Advancements in Oligonucleotide Modifications: Enhancing Stability and Therapeutic Efficacy
Naked oligonucleotides are inherently prone to degradation and exhibit poor drug-like properties. The chemical modification is now one of the most promising ways to make oligonucleotide-based drugs deliver, maintain, and perform. The sugar moiety or the phosphate backbone is changed to improve metabolism and function, increase affinity for protein binding, and delay renal excretion. All the changes confer distinct properties on oligonucleotides, some combinations of which provide customised therapeutics.
What are the Modifications of Oligonucleotides?
First-Generation Modifications: Phosphorothioate Backbone
First-generation oligonucleotide changes mainly addressed the phosphate backbone. Adding a non-bridging oxygen atom instead of a sulphur one gives rise to phosphorothioate (PS) oligonucleotides that are resistant to endonucleases and are more bioavailable by suppressing renal clearance. But those modifications usually decrease target affinity and are associated with increased toxicity. However, despite these restrictions, the PS backbone has become the bedrock of therapeutic oligonucleotides and allowed for FDA-approved medicines such as Fomivirsen.
Second-Generation Modifications: 2'-Sugar Derivatives
Second-generation modifications focus on ribose sugar. Changes at the 2' end - for example, 2'-O-methyl (2'-OMe) and 2'-fluoro (2'-F) - make them more binding-specific to target RNA and also more resistant to nucleases. Conformationally restricted derivatives, including locked nucleic acids (LNA) and tricyclo-DNA (tcDNA), impart rigidity. LNAs are built with a methylene bridge between 2' and 4' carbons, and tcDNAs a cyclopropane ring. These modifications are excellent for binding and thermal stability and are useful in RNA therapeutics.
Third-Generation Modifications: Nucleobase and Backbone Innovations
Advanced nucleotide modifications are about nucleobases and backbones. Phosphorodiamidate morpholino oligomers (PMOs) and peptide nucleic acids (PNAs), for example, dispense with the sugar-phosphate backbone in favour of uncharged units. PMOs have a morpholine ring; PNAs have amide bases. These advances increase nuclease resistance and binding specificity without triggering immune activation. PMO therapies such as Eteplirsen for Duchenne muscular dystrophy, approved by the FDA, point to their clinical promise.
Created: 17 Jul 2025 02:07:54 AM
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