Abstract
Stapled peptides recapitulate the binding affinity and specificity of α-helices in proteins, resist proteolytic degradation, and may provide a novel modality against challenging drug targets such as protein-protein interactions. However, most of the stapled peptides have limited cell permeability or are impermeable to the cell membrane. We show herein that stapled peptides can be rendered highly cell-permeable by conjugating a cyclic cell-penetrating peptide to their N-terminus, C-terminus, or stapling unit. Application of this strategy to two previously reported membrane-impermeable peptidyl inhibitors against the MDM2/p53 and β-catenin/TCF interactions resulted in the generation of potent proof-of-concept antiproliferative agents against key therapeutic targets.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Cell Membrane Permeability / drug effects
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Cell Proliferation / drug effects
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Cell-Penetrating Peptides / chemistry
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Humans
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MCF-7 Cells
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Molecular Dynamics Simulation
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Peptides / chemistry*
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Peptides / pharmacology*
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Peptides, Cyclic / chemistry
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Proof of Concept Study
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Protein Interaction Maps / drug effects
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Proto-Oncogene Proteins c-mdm2 / metabolism*
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TCF Transcription Factors / metabolism
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Tumor Suppressor Protein p53 / metabolism*
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beta Catenin / metabolism*
Substances
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Antineoplastic Agents
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CTNNB1 protein, human
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Cell-Penetrating Peptides
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Peptides
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Peptides, Cyclic
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TCF Transcription Factors
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TP53 protein, human
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Tumor Suppressor Protein p53
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beta Catenin
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2