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Title: Aptamer-enabled uptake of small molecule ligands

Abstract

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”. In conclusion, aptamers with DRAGIN capability in the modern world could be applied for imaging cells, inmore » synthetic cell constructs, or to draw drugs into cells to make “undruggable” targets accessible to small molecule inhibitors.« less

Authors:
 [1];  [2];  [3];  [4];  [5];  [6];  [7];  [2];  [1]
  1. Ames Lab. and Iowa State Univ., Ames, IA (United States); Aptalogic Inc., Ames, IA (United States)
  2. Iowa State Univ., Ames, IA (United States)
  3. Ames Lab. and Iowa State Univ., Ames, IA (United States); Aptalogic Inc., Ames, IA (United States); Middle East Technical Univ., Ankara (Turkey)
  4. Ames Lab. and Iowa State Univ., Ames, IA (United States); Cornell Univ., Ithaca, NY (United States)
  5. Ames Lab., Ames, IA (United States)
  6. Ames Lab. and Iowa State Univ., Ames, IA (United States); Integrated DNA Technologies, Coralville, IA (United States)
  7. Ames Lab. and Iowa State Univ., Ames, IA (United States)
Publication Date:
Research Org.:
Ames Laboratory (AMES), Ames, IA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1481863
Report Number(s):
IS-J-9802
Journal ID: ISSN 2045-2322; PII: 33887
Grant/Contract Number:  
AC02-07CH11358
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 8; Journal Issue: 1; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Auwardt, Supipi Liyamali, Seo, Yeon -Jung, Ilgu, Muslum, Ray, Judhajeet, Feldges, Robert R., Shubham, Shambhavi, Bendickson, Lee, Levine, Howard A., and Nilsen-Hamilton, Marit. Aptamer-enabled uptake of small molecule ligands. United States: N. p., 2018. Web. doi:10.1038/s41598-018-33887-w.
Auwardt, Supipi Liyamali, Seo, Yeon -Jung, Ilgu, Muslum, Ray, Judhajeet, Feldges, Robert R., Shubham, Shambhavi, Bendickson, Lee, Levine, Howard A., & Nilsen-Hamilton, Marit. Aptamer-enabled uptake of small molecule ligands. United States. doi:10.1038/s41598-018-33887-w.
Auwardt, Supipi Liyamali, Seo, Yeon -Jung, Ilgu, Muslum, Ray, Judhajeet, Feldges, Robert R., Shubham, Shambhavi, Bendickson, Lee, Levine, Howard A., and Nilsen-Hamilton, Marit. Wed . "Aptamer-enabled uptake of small molecule ligands". United States. doi:10.1038/s41598-018-33887-w. https://www.osti.gov/servlets/purl/1481863.
@article{osti_1481863,
title = {Aptamer-enabled uptake of small molecule ligands},
author = {Auwardt, Supipi Liyamali and Seo, Yeon -Jung and Ilgu, Muslum and Ray, Judhajeet and Feldges, Robert R. and Shubham, Shambhavi and Bendickson, Lee and Levine, Howard A. and Nilsen-Hamilton, Marit},
abstractNote = {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”. In conclusion, 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.},
doi = {10.1038/s41598-018-33887-w},
journal = {Scientific Reports},
issn = {2045-2322},
number = 1,
volume = 8,
place = {United States},
year = {2018},
month = {10}
}

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