Persistent Degradation of HER2 Protein by Hybrid nanoPROTAC for Programmed Cell Death
Proteolysis-targeting chimera (PROTAC) has emerged as a promising strategy for degrading proteins of interest. Peptide-based PROTACs offer several advantages over small-molecule-based PROTACs, such as high specificity, low toxicity, and large protein-protein interaction surfaces. However, peptide-based PROTACs have several intrinsic shortcomings that strongly limit their application including poor cell permeability and low stability and potency. Herein, we designed a nanosized hybrid PROTAC (GNCTACs) to target and degrade human epidermal growth factor receptor 2 (HER2) in tumor cells. Gold nanoclusters (GNCs) were utilized to connect HER2-targeting peptides and cereblon (CRBN)-targeting ligands. GNCTACs could overcome the intrinsic barriers of peptide-based PROTACs, efficiently delivering HER2-targeting peptides in the cytoplasm and protecting them from degradation. Furthermore, a fasting-mimicking diet was applied to enhance the cellular uptake and proteasome activity. Consequently, more than 95% of HER2 in SKBR3 cells was degraded by GNCTACs, and the degradation lasted for at least 72 h, showing a catalytic-like reaction.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:66 |
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| Enthalten in: |
Journal of medicinal chemistry - 66(2023), 9 vom: 11. Mai, Seite 6263-6273 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wang, Zhihang [VerfasserIn] |
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| Links: |
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| Themen: |
EC 2.3.2.27 |
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| Anmerkungen: |
Date Completed 17.05.2023 Date Revised 29.06.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.3c00013 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM355964074 |
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| 245 | 1 | 0 | |a Persistent Degradation of HER2 Protein by Hybrid nanoPROTAC for Programmed Cell Death |
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| 500 | |a Date Revised 29.06.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Proteolysis-targeting chimera (PROTAC) has emerged as a promising strategy for degrading proteins of interest. Peptide-based PROTACs offer several advantages over small-molecule-based PROTACs, such as high specificity, low toxicity, and large protein-protein interaction surfaces. However, peptide-based PROTACs have several intrinsic shortcomings that strongly limit their application including poor cell permeability and low stability and potency. Herein, we designed a nanosized hybrid PROTAC (GNCTACs) to target and degrade human epidermal growth factor receptor 2 (HER2) in tumor cells. Gold nanoclusters (GNCs) were utilized to connect HER2-targeting peptides and cereblon (CRBN)-targeting ligands. GNCTACs could overcome the intrinsic barriers of peptide-based PROTACs, efficiently delivering HER2-targeting peptides in the cytoplasm and protecting them from degradation. Furthermore, a fasting-mimicking diet was applied to enhance the cellular uptake and proteasome activity. Consequently, more than 95% of HER2 in SKBR3 cells was degraded by GNCTACs, and the degradation lasted for at least 72 h, showing a catalytic-like reaction | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Proteins |2 NLM | |
| 650 | 7 | |a Ubiquitin-Protein Ligases |2 NLM | |
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| 650 | 7 | |a Proteolysis Targeting Chimera |2 NLM | |
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| 700 | 1 | |a Tan, Mixiao |e verfasserin |4 aut | |
| 700 | 1 | |a Su, Wen |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Wenping |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Jia, Fuhao |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Guoliang |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xinyang |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Haohao |e verfasserin |4 aut | |
| 700 | 1 | |a Ran, Haitao |e verfasserin |4 aut | |
| 700 | 1 | |a Nie, Guangjun |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Hai |e verfasserin |4 aut | |
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