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

• DOI: 10.1038/s41467-024-51197-w
• Publication Date: 2024-08-08T11:04:10Z
• Authors: 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; Weihong Tan
• Keywords: Aptamer; SELEX Aptamer Technique

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