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J Biol Chem, Vol. 273, Issue 39, 25125-25131, September 25, 1998

Tetranucleotide GGGA Motif in Primary RNA Transcripts
NOVEL TARGET SITE FOR ANTISENSE DESIGN

Guang-chou TuDagger , Qing-na CaoDagger , Feng ZhouDagger , and Yedy IsraelDagger

From the Dagger  Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 and the  Center for Gene Pharmacotherapy, University of Chile, Olivos 1007, Ojicina C-52, Independencia, Santiago, Chile

Selecting effective antisense target sites on a given mRNA molecule constitutes a major problem in antisense therapeutics. By trial-and-error, only 1 in 18 (6%) of antisense oligonucleotides designed to target the primary RNA transcript of tumor necrosis factor-alpha (TNF-alpha ) strongly inhibited TNF-alpha synthesis. Subsequent studies showed that the area in RNA targeted by antisense oligonucleotides could be moved effectively 10-15 bases in either direction from the original area. We observed that only molecules that incorporated a tetranucleotide motif TCCC (complementary to GGGA on RNA) yielded potent antisense oligonucleotides against TNF-alpha . A comprehensive literature survey showed that this motif is unwittingly present in 48% of the most potent antisense oligonucleotides reported in the literature. This finding was prospectively used to predict the sequences of additional antisense oligonucleotides for the rat TNF-alpha primary RNA transcript. Over 50% of antisense constructs (13 of 22) containing the TCCC motif were found to effectively inhibit TNF-alpha synthesis. Marked reductions in mRNA were also observed. This motif was found to be most effective when targeting introns in the primary RNA transcript, suggesting a nuclear localization for the antisense action. Predicting target sites based on the presence of this motif in primary RNA transcripts should be of value in the development on new antisense pharmacotherapy.

Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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