Document 0930
 DOCN  M9540930
 TI    Suppression of human immunodeficiency virus type 1 activity in vitro by
       oligonucleotides which form intramolecular tetrads.
 DT    9504
 AU    Rando RF; Ojwang J; Elbaggari A; Reyes GR; Tinder R; McGrath MS; Hogan
       ME; Triplex Pharmaceutical Corp., Woodlands, Texas 77380.
 SO    J Biol Chem. 1995 Jan 27;270(4):1754-60. Unique Identifier : AIDSLINE
       MED/95130555
 AB    An oligonucleotide (I100-15) composed of only deoxyguanosine and
       thymidine was able to inhibit human immunodeficiency virus type-1
       (HIV-1) in culture assay systems. I100-15 did not block virus entry into
       cells but did reduce viral-specific transcripts. As assessed by NMR and
       polyacrylamide gel methods, I100-15 appears to form a structure in which
       two stacked guanosine tetrads are connected by three two-base long
       loops. Structure/activity experiments indicated that formation of
       intramolecular guanosine tetrads was necessary to achieve maximum
       antiviral activity. The single deoxyguanosine nucleotide present in each
       loop was found to be extremely important for the overall antiviral
       activity. The toxicity of I100-15 was determined to be well above the
       50% effective dose (ED50) in culture which yielded a high therapeutic
       index (> 100). The addition of a cholesterol moiety to the 3' terminus
       of I100-15 (I100-23) reduced the ED50 value to less than 50 nM (from
       0.12 microM for I100-15) and increased the duration of viral suppression
       to greater than 21 days (versus 7-10 days for I100-15) after removal of
       the drug from infected cell cultures. The favorable therapeutic index of
       such molecules coupled with the prolonged suppression of HIV-1, suggest
       that such compounds further warrant investigation as potential
       therapeutic agents.
 DE    Animal  Antiviral Agents/CHEMISTRY/CHEMICAL SYNTHESIS/*PHARMACOLOGY
       Base Sequence  Cell Survival/*DRUG EFFECTS  Cercopithecus aethiops
       Comparative Study  Electrophoresis, Polyacrylamide Gel  HIV-1/*DRUG
       EFFECTS/PHYSIOLOGY  Kinetics  Mice  Models, Molecular  Molecular
       Sequence Data  Nuclear Magnetic Resonance  *Nucleic Acid Conformation
       Nucleic Acid Denaturation  Oligodeoxyribonucleotides/CHEMISTRY/CHEMICAL
       SYNTHESIS/  *PHARMACOLOGY  Structure-Activity Relationship
       Thionucleotides  Time Factors  Transcription, Genetic/DRUG EFFECTS  Vero
       Cells  Virus Replication/*DRUG EFFECTS  3T3 Cells  JOURNAL ARTICLE

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