Blocker-SELEX: a structure-guided strategy for developing inhibitory aptamers disrupting undruggable transcription factor interactions

Tongqing Li, Xueying Liu, Haifeng Qian, Sheyu Zhang, Yu Hou, Yuchao Zhang, Guoyan Luo, Xun Zhu, Yanxin Tao, Mengyang Fan, Hong Wang, Chulin Sha, Ailan Lin, Jingjing Qin, Kedan Gu, Weichang Chen, Ting Fu, Yajun Wang, Yong Wei (), Qin Wu () and Weihong Tan ()
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Tongqing Li: Chinese Academy of Sciences
Xueying Liu: Chinese Academy of Sciences
Haifeng Qian: Chinese Academy of Sciences
Sheyu Zhang: Chinese Academy of Sciences
Yu Hou: Chinese Academy of Sciences
Yuchao Zhang: Chinese Academy of Sciences
Guoyan Luo: Chinese Academy of Sciences
Xun Zhu: Chinese Academy of Sciences
Yanxin Tao: Chinese Academy of Sciences
Mengyang Fan: Chinese Academy of Sciences
Hong Wang: Zhejiang University of Technology
Chulin Sha: Chinese Academy of Sciences
Ailan Lin: Chinese Academy of Sciences
Jingjing Qin: Chinese Academy of Sciences
Kedan Gu: Chinese Academy of Sciences
Weichang Chen: Chinese Academy of Sciences
Ting Fu: Chinese Academy of Sciences
Yajun Wang: Chinese Academy of Sciences
Yong Wei: Chinese Academy of Sciences
Qin Wu: Chinese Academy of Sciences
Weihong Tan: Chinese Academy of Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Despite the well-established significance of transcription factors (TFs) in pathogenesis, their utilization as pharmacological targets has been limited by the inherent challenges in modulating their protein interactions. The lack of defined small-molecule binding pockets and the nuclear localization of TFs do not favor the use of traditional tools. Aptamers possess large molecular weights, expansive blocking surfaces and efficient cellular internalization, making them compelling tools for modulating TF interactions. Here, we report a structure-guided design strategy called Blocker-SELEX to develop inhibitory aptamers (iAptamers) that selectively block TF interactions. Our approach leads to the discovery of iAptamers that cooperatively disrupt SCAF4/SCAF8-RNAP2 interactions, dysregulating RNAP2-dependent gene expression, which impairs cell proliferation. This approach is further applied to develop iAptamers blocking WDR5-MYC interactions. Overall, our study highlights the potential of iAptamers in disrupting pathogenic TF interactions, implicating their potential utility in studying the biological functions of TF interactions and in nucleic acids drug discovery.

Date: 2024
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DOI: 10.1038/s41467-024-51197-w

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