ANTISENSE OLIGONUCLEOTIDE PHOSPHOROTHIOATES AGAINST HUMAN IMMUNODEFICIENCY VIRUS

Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.

ANTISENSE OLIGONUCLEOTIDE PHOSPHOROTHIOATES AGAINST HUMAN IMMUNODEFICIENCY VIRUS

Int J Immunotherapy; 6(4):187-91 1990. Unique Identifier : AIDSLINE ICDB/92678554
Zon G; Matsukura M; Applied Biosystems, Inc., 850 Lincoln Centre Dr., Foster City, CA; 94404

Abstract: Various types of antisense oligonucleotide constructs were synthesized for screening against human immunodeficiency virus (HIV) in two different cell culture assays. Nuclease-resistant internucleoside linkages that were studied included nonionic methyl phosphonates (5'O-P[O]CH3-O3') and, primarily, negatively charged phosphorothioates (5'O-P[O]S-O3'). Previously reported results, which had been obtained in a de novo infection assay that measured inhibition of the cytopathic effect of HIV-1, revealed an unexpected sequence-nonspecific antiviral effect for phosphorothioate oligomers. The mechanistic basis for this potent antiviral activity (100% at 0.5-1 uM) is not clearly established at this time. In contrast, the companion results derived from a chronically HIV-1-infected cell assay indicated that phosphorothioate oligomers directed against HIV-1 rev RNA also exhibit sequence-specific inhibition of gene expression, albeit at higher concentrations in this system (50% at 5 uM) relative to the de novo infection assay. More recently, alternative targets in HIV-1 RNA, and alternative types of modified oligomers, were examined but none of these had significantly higher activity then the anti-rev phosphorothioate sequence previously reported. Collaborative studies have been directed at the first pharmacokinetic measurements using fluorescently and radioactively (35S)-labeled versions of the anti-rev phosphorothioate. Efforts are underway to achieve relatively low-cost large-scale synthesis of this antisense oligonucleotide phosphorothioate as a prelude for clinical trials against acquired immunodeficiency syndrome. (21 Refs)

Keywords: Antiviral Agents/CHEMICAL SYNTHESIS/*PHARMACOLOGY Base Sequence Genes, rev HIV-1/*DRUG EFFECTS/GENETICS Molecular Sequence Data Oligonucleotides, Antisense/CHEMICAL SYNTHESIS/*PHARMACOLOGY Phosphonic Acids/CHEMICAL SYNTHESIS/PHARMACOLOGY RNA, Viral/GENETICS Thionucleotides/CHEMICAL SYNTHESIS/*PHARMACOLOGY JOURNAL ARTICLE
920430
M9240948

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