Abstract
Chemically modified antisense oligonucleotides are currently progressing in multiple clinical trials. Among several chemical modifications made, modification of the 2-position has proved most successful. Second generation antisense oligonucleotides incorporating these 2-modifications exhibit high binding affinity to target RNA, enhanced metabolic stability, and improved pharmacokinetic and toxicity profiles. This is, in part, due to the enhanced biophysical properties of second generation antisense oligonucleotides. 2-Modifications that influence the sugar to adopt a 3-endo sugar pucker can improve properties such as affinity. 2- Modifications that provide a gauche effect and/or a charge effect can play a significant role in the level of nuclease resistance. The heterocyclic base modifications such as 2-thiothymine provides additive effect on the affinity of 2-F and 2-O-MOE modifications. This review summarizes the structural and biophysical properties of selected 2-modified nucleosides which are candidates for use in oligonucleotide theraputics.
Keywords: RNase H enzyme, DNA decamer duplex, RNA affinity, arabino nucleic acids, antisense oligonucleotides
Current Topics in Medicinal Chemistry
Title: 2-Modified Oligonucleotides for Antisense Therapeutics
Volume: 7 Issue: 7
Author(s): Thazha P. Prakash and Balkrishen Bhat
Affiliation:
Keywords: RNase H enzyme, DNA decamer duplex, RNA affinity, arabino nucleic acids, antisense oligonucleotides
Abstract: Chemically modified antisense oligonucleotides are currently progressing in multiple clinical trials. Among several chemical modifications made, modification of the 2-position has proved most successful. Second generation antisense oligonucleotides incorporating these 2-modifications exhibit high binding affinity to target RNA, enhanced metabolic stability, and improved pharmacokinetic and toxicity profiles. This is, in part, due to the enhanced biophysical properties of second generation antisense oligonucleotides. 2-Modifications that influence the sugar to adopt a 3-endo sugar pucker can improve properties such as affinity. 2- Modifications that provide a gauche effect and/or a charge effect can play a significant role in the level of nuclease resistance. The heterocyclic base modifications such as 2-thiothymine provides additive effect on the affinity of 2-F and 2-O-MOE modifications. This review summarizes the structural and biophysical properties of selected 2-modified nucleosides which are candidates for use in oligonucleotide theraputics.
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Cite this article as:
Prakash P. Thazha and Bhat Balkrishen, 2-Modified Oligonucleotides for Antisense Therapeutics, Current Topics in Medicinal Chemistry 2007; 7 (7) . https://dx.doi.org/10.2174/156802607780487713
DOI https://dx.doi.org/10.2174/156802607780487713 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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