Development of a novel PROTAC using the nucleic acid aptamer as a targeting ligand for tumor selective degradation of nucleolin

doi:10.1016/j.omtn.2022.09.008

	Development of a novel PROTAC using the nucleic acid aptamer as a targeting ligand for tumor selective degradation of nucleolin
	Zhang, Lin 1; Li, Ling 1; Wang, Xia 1; Liu, Huimin 1; Zhang, Yibin 1; Xie, Tiantian 1; Zhang, Hui 1; Li, Xiaodong 1; Peng, Tianhuan 1; Sun, Xing 1
刊名	MOLECULAR THERAPY-NUCLEIC ACIDS
	2022-12-30
卷号	30
ISSN号	2162-2531
DOI	10.1016/j.omtn.2022.09.008
通讯作者	Wu, Wencan(wuwencan118@163.com) ; Ye, Mao(goldleaf@hnu.edu.cn) ; Tan, Weihong(tan@hnu.edu.cn)
英文摘要	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.
资助项目	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]
WOS关键词	PROTEIN-DEGRADATION ; DEGRADER ; DELIVERY ; AS1411 ; DISCOVERY ; COMPLEX
WOS研究方向	Research & Experimental Medicine
语种	英语
出版者	CELL PRESS
WOS记录号	WOS:000870031800002
资助机构	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
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/129801]
专题	中国科学院合肥物质科学研究院
通讯作者	Wu, Wencan; Ye, Mao; Tan, Weihong
作者单位	1.Hunan Univ, Coll Biol, Coll Chem & Chem Engn, Aptamer Engn Ctr Hunan Prov,Mol Sci & Biomed Lab M, Changsha 410082, Hunan, Peoples R China 2.Cent South Univ, Mol Biol Res Ctr, Changsha 410078, Hunan, Peoples R China 3.Cent South Univ, Ctr Med Genet, Sch Life Sci, Changsha 410078, Hunan, Peoples R China 4.Wenzhou Med Univ, Eye Hosp, Wenzhou 325027, Zhejiang, Peoples R China 5.Univ Chinese Acad Sci, Zhejiang Canc Hosp, Inst Basic Med & Canc IBMC, Chinese Acad Sci,Canc Hosp, Hangzhou 310022, Zhejiang, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Lin,Li, Ling,Wang, Xia,et al. Development of a novel PROTAC using the nucleic acid aptamer as a targeting ligand for tumor selective degradation of nucleolin[J]. MOLECULAR THERAPY-NUCLEIC ACIDS,2022,30.
APA	Zhang, Lin.,Li, Ling.,Wang, Xia.,Liu, Huimin.,Zhang, Yibin.,...&Tan, Weihong.(2022).Development of a novel PROTAC using the nucleic acid aptamer as a targeting ligand for tumor selective degradation of nucleolin.MOLECULAR THERAPY-NUCLEIC ACIDS,30.
MLA	Zhang, Lin,et al."Development of a novel PROTAC using the nucleic acid aptamer as a targeting ligand for tumor selective degradation of nucleolin".MOLECULAR THERAPY-NUCLEIC ACIDS 30(2022).