Phosphorothioate oligonucleotides nuclease stability

Because the gut has a very high level of nucleases contributed by both the host and bacteria resident in the GI tract, metabolism of phosphorothioate oligodeoxynucleotides in the gut occurs much too rapidly to support adequate oral bioavailability (370). Chimeric modifications of the oligonucleotides have beai shown to enhance stability and oral bioavailability (328,371). With the development of2 -0-MOE phosphorothioates, oral bioavailability is potentially feasible (215). 

Figure 8.7 Modification of oligonucleotides to increase stability, (a) Oligonucleotides (here shown as DNA) with a phosphodiester backbone (X = 0) are rapidly degraded by nucleases. Modification to create phosphorothioate analogs (X = S ) greatly increases half-life, (b) Peptide nucleic acids represent another DNA analog that can be used to bind with complementary sequences of oligonucleotides. Dashed lines represent hydrogen bonding which follows Watson-Crick base pairs.

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