title: Inhibitors of human immunodeficiency virus integrase.
abstract: In an effort to further extend the number of targets for development of antiretroviral agents, we have used an in vitro integrase assay to investigate a variety of chemicals, including topoisomerase inhibitors, antimalarial agents, DNA binders, naphthoquinones, the flavone quercetin, and caffeic acid phenethyl ester as potential human immunodeficiency virus type 1 integrase inhibitors. Our results show that although several topoisomerase inhibitors--including doxorubicin, mitoxantrone, ellipticines, and quercetin--are potent integrase inhibitors, other topoisomerase inhibitors--such as amsacrine, etoposide, teniposide, and camptothecin--are inactive. Other intercalators, such as chloroquine and the bifunctional intercalator ditercalinium, are also active. However, DNA binding does not correlate closely with integrase inhibition. The intercalator 9-aminoacridine and the polyamine DNA minor-groove binders spermine, spermidine, and distamycin have no effect, whereas the non-DNA binders primaquine, 5,8-dihydroxy-1,4-naphthoquinone, and caffeic acid phenethyl ester inhibit the integrase. Caffeic acid phenethyl ester was the only compound that inhibited the integration step to a substantially greater degree than the initial cleavage step of the enzyme. A model of 5,8-dihydroxy-1,4-naphthoquinone interaction with the zinc finger region of the retroviral integrase protein is proposed.
authors.affiliation: Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, MD 20892.
authors.forename: M R
authors.initials: MR
authors.lastname: Fesen
authors.forename: K W
authors.initials: KW
authors.lastname: Kohn
authors.forename: F
authors.initials: F
authors.lastname: Leteurtre
authors.forename: Y
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D004254:DNA Nucleotidyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology*; D019426:Integrases; D007700:Kinetics; D008969:Molecular Sequence Data; D009285:Naphthoquinones / Q000494:pharmacology*; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000903:Antibiotics, Antineoplastic; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D009285:Naphthoquinones; D009838:Oligodeoxyribonucleotides; D011994:Recombinant Proteins; D004254:DNA Nucleotidyltransferases; D019426:Integrases