Li Tongqing, Liu Xueying, Qian Haifeng, Zhang Sheyu, Hou Yu, Zhang Yuchao, Luo Guoyan, Zhu Xun, Tao Yanxin, Fan Mengyang, Wang Hong, Sha Chulin, Lin Ailan, Qin Jingjing, Gu Kedan, Chen Weichang, Fu Ting, Wang Yajun, Wei Yong, Wu Qin, Tan Weihong
Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, China.
School of Pharmacy, Zhejiang University of Technology, Hangzhou, China.
Nat Commun. 2024 Aug 8;15(1):6751. doi: 10.1038/s41467-024-51197-w.
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.
尽管转录因子（TFs）在发病机制中的重要性已得到充分确立，但其作为药理学靶点的应用一直受到调节其蛋白质相互作用方面固有挑战的限制。缺乏明确的小分子结合口袋以及TFs的核定位不利于传统工具的使用。适体具有大分子量、广泛的阻断表面和高效的细胞内化能力，使其成为调节TF相互作用的有力工具。在此，我们报告一种称为阻断剂-SELEX的结构导向设计策略，用于开发选择性阻断TF相互作用的抑制性适体（iAptamers）。我们的方法导致发现了能协同破坏SCAF4/SCAF8-RNAP2相互作用、失调依赖RNAP2的基因表达并损害细胞增殖的iAptamers。该方法进一步应用于开发阻断WDR5-MYC相互作用的iAptamers。总体而言，我们的研究突出了iAptamers在破坏致病性TF相互作用方面的潜力，暗示了它们在研究TF相互作用的生物学功能以及核酸药物发现中的潜在效用。
