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

Lin Zhang; Ling Li; Xia Wang; Huimin Liu; Yibin Zhang; Tiantian Xie; Hui Zhang; Xiaodong Li; Tianhuan Peng; Xing Sun; Jing Dai; Jing Liu; Wencan Wu; Mao Ye; Weihong Tan

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

Mol Ther Nucleic Acids. 2022 Sep 19:30:66-79. doi: 10.1016/j.omtn.2022.09.008. eCollection 2022 Dec 13.

Authors

Lin Zhang¹, Ling Li¹, Xia Wang¹, Huimin Liu¹, Yibin Zhang¹, Tiantian Xie¹, Hui Zhang¹, Xiaodong Li¹, Tianhuan Peng¹, Xing Sun¹, Jing Dai¹, Jing Liu², Wencan Wu³, Mao Ye¹, Weihong Tan^{1

4}

Affiliations

¹ Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China.
² Molecular Biology Research Center and Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
³ The Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
⁴ The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.

Abstract

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 cell-type 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.

Keywords: MT: Oligonucleotides: Therapies and Applications; PROTAC; aptamer; degradation; nucleolin; ubiquitination.