2-Modified Oligonucleotides for Antisense Therapeutics

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.

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