用于荧光成像肿瘤细胞中 APE1 活性的酸性细胞外 pH 激活型异源 DNA 纳米器件

IF 6.7 1区 化学 Q1 CHEMISTRY, ANALYTICAL Analytical Chemistry Pub Date : 2024-10-30 DOI:10.1021/acs.analchem.4c03934
Hui He, Yuchen Wu, Mingjian Chen, Lanlin Qi, Xiaoxiao He, Kemin Wang
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摘要

异构现象是指配体在一个异构位点的结合会影响另一个配体在活性位点的亲和力。与正交调节不同,异位调节可以更精确地控制生物分子的活性,并提高分子的稳定性。受天然分子异位调控的启发,我们提出了一种 Y 形异位 DNA 纳米器件,称为 YssAP,它具有 pH 响应性,并与 AS1411 aptamer 功能化,可用于对肿瘤细胞中人类嘌呤/近嘧啶内切酶(APE1)的活性进行精确的荧光成像。通过合理设计,YssAP 不能被 APE1 切断,Cy5 靠近 BHQ2,导致信号发射受抑制。相反,由于酸性 pH 是一种异构效应因子,YssAP 在酸性细胞外 pH 下会发生构象变化,变成活化的 DNA 探针(YdsAP)。通过 AS1411 aptamer 的特异性识别进入肿瘤细胞后,肿瘤细胞中过表达的 APE1 切断了 YdsAP 上的 AP 位点。Cy5远离BHQ2,从而产生强烈的信号输出。与直接构建 APE1 底物相比,异构 DNA 纳米器件具有更精确的成像效果,可通过改变开关状态进行精确调节。我们期待这一策略能应用于 APE1 抑制剂的筛选和肿瘤的精确诊断。
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Acidic Extracellular pH-Activated Allosteric DNA Nanodevice for Fluorescence Imaging of APE1 Activity in Tumor Cells
Allostery is a phenomenon where the binding of a ligand at one allosteric site influences the affinity for another ligand at an active site. Different from orthosteric regulation, it allows for more precise control of biomolecular activity and enhances the stability of the molecules. Inspired by allosteric regulation of natural molecules, we present a Y-shaped allosteric DNA nanodevice, termed YssAP, that was pH-responsive and functionalized with the AS1411 aptamer for accurate fluorescence imaging of human apurinic/apyrimidinic endonuclease (APE1) activity in tumor cells. With rational design, YssAP could not be cut by APE1, and Cy5 was in the proximity of BHQ2, leading to suppressed signal emission. In contrast, since acidic pH acted as an allosteric effector, YssAP underwent a conformational change into an activated DNA probe (YdsAP) at acidic extracellular pH. After entering the tumor cell via the specific recognition of AS1411 aptamer, the overexpressed APE1 in the tumor cell cut the AP site on YdsAP. Cy5 moved far away from BHQ2, resulting in a strong signal output. Compared with the direct construction of the APE1 substrate, allosteric DNA nanodevices have more accurate imaging effects, which can be precisely adjusted by changing the switching state. We anticipate that this strategy will be applied in the screening of APE1 inhibitors and precise tumor diagnosis.
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来源期刊
Analytical Chemistry
Analytical Chemistry 化学-分析化学
CiteScore
12.10
自引率
12.20%
发文量
1949
审稿时长
1.4 months
期刊介绍: Analytical Chemistry, a peer-reviewed research journal, focuses on disseminating new and original knowledge across all branches of analytical chemistry. Fundamental articles may explore general principles of chemical measurement science and need not directly address existing or potential analytical methodology. They can be entirely theoretical or report experimental results. Contributions may cover various phases of analytical operations, including sampling, bioanalysis, electrochemistry, mass spectrometry, microscale and nanoscale systems, environmental analysis, separations, spectroscopy, chemical reactions and selectivity, instrumentation, imaging, surface analysis, and data processing. Papers discussing known analytical methods should present a significant, original application of the method, a notable improvement, or results on an important analyte.
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