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).