Document 0496
 DOCN  M9490496
 TI    Inhibition of HIV-1 integrase by flavones, caffeic acid phenethyl ester
       (CAPE) and related compounds.
 DT    9411
 AU    Fesen MR; Pommier Y; Leteurtre F; Hiroguchi S; Yung J; Kohn KW;
       Laboratory of Molecular Pharmacology, National Cancer Institute,;
       National Institutes of Health, Bethesda, MD 20892.
 SO    Biochem Pharmacol. 1994 Aug 3;48(3):595-608. Unique Identifier :
       AIDSLINE MED/94347147
 AB    The inhibition of HIV-1 integrase by flavones and related compounds was
       investigated biochemically and by means of structure-activity
       relationships. Purified enzyme and synthetic oligonucleotides were used
       to assay for three reactions catalysed by integrase: (1) processing of
       3' termini by cleavage of the terminal dinucleotide; (2) strand
       transfer, which models the integration step; and (3) disintegration,
       which models the reversal of the strand transfer reaction. Inhibitions
       of all three reactions by flavones generally occurred in parallel, but
       caffeic acid phenethyl ester (CAPE) appeared to inhibit reaction 2
       selectively. CAPE, however, inhibited reactions 1 and 3 effectively when
       preincubated with the enzyme, suggesting that this compound differs from
       the flavones primarily in requiring more time to block the enzyme. The
       core integrase fragment consisting of amino acids 50-212 retained the
       ability to catalyse reaction 3, and flavones and CAPE retained the
       ability to inhibit. Hence, the putative zinc-finger region that is
       deleted in this fragment is probably not the target of inhibition.
       Inhibition by flavones usually required the presence of at least one
       ortho pair of phenolic hydroxyl groups and at least one or two
       additional hydroxyl groups. Potency was enhanced by the presence of
       additional hydroxyl groups, especially when present in ortho pairs or in
       adjacent groups of three. Inhibitory activity was reduced or eliminated
       by methoxy or glycosidic substitutions or by saturation of the 2,3
       double bond. These structure-activity findings for flavones were
       generally concordant with those previously reported for reverse
       transcriptase and topoisomerase II. These findings are discussed in the
       context of a review of the effects of flavones on various enzymes, the
       possible mechanisms of inhibition, and the potential for building upon a
       general pharmacophore to generate target specificity.
 DE    Base Sequence  Caffeic Acids/*PHARMACOLOGY  Cations, Divalent
       Comparative Study  Dose-Response Relationship, Drug  DNA/DRUG EFFECTS
       DNA Nucleotidyltransferases/*ANTAGONISTS & INHIB/GENETICS
       Flavones/*PHARMACOLOGY  HIV-1/*ENZYMOLOGY  Kinetics  Molecular Sequence
       Data  Oligonucleotides/METABOLISM  Phenethyl Alcohol/*ANALOGS &
       DERIVATIVES/PHARMACOLOGY  Structure-Activity Relationship  JOURNAL
       ARTICLE

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