Novel Cell-Penetrating Peptide Conjugated Proteasome Inhibitors: Anticancer and Antifungal Investigations
| Autor: | Gayan Heruka De Zoysa, Zimei Wu, Lisa I. Pilkington, Manju Kanamala, Jóhannes Reynisson, Krunal Patel, Vijayalekshmi Sarojini, David Barker, Kamal Patel |
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| Rok vydání: | 2019 |
| Předmět: |
Proteasome Endopeptidase Complex
Antifungal Agents Antineoplastic Agents Apoptosis Peptide Cell-Penetrating Peptides Microbial Sensitivity Tests Q1 Hemolysis 01 natural sciences Ixazomib HeLa QH301 Mice 03 medical and health sciences chemistry.chemical_compound Annexin Amphotericin B Cell Line Tumor Candida albicans Drug Discovery Animals Humans 030304 developmental biology chemistry.chemical_classification Aldehydes 0303 health sciences biology Cell Membrane Drug Synergism DNA biology.organism_classification Molecular biology QR 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Proteasome chemistry Cell culture Biofilms Cell-penetrating peptide Molecular Medicine Cisplatin Reactive Oxygen Species Proteasome Inhibitors |
| Zdroj: | Journal of Medicinal Chemistry. 63:334-348 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.9b01694 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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