Chen Qingwen, Fujiwara Aina, Nakatani Kazuhiko, Kawai Gota, Murata Asako
Department of Regulatory Bioorganic Chemistry, SANKEN, The University of Osaka 8-1 Mihogaoka, Ibaraki Osaka 567-0047 Japan
Department of Life Science, Faculty of Advanced Engineering, Chiba Institute of Technology Tsudanuma 2-17-1, Narashino Chiba 275-0016 Japan.
Chem Sci. 2025 Aug 21. doi: 10.1039/d5sc05255f.
RNA-targeting small molecules have the potential to modulate RNA function and offer possible applications in drug development. However, their molecular recognition mechanisms remain poorly understood due to limited structural insights. To advance our understanding of how these small molecules interact with their target RNAs, it is essential to identify and analyze RNA-small molecule complexes that can serve as models for structural studies. In this study, we identified novel RNA motifs that bind selectively to the small molecule naphthyridine-azaquinolone (NA), previously known to interact with CAG/CAG motif in DNA. Using different methods, including surface plasmon resonance (SPR), thermal melting, and cold-spray ionization mass spectrometry, we investigated the interaction between NA and the RNA motifs. Furthermore, we determined the solution structure of the NA-RNA complex, revealing a distinct binding mode from its DNA interaction. The findings in this study provide molecular-level insight into RNA-small molecule recognition and highlight the potential of NA as a scaffold for developing RNA-targeting small molecules.
靶向RNA的小分子有调节RNA功能的潜力，并在药物开发中具有潜在应用。然而，由于结构见解有限，它们的分子识别机制仍知之甚少。为了加深我们对这些小分子如何与靶RNA相互作用的理解，识别和分析可作为结构研究模型的RNA-小分子复合物至关重要。在本研究中，我们鉴定了与小分子萘啶氮杂喹啉（NA）选择性结合的新型RNA基序，此前已知该小分子与DNA中的CAG/CAG基序相互作用。我们使用了不同方法，包括表面等离子体共振（SPR）、热熔解和冷喷雾电离质谱，研究了NA与RNA基序之间的相互作用。此外，我们确定了NA-RNA复合物的溶液结构，揭示了其与DNA相互作用不同的结合模式。本研究的结果提供了对RNA-小分子识别的分子水平见解，并突出了NA作为开发靶向RNA小分子支架的潜力。
