Document 0791
 DOCN  M9650791
 TI    T30177, an oligonucleotide stabilized by an intramolecular guanosine
       octet, is a potent inhibitor of laboratory strains and clinical isolates
       of human immunodeficiency virus type 1.
 DT    9605
 AU    Ojwang JO; Buckheit RW; Pommier Y; Mazumder A; De Vreese K; Este JA;
       Reymen D; Pallansch LA; Lackman-Smith C; Wallace TL; et al; Triplex
       Pharmaceutical Corporation, The Woodlands, Texas 77380,; USA.
 SO    Antimicrob Agents Chemother. 1995 Nov;39(11):2426-35. Unique Identifier
       : AIDSLINE MED/96139534
 AB    T30177, an oligonucleotide composed of only deoxyguanosine and
       thymidine, is 17 nucleotides in length and contains single
       phosphorothioate internucleoside linkages at its 5' and 3' ends for
       stability. This oligonucleotide does not share significant primary
       sequence homology with or possess any complementary (antisense) sequence
       motifs to the human immunodeficiency virus type 1 (HIV-1) genome. T30177
       inhibited replication of multiple laboratory strains of HIV-1 in human
       T-cell lines, peripheral blood lymphocytes, and macrophages. T30177 was
       also found to be capable of inhibiting multiple clinical isolates of
       HIV-1 and preventing the cytopathic effect of HIV-1 in primary CD4+ T
       lymphocytes. In assays with human peripheral blood lymphocytes there was
       no observable toxicity associated with T30177 at the highest
       concentration tested (100 microM), while the median inhibitory
       concentration was determined to be in the range of 0.1 to 1.0 microM for
       the clinical isolates tested, resulting in a high therapeutic index for
       this drug. In temporal studies, the kinetics of addition of T30177 to
       infected cell cultures indicated that, like the known viral adsorption
       blocking agents dextran sulfate and Chicago sky blue, T30177 needed to
       be added to cells during or very soon after viral infection. However,
       analysis of nucleic acids extracted at 12 h postinfection from cells
       treated with T30177 at the time of virus infection established the
       presence of unintegrated viral cDNA, including circular proviral DNA, in
       the treated cells. In vitro analysis of viral enzymes revealed that
       T30177 was a potent inhibitor of HIV-1 integrase, reducing enzymatic
       activity by 50% at concentrations in the range of 0.050 to 0.09 microM.
       T30177 was also able to inhibit viral reverse transcriptase activity;
       however, the 50% inhibitory value obtained was in the range of 1 to 10
       microM, depending on the template used in the enzymatic assay. No
       observable inhibition of viral protease was detected at the highest
       concentration of T30177 used (10 microM). In experiments in which T30177
       was removed from infected cell cultures at 4 days post-HIV-1 infection,
       total suppression of virus production was observed for more than 27
       days. PCR analysis of DNA extracted from cells treated in this fashion
       was unable to detect the presence of viral DNA 11 days after removal of
       the drug from the infected cell cultures. The ability of T30177 to
       inhibit both laboratory and clinical isolates of HIV-1 and the
       experimental data which suggest that T30177 represents a novel class of
       integrase inhibitors indicate that this compound is a viable candidate
       for evaluation as a therapeutic agent against HIV-1 in humans.
 DE    Antiviral Agents/*PHARMACOLOGY  Base Sequence  Cell Fusion/DRUG EFFECTS
       Cell Line  Cell Survival/DRUG EFFECTS  Cells, Cultured  DNA
       Nucleotidyltransferases/ANTAGONISTS & INHIB  DNA, Viral/BIOSYNTHESIS
       Flow Cytometry  Human  HIV Infections/*VIROLOGY  HIV-1/*DRUG
       EFFECTS/ENZYMOLOGY/PHYSIOLOGY  Lymphocytes/DRUG EFFECTS/VIROLOGY
       Macrophages/VIROLOGY  Molecular Sequence Data
       Oligonucleotides/*PHARMACOLOGY  Reverse Transcriptase
       Inhibitors/PHARMACOLOGY  T-Lymphocyte Subsets/VIROLOGY  Virus
       Replication/DRUG EFFECTS  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).