Document 0702
 DOCN  M9590702
 TI    HIV-1 integrase inhibitors: discovery, structure-activity, inhibition
       mechanisms, selectivity.
 DT    9509
 AU    Pommier Y; Mazumder A; Kohn KW; Laboratory of Molecular Pharmacology,
       National Cancer Institute,; NIH, Bethesda, MD
 SO    NIH Conf Retroviral Integrase. 1995 Jan 19-20;:(Session III, speakers'
       abstracts - unpaged). Unique Identifier : AIDSLINE AIDS/95920017
 AB    Several assays can be used to identify HIV-1 integrase inhibitors. We
       are using recombinant HIV-1 integrase and radiolabeled oligonucleotides
       to study various reactions of HIV-1 integrase: DNA binding,
       3'-processing, strand transfer, and disintegration. The disintegration
       reaction offers the advantage of being catalyzed by truncated integrase
       lacking the N-terminus (zinc finger) and the C- terminus (DNA binding)
       regions. Inhibition of the truncated enzyme suggests that the drugs act
       with the catalytic site of HIV-1 integrase. A number of inhibitors have
       been discovered using in vitro assays. They belong to three main
       categories: DNA binders, polyhydroxylated aromatic compounds, and
       nucleotides. Polyhydroxylated aromatic compounds are common in various
       plants. Many derivatives are available as natural or synthetic
       compounds. We have performed structure-activity relationships with
       flavones, lignans, and caffeic acid phenethylester (CAPE) derivatives
       CAPE is a main component of Propolis that bees use to reduce the size of
       the entrance and seal holes in their hives. Some of the synthetic
       derivatives are 10-fold more potent than CAPE and exhibit some activity
       in the anti-AIDS Screen of the National Cancer Institute. Based on drug
       structure and activity against the core HIV-1 integrase, we speculate
       that polyhydroxylated compounds and derivatives of phenanthroline
       cuprous complexes react with the conserved acidic amino acid that
       probably constitute the metal and polynucleotide binding site (DD[35]E).
       A variety of polyhydroxylated compounds from natural source are being
       investigated to discover lead structures with both anti- integrase and
       anti-viral activities. Nucleotides such as AZT-MP also inhibit purified
       HIV-1 integrase probably by binding to the polynucleotide binding site.
       Examples of sugar substituted nucleotides, polynucleotides and analogs
       with greater activity will be discussed. HIV-1 integrase inhibitors with
       antiviral activity are being actively searched as part of the NCI
       Antiviral Program and elsewhere. The combined administration of
       inhibitors of HIV-1 integrase, reverse transcriptase and/or protease may
       reduce the risk of acquired resistance during the treatment of HIV
       infections and AIDS.
 DE    Binding Sites  Catalysis  DNA Nucleotidyltransferases/*ANTAGONISTS &
       INHIB/METABOLISM  DNA, Viral/METABOLISM  Drug Design  Enzyme
       Inhibitors/CHEMISTRY/*PHARMACOLOGY  HIV-1/*ENZYMOLOGY
       Nucleotides/CHEMISTRY/PHARMACOLOGY  Structure-Activity Relationship
       MEETING ABSTRACT

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       protected by Copyright Law (Title 17, U.S.Code).