Abstract
Cell-penetrating peptide conjugated peptide aldehydes Tat-A and Tat-B showed low micromolar anticancer and antifungal activities and synergistic action in combination with cisplatin and amphotericin B against cancer and fungal cells, respectively. Tat-A and Tat-B were significantly more potent than Ixazomib in inhibiting the human 20S proteasomes with IC50 values in the low nanomolar range. Treatment with Tat-A and Tat-B caused membrane disruption and pore formation in HeLa and BE(2)-C cells and inhibition and eradication of C. albicans biofilms. Apoptotic cell death of the treated HeLa and BE(2)-C cells was demonstrated by Annexin V/PI staining. Flow cytometry analyses showed that more than 78% (HeLa) and 92% (BE(2)-C cells showed signs of apoptosis and necrosis upon treatment with Tat-A and Tat-B. This study forms the first report that documents the benefits of cell-penetrating peptide conjugation to enhance the potential of peptide aldehydes as therapeutics.
MeSH terms
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Aldehydes / chemical synthesis
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Aldehydes / pharmacology*
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Amphotericin B / pharmacology
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Animals
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Antifungal Agents / chemical synthesis
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Antifungal Agents / pharmacology*
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Biofilms / drug effects
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Candida albicans / drug effects
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Candida albicans / physiology
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Cell Line, Tumor
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Cell Membrane / drug effects
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Cell-Penetrating Peptides / chemical synthesis
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Cell-Penetrating Peptides / pharmacology*
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Cisplatin / pharmacology
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DNA / drug effects
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Drug Synergism
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Hemolysis / drug effects
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Humans
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Mice
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Microbial Sensitivity Tests
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Molecular Docking Simulation
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Proteasome Endopeptidase Complex / metabolism
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Proteasome Inhibitors / chemical synthesis
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Proteasome Inhibitors / pharmacology*
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Reactive Oxygen Species / metabolism
Substances
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Aldehydes
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Antifungal Agents
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Antineoplastic Agents
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Cell-Penetrating Peptides
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Proteasome Inhibitors
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Reactive Oxygen Species
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Amphotericin B
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DNA
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Proteasome Endopeptidase Complex
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Cisplatin