Persistent Degradation of HER2 Protein by Hybrid nanoPROTAC for Programmed Cell Death.
J Med Chem
; 66(9): 6263-6273, 2023 05 11.
Article
em En
| MEDLINE
| ID: mdl-37092695
ABSTRACT
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas
/
Apoptose
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article