Wang Rui-Wen, Yang Wei-Guo, Su Ming-Li, Qin Jia-Min, Liu Jia-Qi, Yang Xiao-Han, Cao Jun-Yi, Yuan Ruo, Zhuo Ying, Chen Ming, Yang Chaoyong, Liang Wen-Bin
Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, Institute of Developmental Biology and Regenerative Medicine, College of Chemistry and Chemical Engineering, Southwest University Chongqing 400715 P. R. China
Department of Clinical Laboratory Medicine, Southwest Hospital, Third Military Medical University (Army Medical University) Chongqing 400038 China
Chem Sci. 2025 Aug 30. doi: 10.1039/d5sc04624f.
Small-molecule drugs, constituting over 60% of FDA-approved therapeutics (2017-2022), present unresolved challenges relating to elucidating their intracellular mechanisms. We present a dual-strategy platform integrating " aptamer affinity maturation" (ISAAM) and "structural reorganization-catalytic hairpin assembly" (SR-CHA). ISAAM computationally designs high-affinity aptamers, while SR-CHA eliminates undesired signals energy-minimized conformational control, achieving a signal-to-background improvement over conventional CHA. This system enables ultrasensitive small-molecule monitoring in live cells, resolving traditional challenges of false positives and inefficiency. Demonstrated through intracellular imaging and kinetic studies, SR-CHA offers a robust tool for probing small-molecule interactions in biological systems, advancing drug discovery and diagnostic applications.
小分子药物占美国食品药品监督管理局（FDA）2017年至2022年批准的治疗药物的60%以上，在阐明其细胞内作用机制方面存在尚未解决的挑战。我们提出了一个整合“适体亲和力成熟”（ISAAM）和“结构重组-催化发夹组装”（SR-CHA）的双策略平台。ISAAM通过计算设计高亲和力适体，而SR-CHA通过能量最小化的构象控制消除不需要的信号，实现了比传统CHA更高的信号背景比。该系统能够在活细胞中进行超灵敏的小分子监测，解决了传统的假阳性和低效问题。通过细胞内成像和动力学研究证明，SR-CHA为探测生物系统中的小分子相互作用提供了一个强大的工具，推动了药物发现和诊断应用。
