Advances in Pharmacology by J. Thomas August (Eds.) PDF

By J. Thomas August (Eds.)

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1. Nuclease Stability The principal metabolic pathway for oligonucleotides is cleavage via endonucleases and exonucleases. , 1991; S . T. , 1995). Consequently, the stability of phosphorothioate oligonucleotides to nucleases is probably less than initially thought, as high concentrations (that inhibited nucleases) of oligonucleotides were employed in the early studies. , 1991; S . T. , 1993). The pattern of metabolites suggests primarily exonuclease activity with perhaps modest contributions by endonucleases.

T. , 1995). Again, the oligonucleotides appear to be competitive antagonists for the DNA-RNA substrate. , 1991). , 1991; S. T. , 1995). In our laboratories, we have shown extensions of 2-3 nucleotides only. At present, a full explanation as to why no longer extensions are observed is not available. , 1991). , 1991), and to protein kinase C. Various viral polymerases have also been shown to be inhibited by phosphorothioates (for review, see Stein and Cheng, 1993). In addition, we have shown potent, non-sequence-specific inhibition of RNA splicing by phosphorothioates (Hodges and Crooke, 1995).

Introduction The core of any rational drug discovery program is medicinal chemistry. Although the synthesis of modified nucleic acids has been a subject of interest for some time, the intense focus on the medicinal chemistry of oligonucleotides dates perhaps to no more than 5 years prior to the publication of this chapter. Consequently, the scope of medicinal chemistry has expanded enormously, but the biological data to support conclusions about synthetic strategies are only beginning to emerge.

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