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Updated: Jul 19, 2026
15:22
Nucleoside Triphosphates - From Synthesis to Biochemical Characterization
Published on: April 3, 2014
Building oligonucleotide therapeutics using non-natural chemistries
Charles Wilson1, Anthony D Keefe
1Archemix Corp., 300 Third Street, Cambridge, MA 02142, USA.
Current Opinion in Chemical Biology
|October 20, 2006
Summary
Modified nucleotides enhance therapeutic oligonucleotides, improving resistance and specificity. Fully modified versions are now available for antisense oligonucleotides, siRNA, and aptamers, leading to more drug-like candidates.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Biotechnology
Background:
- Therapeutic oligonucleotides are increasingly incorporating modified nucleotides.
- These modifications aim to enhance properties like nuclease resistance, target affinity, and specificity.
- The tolerance for modifications varies across different oligonucleotide modalities and mechanisms of action.
Purpose of the Study:
- To review the development and application of modified nucleotides in therapeutic oligonucleotides.
- To highlight the successful creation of fully modified oligonucleotides for various therapeutic classes.
- To project future trends in oligonucleotide therapeutics incorporating enhanced drug-like characteristics.
Main Methods:
- Review of existing literature on modified nucleotides in therapeutic oligonucleotides.
- Analysis of reported fully modified oligonucleotide examples, including antisense oligonucleotides, siRNA, and aptamers.
- Discussion of the impact of modifications on oligonucleotide properties and therapeutic potential.
Main Results:
- Fully modified oligonucleotides have been developed for most therapeutic categories.
- Phosphorothioate substitutions are established in antisense oligonucleotides.
- The first fully modified siRNA (2'-O-methyl sense, phosphorothioate antisense) was reported in 2006, and the first fully modified aptamer (2'-O-methyl) in 2005.
Conclusions:
- Modified nucleotides are crucial for advancing therapeutic oligonucleotides.
- The development of fully modified oligonucleotides signifies progress towards more robust and effective therapies.
- Future oligonucleotide therapeutics are expected to possess improved drug-like properties due to continued nucleotide modification research.
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