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Mapping the Binding Site of an Aptamer on ATP Using MicroScale Thermophoresis
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Aptamer-enabled uptake of small molecule ligands.

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|October 26, 2018
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RNA aptamers, named DRAGINs (Drug Binding Aptamers for Growing Intracellular Numbers), can increase intracellular drug concentrations. This property can enhance or protect cells from drug toxicity, with implications for drug delivery and early life evolution.

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Area of Science:

  • Molecular Biology
  • Biochemistry
  • Synthetic Biology

Background:

  • Natural RNAs exhibit molecular recognition capabilities, facilitating aptamer isolation.
  • Aptamers, RNA molecules with specific binding properties, are being explored for various biological applications.

Purpose of the Study:

  • To investigate if expressed aptamers can alter intracellular concentrations of small molecule ligands.
  • To characterize the 'DRAGIN' (Drug Binding Aptamer for Growing Intracellular Numbers) property and its effect on ligand toxicity.
  • To explore the evolutionary and therapeutic implications of aptamer-mediated intracellular concentration changes.

Main Methods:

  • Expression of aptamers within cellular environments.
  • Assessment of aptamer-ligand interactions and their impact on cellular toxicity.
  • Mathematical modeling to understand factors influencing cellular response (protection vs. killing).

Main Results:

  • Some aptamers, termed DRAGINs, successfully increased intracellular concentrations of their small molecule ligands.
  • The DRAGIN property varied among aminoglycoside aptamers, with some enhancing ligand toxicity and others providing protection.
  • A mathematical model indicated that aptamer affinity and cell membrane accessibility critically determine whether cells are protected or killed by the ligand.

Conclusions:

  • Aptamers can be engineered to modulate intracellular drug levels, offering a novel approach to drug delivery and efficacy.
  • The DRAGIN property has potential applications in cell imaging, synthetic cell design, and enhancing the accessibility of 'undruggable' targets.
  • Ancient RNA structures may have utilized similar mechanisms for concentrating precursor molecules, suggesting a link to the origins of life and the evolution of riboswitches.