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Updated: Jan 31, 2026

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Transient Cyclic Structured Oligonucleotide Designs for Therapeutic Applications.

Sudhir Agrawal1

  • 1ARNAY Sciences, Shrewsbury, MA.

Current Protocols
|January 30, 2026
PubMed
Summary

New cyclic oligonucleotide designs improve drug-like properties for RNA therapeutics. These novel structures enhance potency and specificity by protecting functional sequences during delivery, offering broad applicability for various therapeutic mechanisms.

Keywords:
circular structurecyclic structuredeliverynuclease resistancenucleic acidsoligonucleotide therapeutics

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Area of Science:

  • Medicinal Chemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Oligonucleotide therapeutics have evolved significantly, with early efforts focusing on nuclease stability and target affinity, leading to gapmer designs and chemical modifications.
  • Established antisense, splice-modulating, and siRNA therapies, now comprising over 25 approved drugs, have advanced the field.
  • Recent understanding reveals that oligonucleotides interact with cellular proteins, influencing delivery and innate immune responses.

Purpose of the Study:

  • To optimize oligonucleotide drug-like properties by integrating historical chemical advancements with current knowledge of protein interactions.
  • To introduce novel cyclic structured oligonucleotide designs that enhance therapeutic efficacy and specificity.

Main Methods:

  • Development of cyclic oligonucleotide structures where 3' and 5' ends are temporarily linked through Watson-Crick base pairing.
  • Evaluation of these cyclic designs for nuclease resistance during delivery and intracellular release mechanisms.
  • Comparative analysis of cyclic designs against traditional gapmer antisense therapeutics.

Main Results:

  • Cyclic oligonucleotide structures demonstrate enhanced protection against nucleases during delivery and cell entry.
  • These designs facilitate effective release of the oligonucleotide drug into the intracellular environment.
  • Significant improvements in potency and specificity were observed compared to gapmer antisense approaches.

Conclusions:

  • Cyclic oligonucleotide designs represent a promising advancement in RNA therapeutics, offering improved drug-like properties.
  • The transient cyclic structure effectively balances stability for delivery with functional release.
  • These designs show broad applicability across diverse RNA therapeutic modalities and mechanisms of action.