期刊
MOLECULAR THERAPY-NUCLEIC ACIDS
卷 30, 期 -, 页码 66-79出版社
CELL PRESS
DOI: 10.1016/j.omtn.2022.09.008
关键词
-
资金
- National Key Research and Development Program of China
- Na-tional Natural Science Foundation of China
- Natural Science Foundation of Hunan Province
- Changsha Science and Technology Project
- [2021YFA0909403]
- [21890744]
- [81672760]
- [2022JJ30183]
- [kq2001012]
In this study, a novel PROTAC ZL216 was developed by using nucleic acid aptamer AS1411 as a targeting ligand of nucleolin and conjugating it with a small molecule ligand of E3 ligase VHL, achieving selective degradation of breast cancer cells. This study broadens the methods of constructing PROTACs and provides a promising strategy for tumor-selective therapy.
PROteolysis TArgeting Chimeras (PROTACs) induce targeted protein degradation by hijacking the intracellular ubiquitin proteasome system, thus emerging as a new strategy for drug development. However, most PROTACs generated lack celltype selectivity and are poorly soluble in water. To address this drawback, we developed a novel PROTAC ZL216 using aptamer AS1411 as a targeting ligand of nucleolin to conjugate with a small molecule ligand of E3 ligase VHL, which shows high aqueous solubility and serum stability. Based on the differential expression of nucleolin on the cell surface, ZL216 could bind to and internalize into breast cancer cells, but not normal breast cells. Furthermore, we revealed that ZL216 promoted the formation of a nucleolin-ZL216-VHL ternary complex in breast cancer cells and potently induced nucleolin degradation in vitro and in vivo. As a result, ZL216 inhibited the proliferation and migration of breast cancer cells. These studies demonstrate that in addition to peptides and small molecule compounds, nuclei acid aptamers can also be used to generate PROTACs, which broadens the toolbox constructing PROTACs and provides a promising strategy for development of tumor-selective PROTACs.
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