Nuclease-resistant composite 2',5'-oligoadenylate-3', 5'-oligonucleotides for the targeted destruction of RNA: 2-5A-iso-antisense

Journal of Medicinal Chemistry
W XiaoP F Torrence

Abstract

A new modification of 2-5A-antisense, 2-5A-iso-antisense, has been developed based on a reversal of the direction of the polarity of the antisense domain of a 2-5A-antisense composite nucleic acid. This modification was able to anneal with its target RNA as well as the parental 2-5A-antisense chimera. The 2-5A-iso-antisense oligonucleotide displayed enhanced resistance to degradation by 3'-exonuclease enzyme activity such as that represented by snake venom phosphodiesterase and by that found in human serum. 2-5A-Iso-antisense was able to effect the degradation of a synthetic nontargeted substrate, [5'-32P]pC11U2C7, and two targeted RNAs, PKR and BCR mRNAs, in a cell-free system containing purified recombinant human 2-5A-dependent RNase L. These results demonstrated that the novel structural modification represented by 2-5A-iso-antisense provided a stabilized biologically active formulation of the 2-5A-antisense strategy.

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Citations

Oct 11, 2003·Pharmacology & Therapeutics·Dhananjaya V Kalvakolanu
May 12, 2000·Biochimica Et Biophysica Acta·B F Baker, B P Monia
Apr 17, 1999·Bioorganic & Medicinal Chemistry Letters·M R Player, P F Torrence
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Oct 24, 2001·The Journal of Organic Chemistry·Xian-Bin YangMichal W. Wieczorek

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