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Sequence-specific and Selective Recognition of Double-stranded RNAs over Single-stranded RNAs by Chemically Modified Peptide Nucleic Acids
Published on: September 21, 2017
Phosphorothioate-Free and Self-Interaction-Reduced Acyclic Nucleic Acids for Effective Antisense Oligonucleotide
Yukiko Kamiya1,2,3, Fuminori Sato2, Kiyoka Sakashita2
1Bioanalytical Chemistry Laboratory, Kobe Pharmaceutical University, 4-19-1 Motoyama-Kitamachi, Higashinada-ku, Kobe 658-8558, Japan.
Journal of Medicinal Chemistry
|June 2, 2026
Summary
Novel acyclic nucleic acids, serinol nucleic acid (SNA) and acyclic l-threoninol nucleic acid (L-aTNA), overcome self-interaction issues using pseudocomplementary bases. This enhances therapeutic potential for safer and more effective nucleic acid treatments.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Acyclic artificial nucleic acids like serinol nucleic acid (SNA) and acyclic l-threoninol nucleic acid (L-aTNA) offer nuclease resistance and stable RNA hybridization.
- Current limitations include self-interactions in self-complementary regions, hindering therapeutic applications.
- Phosphorothioate (PS) modifications, often used to improve stability, introduce toxicities and manufacturing complexities.
Purpose of the Study:
- To address self-interaction limitations in SNA and L-aTNA by incorporating pseudocomplementary bases.
- To enhance RNA binding affinity and therapeutic efficacy of these acyclic nucleic acids.
- To demonstrate the *in vitro* and *in vivo* therapeutic potential of modified SNA and L-aTNA.
Main Methods:
- Incorporation of pseudocomplementary bases, 2,6-diaminopurine (D) and 2-thiouracil (sU), into SNA and L-aTNA oligonucleotides.
- Evaluation of self-interaction suppression and RNA affinity enhancement.
- Assessment of anti-miR-21 activity in cancer cell lines and *in vivo* tumor growth suppression using modified oligonucleotides.
Main Results:
- Pseudocomplementary base substitutions effectively suppressed self-interactions in SNA and L-aTNA.
- Modified oligonucleotides exhibited enhanced RNA affinity and improved anti-miR-21 activity in cancer cell lines.
- Phosphorothioate-free L-aTNA with D and sU substitutions demonstrated significant *in vivo* tumor growth suppression with low toxicity.
Conclusions:
- Pseudocomplementary base modification is a viable strategy to overcome self-interaction limitations in acyclic nucleic acids.
- Modified SNA and L-aTNA represent a safer and more effective platform for next-generation nucleic acid therapeutics.
- This approach offers a promising alternative to traditional antisense oligonucleotide modifications, reducing toxicity and manufacturing challenges.
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