2018: 50 · 2017: 71 · 2016: 75 · 2015: 85 · 2014: 77 · 2013: 86 · 2012: 78
FWCI: 21.43
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Science (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Heart, Lung, and Blood Institute (K08HL074049)
National Cancer Institute (R37 CA50239, R37CA050239)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Keywords: apoptosis, BH3 peptides, Bcl-2 family proteins, Bid, protein-protein interaction, leukemia, xenografts, cell-permeable peptide, death domain
MeSH terms: Alkenes, Animals, Bridged-Ring Compounds, Carrier Proteins, Cell Division, Cell Membrane, Dose-Response Relationship, Drug, Humans, Leukemia, Experimental, Mitochondria, Liver, Neoplasm Transplantation, Peptide Fragments, Peptides, Protein Binding, Proto-Oncogene Proteins, Endosomes, Transplantation, Heterologous, Protein Engineering, Mice, SCID, Apoptosis, Leukemic Infiltration, Protein Structure, Secondary, Protein Structure, Tertiary, Molecular Mimicry, Jurkat Cells, Proto-Oncogene Proteins c-bcl-2, Cytochromes c, Cell Line, Tumor, BH3 Interacting Domain Death Agonist Protein, Mice

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

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