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Correlation of activity with stability of chemically modified ribozymes in nuclei suspension

Lookup NU author(s): Professor Olaf Heidenreich


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To examine hammerhead ribozyme activity in the nuclear environment, we have used nuclei isolated from HTLV-I tax transformed fibroblasts to evaluate ribozymes targeted against HTLV-I tax RNA. The ribozyme activity in nuclei suspension was strongly dependent on the resistance of the particular ribozyme to endogenous nucleases. A ribozyme containing exclusively 2'-deoxynucleotides in its stems cleaved target RNA by its catalytic activity in the absence of proteins and caused degradation in their presence by induction of nuclear RNase H activity. A ribozyme containing 2'-amino- and 2'-fluoropyrimidine nucleosides in combination with terminal phosphorothioate linkages was significantly more stable in nuclei suspension and also exhibited a more than threefold higher cleavage efficacy than its unmodified counterpart. The increased resistance against nuclease degradation is mainly due to terminal phosphorothioate linkages, suggesting that both 5' and 3'-exonucleases are primarily responsible for the nuclear degradation of oligonucleotides.

Publication metadata

Author(s): Heidenreich O, Xu X, Swiderski P, Rossi JJ, Nerenberg M

Publication type: Article

Publication status: Published

Journal: Antisense and Nucleic Acid Drug Development

Year: 1996

Volume: 6

Issue: 2

Pages: 111-118

ISSN (print): 1545-4576

ISSN (electronic): 1557-8526