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Nucleic Acids Research, 1994, Vol. 22, No. 6 977-986
© 1994

MOLECULAR BIOLOGY

Biological availability and nuclease resistance extend the in vitro activity of a phosphorothioate-3'hydroxypropylamine oligonucleotide

Robert C. Tam*, Ying Li, Sarah Noonberg1, David G. Hwang2, Geming Lui2, C.Anthony Hunt1,3 and Marvin R. Garovoy

Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California - San Francisco San Francisco, CA 94143, USA 1Bioengineering Graduate Group, School of Medicine, University of California - San Francisco San Francisco, CA 94143, USA 2Ocular Cell Transplantation Laboratory, Department of Ophthamology, University of California - San Francisco San Francisco, CA 94143, USA 3Departments of Pharmacy and Pharmaceutical Chemistry, University of California - San Francisco San Francisco, CA 94143, USA

*To whom correspondence should be addressed

Received December 23, 1993. Accepted February 11, 1994.

Augmented biological activity in vitro has been demonstrated in ollgonucleotldes (oligos) modified to provide nuclease resistance, to enhance cellular uptake or to increase target affinity. How chemical modification affects the duration of effect of an ollgo with potent activity has not been investigated directly. We postulated that modification with internucleotide phosphorothloates and 3' alkylamine provided additional nuclease protection which could significantly extend the biological activity of a 26 mer, (T2). We showed this analog, sT2a, could maximally inhibit interferon gamma-induced HLA-DR mRNA synthesis and surface expression in both HeLa and retinal pigmented epithelial cells and could continue to be effective, in the absence of oligo, 15 days following initial oligo treatment; an effect not observed with its 3'amine counterpart, T2a. in vitro stability studies confirmed that sT2a conferred the greatest stability to nucleases and that cellular accumulation of 32P-sT2a in both cell types was also greater than other T2 oligos. Using confocal microscopy, we revealed that the intracellular distribution of sT2a favored greater nuclear accumulation and release of oligo from cytoplasmlc vesicles; a pattern not observed with T2a. These results suggest that phosphorothioate-3' amine modification could increase the duration of effect of T2 ollgo by altering nuclease resistance as well as intracellular accumulation and distribution; factors known to affect biological availability.


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