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Cited by 372RNA Interference and Gene DeliveryDNA and Nucleic Acid ChemistryRNA and protein synthesis mechanisms

Phosphorothioate modified oligonucleotide–protein interactions

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Crooke, Stanley T, Vickers, Timothy A, Liang, Xue-hai·2020·Nucleic Acids Research
DOI 10.1093/nar/gkaa299PMC PMC7261153
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Abstract

Antisense oligonucleotides (ASOs) interact with target RNAs via hybridization to modulate gene expression through different mechanisms. ASO therapeutics are chemically modified and include phosphorothioate (PS) backbone modifications and different ribose and base modifications to improve pharmacological properties. Modified PS ASOs display better binding affinity to the target RNAs and increased binding to proteins. Moreover, PS ASO protein interactions can affect many aspects of their performance, including distribution and tissue delivery, cellular uptake, intracellular trafficking, potency and toxicity. In this review, we summarize recent progress in understanding PS ASO protein interactions, highlighting the proteins with which PS ASOs interact, the influence of PS ASO protein interactions on ASO performance, and the structure activity relationships of PS ASO modification and protein interactions. A detailed understanding of these interactions can aid in the design of safer and more potent ASO drugs, as illustrated by recent findings that altering ASO chemical modifications dramatically improves therapeutic index.

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Cited by

Sorted by citations

Authors
Crooke, S. T., Vickers, T. A., & Liang, X.-H.
Affiliations
Ionis Pharmaceuticals (United States) (US)
Corresponding author
Crooke, Stanley T
ORCID
Venue
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Published
2020-05-01
Volume
48
Issue
10
Pages
5235-5253
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
DOI
10.1093/nar/gkaa299
PMC
PMC7261153
OpenAlex
W3023644567
Cited by
372
References
7
Citations by year
2026: 74 · 2025: 76 · 2024: 64 · 2023: 56 · 2022: 48 · 2021: 40 · 2020: 14
FWCI
12.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Nucleic Acids Research (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
Ionis Pharmaceuticals
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords
phosphorothioate oligonucleotides, antisense oligonucleotides, protein-protein interaction, oligonucleotide therapeutics, chemical modification, structure-activity relationship, RNA hybridization, cellular uptake, intracellular trafficking, toxicity, therapeutic index
MeSH terms
Protein Domains, Cell Membrane, DNA-Binding Proteins, Humans, Ligands, Protein Binding, Proteins, Structure-Activity Relationship, Transcription Factors, RNA-Binding Proteins, Ribonuclease H, Intracellular Space, Phosphorothioate Oligonucleotides

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