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A kainate receptor-selective RNA aptamer.

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  • 1Department of Chemistry, and Center for Neuroscience Research, University at Albany, SUNY, Albany, New York 12222.

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|March 13, 2020
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Summary

Researchers developed chemically modified RNA aptamers to inhibit kainate and AMPA receptors, crucial for treating neurological diseases. These stable aptamers show promise as therapeutic tools for conditions linked to excessive receptor activity.

Keywords:
2′-fluoro–modified RNAsAMPA receptorsRNARNA modificationSELEXaptamerdrug developmentinhibitorionotropic glutamate receptorkainate receptorsneurological diseaseselective antagonist

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • Kainate and AMPA receptors are glutamate ion channel subtypes implicated in CNS diseases.
  • Developing selective antagonists for these receptors, particularly kainate receptors, is vital for therapeutic strategies.

Purpose of the Study:

  • To design and characterize RNA aptamers targeting kainate and AMPA receptors.
  • To enhance aptamer biostability through chemical modification for improved therapeutic potential.

Main Methods:

  • Design of two RNA aptamers for individual inhibition of kainate and AMPA receptors.
  • Chemical modification of aptamers by 2'-OH to 2'-fluorine substitution to increase resistance to degradation.
  • Assessment of aptamer stability in rat cerebrospinal fluid and serum-containing medium.
  • Evaluation of aptamer inhibitory activity against specific receptor subunits and heteromers.

Main Results:

  • 2'-fluoro aptamers (FB9s-b and FB9s-r) exhibited enhanced resistance to RNase degradation, with a half-life of approximately 5 days.
  • FB9s-r effectively blocked AMPA receptor activity.
  • FB9s-b selectively inhibited GluK1 and GluK2 kainate receptor subunits and GluK1/GluK5 and GluK2/GluK5 heteromeric receptors with equal potency.

Conclusions:

  • Chemically modified RNA aptamers demonstrate significant biostability and potent inhibitory activity against specific kainate and AMPA receptor subtypes.
  • FB9s-b serves as a valuable template for developing novel therapeutic agents for neurological disorders associated with aberrant GluK1 and GluK2 activity.