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Phosphorothioates, Essential Components of Therapeutic Oligonucleotides

Eckstein, Fritz·2014·Nucleic Acid Therapeutics

DOI 10.1089/nat.2014.0506

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Abstract

Phosphorothioates have found their usefulness in the general area of oligonucleotide therapeutic applications. Initially this modification was introduced into the antisense methodology because of the nuclease resistance of the phosphorothioate linkage in comparison with that of the phosphate linkage. However, as experimental data accumulated, it was detected that this chemical modification also facilitates cellular uptake and bioavailibity in vivo. Thus, today the majority of therapeutic oligonucleotides contain this modification. This review will discuss the historical development of this modification and present some of its chemical properties where they differ from those of the phosphate group. The antisense application will be discussed in the original context with cleavage of the target mRNA, but other target RNAs such as microRNAs and long noncoding RNAs will also be covered. It continues with applications where the target RNA should not be cleaved. A brief presentation of decoy oligonucleotides will be included, as well as some miscellaneous applications. Cellular uptake is a crucial step for oligonucleotides to reach their target and will be briefly reviewed. Lastly, a most surprising recent observation is the presence of phosphorothioate groups in bacterial DNA where functions still remain to be fully determined.

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Authors: Eckstein, F.
Affiliations: Max Planck Society (DE)
Corresponding author: Eckstein, Fritz
Venue: Nucleic Acid Therapeutics
Publisher: SAGE Publications
Published: 2014-12
Volume: 24
Issue: 6
Pages: 374-387
ISSN: 2159-3337 (ISSN-L)
2159-3345
DOI: 10.1089/nat.2014.0506
OpenAlex: W2316132657
Cited by: 684
References: 123
Citations by year: 2026: 69 · 2025: 87 · 2024: 86 · 2023: 75 · 2022: 81 · 2021: 69 · 2020: 64 · 2019: 49 · 2018: 39 · 2017: 25 · 2016: 20 · 2015: 20
FWCI: 2.04
Type: journal article
Language: en
Open access: closed
Licence: journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
Locations: Nucleic Acid Therapeutics (publishedVersion)
PubMed (publishedVersion)
MPG.PuRe (Max Planck Society) (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords: phosphorothioate, oligonucleotide therapeutics, antisense oligonucleotides, nuclease resistance, cellular uptake, bioavailability, microRNA targeting, long non-coding RNA, decoy oligonucleotides, bacterial DNA
MeSH terms: Animals, Humans, Protein Binding, Rabbits, Transcription Factors, Oligonucleotides, Antisense, History, 20th Century, Mice, Phosphorothioate Oligonucleotides

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Phosphorothioates, Essential Components of Therapeutic Oligonucleotides

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