Identification of a non-inhibitory aptameric ligand to CRL2ZYG11B E3 ligase for targeted protein degradation

As a crucial element of proteolysis targeting chimeras (PROTACs), the choice of E3 ubiquitin ligase significantly influences degradation efficacy and selectivity. However, the available arsenal of E3 ligases for PROTAC development remains underexplored, severely limiting the scope of targeted protein degradation. In this study, we identify a non-inhibitory aptamer targeting ZYG11B, a substrate receptor of the Cullin 2-RING ligase complex, as an E3 warhead for targeted protein degradation. This aptamer-based PROTAC platform, termed ZATAC, is facilely produced through bioorthogonal chemistry or self-assembly and shows promise in eliminating several undruggable target proteins, including nucleolin (NCL), SRY-box transcription factor 2 (SOX2), and mutant p53-R175H, underscoring its universality and versatility. To specifically deliver ZATACs into cancer cells, we further develop DNA three-way junction-based ZATACs (3WJ-ZATACs) by integrating an additional aptamer that selectively recognizes the protein overexpressed on the surface of cancer cells. The 3WJ-ZATACs demonstrate in vivo tumor-specific distribution and achieve dual-target degradation, thereby suppressing tumor growth without causing noticeable toxicity. In summary, ZATACs represent a general, modular, and straightforward platform for targeted protein degradation, offering insights into the potential of other untapped E3 ligases.

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Publication Details

Journal
Nature Communications
Published
2025-03-13
DOI
https://doi.org/10.1038/s41467-025-57823-5
Citations
8
Primary Topic
Protein Degradation and Inhibitors
Type
article
Field-Weighted Citation Impact
6.45

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article

Identification of a non-inhibitory aptameric ligand to CRL2ZYG11B E3 ligase for targeted protein degradation

Wenyi Mi, Xifeng Dong, He Chen, Jun Zhou et al.
8 citations
Nature Communications
Protein Degradation and Inhibitors
6.45
article

Identification of a non-inhibitory aptameric ligand to CRL2ZYG11B E3 ligase for targeted protein degradation

Wenyi Mi, Xifeng Dong, He Chen, Jun Zhou, Mengyu Zhou, Dong Cheng, Chenghao Xuan, Ping Zhou, Zhihao Yang, Hanyu Ni, Ruixin Ge, Shuwen Ma, Songbo Xie, Hua Yan, Chenyu Xu, Yan Chen, Miao Chen, Song Chen, Yao Xue, Wei Pan, Jiayi Song
article en
8 citations

Abstract

As a crucial element of proteolysis targeting chimeras (PROTACs), the choice of E3 ubiquitin ligase significantly influences degradation efficacy and selectivity. However, the available arsenal of E3 ligases for PROTAC development remains underexplored, severely limiting the scope of targeted protein degradation. In this study, we identify a non-inhibitory aptamer targeting ZYG11B, a substrate receptor of the Cullin 2-RING ligase complex, as an E3 warhead for targeted protein degradation. This aptamer-based PROTAC platform, termed ZATAC, is facilely produced through bioorthogonal chemistry or self-assembly and shows promise in eliminating several undruggable target proteins, including nucleolin (NCL), SRY-box transcription factor 2 (SOX2), and mutant p53-R175H, underscoring its universality and versatility. To specifically deliver ZATACs into cancer cells, we further develop DNA three-way junction-based ZATACs (3WJ-ZATACs) by integrating an additional aptamer that selectively recognizes the protein overexpressed on the surface of cancer cells. The 3WJ-ZATACs demonstrate in vivo tumor-specific distribution and achieve dual-target degradation, thereby suppressing tumor growth without causing noticeable toxicity. In summary, ZATACs represent a general, modular, and straightforward platform for targeted protein degradation, offering insights into the potential of other untapped E3 ligases.

Nature CommunicationsVol. 16(1)
Shandong University of Technology (CN), Nankai University (CN), Shandong Normal University (CN), Tianjin Medical University General Hospital (CN), Ministry of Education (KR), Tianjin Medical University Eye Hospital (CN), Tianjin Medical University (CN)
National Natural Science Foundation of China
Openalex Percentile: Top 3%
Protein Degradation and Inhibitors
6.45
DOIOpen Access PDFOpenAlex
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