Downsizing the BAD BH3 peptide to small contrained alpha-helices with improved ligand efficiency

Shepherd, Nicholas E., Harrison, Rosemary S., Ruiz-Gomez, Gloria, Abbenante, Giovanni, Mason, Jody M. and Fairlie, David P. (2016) Downsizing the BAD BH3 peptide to small contrained alpha-helices with improved ligand efficiency. Organic and Biomolecular Chemistry, 46 14: 10939-10945. doi:10.1039/C6OB02185A

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Author Shepherd, Nicholas E.
Harrison, Rosemary S.
Ruiz-Gomez, Gloria
Abbenante, Giovanni
Mason, Jody M.
Fairlie, David P.
Title Downsizing the BAD BH3 peptide to small contrained alpha-helices with improved ligand efficiency
Formatted title
Downsizing the BAD BH3 peptide to small constrained α-helices with improved ligand efficiency
Journal name Organic and Biomolecular Chemistry   Check publisher's open access policy
ISSN 1477-0520
Publication date 2016-11-07
Year available 2016
Sub-type Article (original research)
DOI 10.1039/C6OB02185A
Open Access Status File (Author Post-print)
Volume 46
Issue 14
Start page 10939
End page 10945
Total pages 7
Place of publication Cambridge, United Kingdom
Publisher Royal Society of Chemistry
Language eng
Formatted abstract
Bcl2 Homology (BH) proteins can either trigger or prevent programmed cell death or apoptosis. Deregulation of the BH protein family network leads to evasion of apoptosis, uncontrolled proliferation and is a hallmark of cancer. Inhibition of pro-survival BH proteins is a promising chemotherapeutic strategy for certain cancers. We have examined whether helix-constrained peptides based on the BAD BH3 domain (residues 103–127) can be downsized to much smaller more drug-like peptides. We report the preparation, structural characterisation, in vitro Bcl-xL inhibition and leukemic T-cell killing ability of 45 linear, mono-, bi- and tricyclic helical peptidomimetics between 8- and 19-residues in length. We show that the BAD BH3 can be downsized to 8–14 residues and still maintain appreciable affinity for Bcl-xL. In addition, the binding efficiency indices (BEI) of the downsized mimetics are significantly higher than the BAD BH3 and similar stapled BH3 mimetics, approaching drug-like molecules. This suggests that bicyclic and monocyclic mimetics based on BH3 domains are much more efficient binding ligands than the longer peptides which they mimic.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 3 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 2 times in Scopus Article | Citations
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Created: Tue, 06 Dec 2016, 00:26:41 EST by Susan Allen on behalf of Institute for Molecular Bioscience