ASODN Design

Unmodified DNA oligonucleotides are either poorly taken up or rapidly degraded by serum and cell-associated nucleases. To prevent this, phosphor-

othioate oligonucleotides (P-ODNs) approx 16-18 bases long in which one of the nonbridging oxygen atoms in the nucleotide is replaced with sulfur provide protection from nuclease degradation without significantly interfering with RNase H activity. 2'-Methoxy-ethoxy modifications in the first and last four or five nucleotides flanking the central region, in combination with the phosphorothioate backbone, further increase resistance to nucleases and affinity of the oligonucleotide for an accessible target sequence in mRNA (5). In addition to the methoxy-ethoxy and phosphorothioate modification, which decreases susceptibility to degradation, specificity is a major issue. The limited length of the AS-ODN is chosen to have both selectivity and potency. A short oligonucleotide of <15 bases may be more selective but show low efficacy.

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