title: DNA aptamers derived from HIV-1 RNase H inhibitors are strong anti-integrase agents.
abstract: HIV-1 integrase, the retroviral-encoded enzyme involved in the integration of the retrotranscribed viral genome into the host nuclear DNA, is an attractive and still unexploited target. To date, very few inhibitors of this enzyme with a potential therapeutic value have been described. During the search for new HIV-1 targets, we recently described DNA oligodeoxynucleotide aptamers (ODN 93 and ODN 112) that are strong inhibitors of the RNase H activity associated with HIV-1 reverse transcriptase. The striking structural homology between RNase H and integrase led us to study the effect of the RNase H inhibitors on the integrase. Shorter DNA aptamers derived from ODNs 93 and 112 (ODNs 93del and 112del) were able to inhibit HIV-1 integrase in the nanomolar range. They had G-rich sequences able to form G-quartets stabilized by the presence of K(+). The presence of these ions increased the inhibitory efficiency of these agents dramatically. Inhibition of enzymatic activities by ODN 93del and ODN 112del was observed in a cell-free assay system using a recombinant integrase and HIV-1 replication was abolished in infected human cells. Moreover, cell fusion assays showed that these agents do not block viral cell entry at concentrations where viral replication is stopped.
authors.affiliation: UMR 5097, CNRS-Université Victor Segalen Bordeaux 2, 146 rue Léo Saignat, Bordeaux, France.
authors.forename: V R
authors.initials: VR
authors.lastname: de Soultrait
authors.forename: Pierre Yves
authors.initials: PY
authors.lastname: Lozach
authors.forename: Ralf
authors.initials: R
authors.lastname: Altmeyer
authors.forename: L
authors.initials: L
authors.lastname: Tarrago-Litvak
authors.forename: S
authors.initials: S
authors.lastname: Litvak
authors.forename: M L
authors.initials: ML
authors.lastname: Andréola
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D017931:DNA Primers / Q000737:chemistry; D004279:DNA, Viral / Q000737:chemistry*; D015195:Drug Design; D015723:Gene Library; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D016325:HIV Long Terminal Repeat; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D006801:Humans; D008024:Ligands; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D016914:Ribonuclease H / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014162:Transfection; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D017931:DNA Primers; D004279:DNA, Viral; D019428:HIV Integrase Inhibitors; D008024:Ligands; D009838:Oligodeoxyribonucleotides; D011994:Recombinant Proteins; D019427:HIV Integrase; D054303:HIV Reverse Transcriptase; D016914:Ribonuclease H