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M9460272.TXT
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1994-06-12
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Document 0272
DOCN M9460272
TI Inhibition of human immunodeficiency virus type 1 activity in vitro by
oligonucleotides composed entirely of guanosine and thymidine.
DT 9408
AU Ojwang J; Elbaggari A; Marshall HB; Jayaraman K; McGrath MS; Rando RF;
Triplex Pharmaceutical Corporation, the Woodlands, Texas 77380.
SO J Acquir Immune Defic Syndr. 1994 Jun;7(6):560-70. Unique Identifier :
AIDSLINE MED/94231460
AB Oligonucleotide compounds composed of only deoxyguanosine and
deoxythymidine were able to significantly inhibit human immunodeficiency
virus type -1 (HIV-1)-induced syncytium formation and virus production
(as measured by p24 core antigen expression) in an acute infection assay
system. The oligonucleotides did not share any homology with or possess
any complementary (antisense) sequence motifs to the HIV-1 genome. The
guanosine/thymidine-containing oligonucleotides (GTOs) that showed this
anti-HIV activity contained natural phosphodiester (PD) linkages
(backbones) between the nucleosides. One of the PD oligonucleotide
sequence motifs tested was capable of inhibiting HIV-1-induced syncytium
formation and p24 production with a median effective dose in culture
(ED50) in the submicromolar range. In addition, oligonucleotides tested
were able to significantly suppress HIV-1 p24 levels > or = 7 days after
removal of the drug from the infected cell culture medium. The growth
inhibition properties (toxicity) of this genre of oligonucleotides was
determined to be well above the ED50 values yielding high selective
indexes. In vitro results showed that GTOs with PD backbones were potent
competitive inhibitors of HIV-1 reverse transcriptase. These same
molecules were capable of blocking the interaction between gp120 and
CD4. All measured activities of these molecules were increased by
factors of 10-500 when the PD backbone was replaced with a PT backbone
in a sequence-dependent manner. The enhanced antiviral activity
displayed by the sulfur group on the oligonucleotide backbone and the
lack of any sequence-specific interactions suggest that a percentage of
antiviral activity of oligonucleotide-based therapeutics is due to
mechanisms other than those originally postulated for oligonucleotides.
The good selective index of GTOs coupled with the prolonged suppression
of HIV-1 in culture after removal of oligonucleotides from the infected
cell culture make this a class of compounds that warrant investigation
as therapeutic agents to be used against HIV-1.
DE Animal Antibodies, Monoclonal/IMMUNOLOGY Antigens, CD4/IMMUNOLOGY
Base Sequence Binding, Competitive Cell Division/DRUG EFFECTS Cell
Line Giant Cells/DRUG EFFECTS Guanosine/*CHEMISTRY Human HIV Core
Protein p24/BIOSYNTHESIS/DRUG EFFECTS HIV Envelope Protein
gp120/IMMUNOLOGY HIV-1/*DRUG EFFECTS/IMMUNOLOGY/PHYSIOLOGY Molecular
Sequence Data Oligonucleotides/CHEMISTRY/*PHARMACOLOGY Peptide
Fragments/IMMUNOLOGY Reverse Transcriptase/ANTAGONISTS & INHIB
Thymidine/*CHEMISTRY Vero Cells JOURNAL ARTICLE
SOURCE: National Library of Medicine. NOTICE: This material may be
protected by Copyright Law (Title 17, U.S.Code).