Dna

FIGURE 10.25 Mechanism of action of antisense oligonucleotides.

The first-generation antisense nucleotides in clinical use are characterized by having one of the phosphate nonbridging oxygens of the phosphodiester linkages replaced by sulfur (10.27). These phosphorothioate (PS) linkages lead to resistance to RNAase H, which slows the degradation of antisense oligonucleotide in the cells. Other common structures are phosphoroamidates (10.28) and phosphorothioami-dates (10.29). Some structural modifications that increase the affinity of antisense molecules for their specific targets are 2'-methoxylation (10.30) and 2'-(2-methoxy) ethoxylation (10.31). Peptide nucleic acids (10.32) are structures in which the antisense bases are connected to various peptide backbones, a structural feature that improves their half-lives and enhances their hybridization properties.

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