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Downsizing the BAD BH3 peptide to small constrained α-helices with improved ligand efficiency
Nicholas E Shepherd1, Rosemary S Harrison1, Gloria Ruiz-Gomez2
1Centre of Excellence in Advanced Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld 4072, Australia. d.fairlie@imb.uq.edu.au n.shepherd@imb.uq.edu.au.
Organic & Biomolecular Chemistry
|November 8, 2016
Summary
Researchers developed smaller, drug-like peptides that inhibit pro-survival Bcl2 Homology (BH) proteins, a key target in cancer therapy. These novel BH3 mimetics effectively kill leukemic T-cells by binding strongly to Bcl-xL.
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- Bcl2 Homology (BH) proteins regulate apoptosis, and their dysregulation is a hallmark of cancer.
- Targeting pro-survival BH proteins is a promising strategy for cancer chemotherapy.
- The BAD BH3 domain is a known inhibitor of these proteins.
Purpose of the Study:
- To investigate if helix-constrained peptides based on the BAD BH3 domain can be reduced in size to create more drug-like molecules.
- To assess the binding affinity, structural characteristics, and anti-leukemic activity of these smaller peptidomimetics.
Main Methods:
- Preparation and structural characterization of 45 linear, mono-, bi-, and tricyclic helical peptidomimetics (8-19 residues).
- In vitro assessment of Bcl-xL inhibition.
- Evaluation of leukemic T-cell killing ability.
Main Results:
- The BAD BH3 domain can be effectively downsized to 8-14 residues while retaining significant Bcl-xL binding affinity.
- Downsized mimetics exhibit higher binding efficiency indices (BEI) compared to the original BAD BH3 and stapled BH3 mimetics.
- Monocyclic and bicyclic mimetics demonstrate superior binding efficiency, approaching that of drug-like molecules.
Conclusions:
- Smaller, constrained peptidomimetics based on the BAD BH3 domain are highly efficient ligands for Bcl-xL.
- These downsized BH3 mimetics represent a promising avenue for developing novel anti-cancer therapeutics.
- The findings suggest that optimized BH3 mimetics can be significantly smaller and more drug-like than previously thought.
