Bicyclic Helical Peptides as Dual Inhibitors Selective for Bcl2A1 and Mcl-1 Proteins.
Aline Dantas de AraujoJunxian LimKai-Chen WuYibin XiangAndrew C GoodRenato SkerljDavid P FairliePublished in: Journal of medicinal chemistry (2018)
A 26-residue peptide BimBH3 binds indiscriminately to multiple oncogenic Bcl2 proteins that regulate apoptosis of cancer cells. Specific inhibition of the BimBH3-Bcl2A1 protein-protein interaction was obtained in vitro and in cancer cells by shortening the peptide to 14 residues, inserting two cyclization constraints to stabilize a water-stable α-helix, and incorporating an N-terminal acrylamide electrophile for selective covalent bonding to Bcl2A1. Mass spectrometry of trypsin-digested bands on electrophoresis gels established covalent bonding of an electrophilic helix to just one of the three cysteines in Bcl2A1, the one (Cys55) at the BimBH3-Bcl2A1 protein-protein interaction interface. Optimizing the helix-inducing constraints and the sequence subsequently enabled electrophile removal without loss of inhibitor potency. The bicyclic helical peptides were potent, cell permeable, plasma-stable, dual inhibitors of Bcl2A1 and Mcl-1 with high selectivity over other Bcl2 proteins. One bicyclic peptide was shown to inhibit the interaction between a pro-apoptotic protein (Bim) and either endogenous Bcl2A1 or Mcl-1, to induce apoptosis of SKMel28 human melanoma cells, and to sensitize them for enhanced cell death by the anticancer drug etoposide. These approaches look promising for chemically silencing intracellular proteins.
Keyphrases
- protein protein
- cell death
- small molecule
- mass spectrometry
- endothelial cells
- endoplasmic reticulum stress
- emergency department
- risk assessment
- dna binding
- bone marrow
- cell proliferation
- mesenchymal stem cells
- cell therapy
- liquid chromatography
- drug induced
- heavy metals
- high performance liquid chromatography
- tandem mass spectrometry