Document 0181
 DOCN  M9460181
 TI    3,5,8-Trihydroxy-4-quinolone, a novel natural inhibitor of the reverse
       transcriptases of human immunodeficiency viruses type 1 and type 2.
 DT    9404
 AU    Loya S; Rudi A; Tal R; Kashman Y; Loya Y; Hizi A; Department of Cell
       Biology and Histology, Sackler School of; Medicine, Tel Aviv, Israel.
 SO    Arch Biochem Biophys. 1994 Mar;309(2):315-22. Unique Identifier :
       AIDSLINE MED/94182946
 AB    The natural product of the Red Sea sponge Verongia sp., identified as
       3,5,8-trihydroxy-4-quinolone, was found to be a potent inhibitor of the
       RNA-directed DNA synthesis of the reverse transcriptases (RTs) of human
       immunodeficiency viruses type 1 and type 2 (HIV-1 and HIV-2,
       respectively). This inhibition was unaffected by the nature of the
       primer template used for DNA synthesis. The DNA-dependent DNA polymerase
       activity was inhibited to a lesser extent, whereas the ribonuclease H
       (RNase H) function associated with both HIV RTs was only slightly
       inhibited. The inhibition by the trihydroxyquinolone is reversible and
       noncompetitive with respect to both substrates--dTTP and the template
       primer poly(rA)n.oligo(dT)12-18. The inhibitor binds HIV-1 RT with a
       high affinity (Ki = 0.46 microM). This compound was shown also to
       inhibit the catalytic activities of the RT of murine leukemia virus,
       establishing the general inhibitory effect on retroviral RTs.
       Introductions of acetyl or methoxy moieties at positions with potential
       activity have generated three synthetic analogs of the natural compound.
       Only one analog, 5,8-dimethoxy-4-quinolone, exhibited an inhibition
       potency similar to that of the unmodified compound. Analysis of the
       three analogs has led us to the conclusion that the hydroxyl group at
       the ortho position to the carbonyl group in the pyridinone ring is a key
       structural element for the inhibitory activity. Thus, it could well be
       that the inhibitor interacts with the enzyme through a hydrogen bond of
       this hydroxyl group. We hope that the identification of the inhibitory
       site of the compound might be an important step toward the rational
       design of new potent anti-HIV RT drugs.
 DE    Animal  DNA Polymerases/ANTAGONISTS & INHIB  Hydrogen Bonding
       HIV-1/*ENZYMOLOGY  HIV-2/*ENZYMOLOGY  Kinetics  Leucine Zippers
       Leukemia Viruses, Murine/ENZYMOLOGY  Molecular Structure
       Oligodeoxyribonucleotides/METABOLISM  Poly A/METABOLISM
       Porifera/METABOLISM  Quinolones/CHEMISTRY/*PHARMACOLOGY  Reverse
       Transcriptase/*ANTAGONISTS & INHIB/METABOLISM  Ribonuclease H, Calf
       Thymus/ANTAGONISTS & INHIB  Structure-Activity Relationship  Support,
       U.S. Gov't, P.H.S.  Templates  Thymine Nucleotides/METABOLISM  JOURNAL
       ARTICLE

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