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RNA Stability

RNA Stability

Intact DNA strands can be found in fossils, while scientists sometimes struggle to keep RNA intact under laboratory conditions. The structural variations between RNA and DNA underlie the differences in their stability and longevity. Because DNA is double-stranded, it is inherently more stable. The single-stranded structure of RNA is less stable but also more flexible and can form weak internal bonds. Additionally, most RNAs in the cell are relatively short, while DNA can be up to 250 million...

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Related Experiment Video

Updated: May 13, 2025

Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors

Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors

Published on: May 9, 2025

In Vitro Structure-Activity Relationship Stability Study of Antisense Oligonucleotide Therapeutics Using Biological

Jelena Lovrić¹, Jingjing Yan¹, XueQing Li¹

¹DMPK, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

Pharmacology Research & Perspectives

|April 16, 2025

Summary

Antisense oligonucleotides (ASOs) stability is crucial for drug development. This study developed in vitro assays to predict ASO metabolism, finding backbone chemistry and sequence influence stability, aiding in selecting optimal drug candidates.

Keywords:

ASO metabolic stability nuclease

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Area of Science:

Oligonucleotide chemistry
Drug discovery and development
Pharmacokinetics and metabolism

Background:

Antisense oligonucleotides (ASOs) are susceptible to degradation by endonucleases and exonucleases.
Systematic investigation of chemical modifications' effects on oligonucleotide stability is lacking.
Predictive in vitro assays for ASO in vivo metabolism are needed.

Purpose of the Study:

To develop in vitro assays for predicting the in vivo metabolism of antisense oligonucleotides (ASOs).
To systematically investigate the impact of chemical modifications on ASO stability.

Main Methods:

Stability studies of ASOs with varying phosphorothioate/phosphodiester (PS/PO) content.
Utilized nucleolytic matrices: snake venom phosphodiesterase I (PDEI), mouse serum, and mouse liver homogenate.
Analysis via gel electrophoresis and LC-UV/MS.

Main Results:

Both sequence composition and backbone chemistry significantly influence ASO stability.
ASOs with one PO modification showed higher stability than those with two or three PO links.
A 5-methylcytidine nucleoside enhanced nuclease resistance when PO link was 3' to it.

Conclusions:

In vitro assays using nucleases and animal matrices can predict ASO stability.
These assays offer a fast-track assessment for selecting optimal ASO drug candidates.
Understanding stability factors enables efficient development of therapeutic oligonucleotides.