Title: Activation of Aptamers with Gain‐of‐Function by Small‐Molecule‐Clipping of Intramolecular Motifs

Authors: Mengjiao Huang  Tingyu Li  Yuanfeng Xu  Xinyu Wei  Jia Song  Bingqian Lin  Zhi Zhu  Yanling Song Chaoyong James Yang

Abstract: Click reactions, which are commonly used in the challenging task of biology‐oriented modular conjugation, have the advantages of high reactivity, excellent orthogonality, and synthetic accessibility, and they accelerate the generation of molecules possessing well‐defined functions. Inspired by click reactions, we propose the concept of “clipped aptamers,” whose binding affinity is regulated by the "clip"‐like specific interaction between a synthetic DNA‐mismatch‐binding small molecule (molecular glue, Z‐NCTS) and the preset CGG/CGG sequences in nucleic acid sequences. In this study, we investigated a Z‐NCTS‐mediated de novo selection of “clipped aptamers” against epithelial cell adhesion molecule. The generated “clipped aptamers” can achieve the efficient transition from a binding inactive state to an active state by clipping of Z‐NCTS with two CGG sites, which otherwise would not hybridize. The experimental and simulation results proved that the “clipped aptamer” had ideal binding thermodynamics and the ability to regulate cellular adhesion. Because of this superior activated mechanism and structural diversity, “clipped aptamers” hold great potential in biosensing, imaging, conditional gene‐ and cellular behavior‐regulation, and drug delivery.

Full-Link: https://onlinelibrary.wiley.com/doi/10.1002/anie.202013570