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通过小分子“夹住”分子内单元实现核酸适配体功能获得性活化
作者:小柯机器人 发布时间:2020/11/20 16:52:15

厦门大学化学与化工学院杨朝勇课题组在小分子诱导的核酸适配体活化方面取得新进展。 2020年11月18日,国际知名学术期刊《德国应用化学》发表了这一成果。

点击反应是一种常用于实现富有挑战性的生物相关模块间偶合的途径,其优点包括高反应活性、高生物正交性以及容易合成等,大大提高了产生功能明确的分子的速度。受点击反应的启发,该课题组提出了“夹住的适配体”的概念,即通过一个人工合成的、与DNA错配结合的小分子(分子胶水,Z-NCTS)“夹住”核酸序列中预设的CGG/CGG序列,以调控核酸适配体的结合能力。

课题组还研究了由Z-NCTS分子介导的、面向表皮细胞粘附分子的“夹住的适配体”的从头筛选。生成的“夹住的适配体”分子可以通过Z-NCTS“夹住”两个CGG位点改变两条链的杂交状态,实现无结合活性和有结合活性两种状态间的高效切换。

实验和仿真结果表明,“夹住的适配体”具有理想的结合热力学和调节细胞粘附的能力。由于这种优越的活化机制和结构多样性,“夹住的适配体”在生物传感、成像、根据外部条件调控基因和细胞行为以及药物传递方面具有巨大的潜力。

附:英文原文

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

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

Issue&Volume: November 18, 2020

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.

DOI: 10.1002/anie.202013570

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202013570

期刊信息

Angewandte Chemie:《德国应用化学》,创刊于1887年。隶属于德国化学会,最新IF:12.959
官方网址:https://onlinelibrary.wiley.com/journal/15213773
投稿链接:https://www.editorialmanager.com/anie/default.aspx