Aptamer-enabled uptake of small molecule ligands.
Aptamer-enabled uptake of small molecule ligands.
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DOI：
10.1038/s41598-018-33887-w
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发表时间：
2018-10-24
影响因子：
4.6
通讯作者：
Nilsen-Hamilton M
中科院分区：
文献类型：
--
作者：
Auwardt SL;Seo YJ;Ilgu M;Ray J;Feldges RR;Shubham S;Bendickson L;Levine HA;Nilsen-Hamilton M
对靶分子具有高度特异性的适体的分离相对容易，这表明分子识别可能在天然RNA的折叠中是常见的。我们在这里表明，当在细胞中表达时，适配子可以增加其小分子配体的细胞内浓度。我们将这些适配子命名为DRAGINs(用于细胞内数量增长的药物结合适配子)。在这里，通过增强其配体的毒性来评估Dragin性质，发现了一些但不是全部的氨基糖苷适配子。一个适配子保护细胞免受其配体的杀伤。另一位适配者将杀戮作为一种单一分子来促进，并作为一种单链分子来保护人们免受杀戮。基于一个数学模型，细胞保护与杀伤被认为是由适体亲和力和对细胞膜内表面的访问决定的，后者是一个关键的决定因素。由于RNA分子被认为是最早驱动生命进化的功能聚合物，我们认为原始细胞中存在的RNA适体样结构可能选择性地浓缩了聚合物合成的前体。核糖开关可能是这些古老的适体类“营养采集器”的进化形式。在现代世界中，具有Dragin能力的适配子可以应用于成像细胞、合成细胞结构，或者将药物引入细胞，使小分子抑制剂能够接触到“不能下药的”靶标。
The relative ease of isolating aptamers with high specificity for target molecules suggests that molecular recognition may be common in the folds of natural RNAs. We show here that, when expressed in cells, aptamers can increase the intracellular concentrations of their small molecule ligands. We have named these aptamers as DRAGINs (Drug Binding Aptamers for Growing Intracellular Numbers). The DRAGIN property, assessed here by the ability to enhance the toxicity of their ligands, was found for some, but not all, aminoglycoside aptamers. One aptamer protected cells against killing by its ligand. Another aptamer promoted killing as a singlemer and protected against killing as a tandemer. Based on a mathematical model, cell protection vs. killing is proposed as governed by aptamer affinity and access to the inner surface of the cell membrane, with the latter being a critical determinant. With RNA molecules proposed as the earliest functional polymers to drive the evolution of life, we suggest that RNA aptamer-like structures present in primitive cells might have selectively concentrated precursors for polymer synthesis. Riboswitches may be the evolved forms of these ancient aptamer-like “nutrient procurers”. Aptamers with DRAGIN capability in the modern world could be applied for imaging cells, in synthetic cell constructs, or to draw drugs into cells to make “undruggable” targets accessible to small molecule inhibitors.
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影响因子：
3.3
作者：
Wei, Chenyu;Pohorille, Andrew
通讯作者：
Pohorille, Andrew
影响因子：
--
作者：
Ray J;Shin I;Ilgu M;Bendickson L;Gupta V;Kraus GA;Nilsen-Hamilton M
通讯作者：
Nilsen-Hamilton M
影响因子：
14.9
作者：
Shin I;Ray J;Gupta V;Ilgu M;Beasley J;Bendickson L;Mehanovic S;Kraus GA;Nilsen-Hamilton M
通讯作者：
Nilsen-Hamilton M
影响因子：
11
作者：
Moran, Mary Ann;Satinsky, Brandon;Hopkinson, Brian M.
通讯作者：
Hopkinson, Brian M.
影响因子：
2.9
作者：
Wang, Y;Killian, J;Rando, RR
通讯作者：
Rando, RR