title: Effects of diterpenes isolated from the Brazilian marine alga Dictyota menstrualis on HIV-1 reverse transcriptase.
abstract: It has been recently demonstrated that HIV-1 reverse transcriptase is the target of two diterpenes, (6 R)-6-hydroxydichotoma-3,14-diene-1,17-dial (compound 1) and (6 R)-6-acetoxydichotoma-3,14-diene-1,17-dial (compound 2), that inhibit HIV-1 replication in vitro. In this work, the effects of both diterpenes on the kinetic properties of the recombinant HIV-1 reverse transcriptase (RT) enzyme were evaluated. RNA-dependent DNA-polymerase (RDDP) activity assays demonstrated that both diterpenes behave as non-competitive inhibitors with respect to dTTP and uncompetitive inhibitors with respect to poly(rA).oligo(dT) template primers. The K(i) values obtained for compounds 1 and 2 were 10 and 35 microM, respectively. Neither of these diterpenes affected the DNA-dependent DNA-polymerase (DDDP) activity of the HIV-1 RT. The RDDP activities of AMV-RT and MMLV-RT enzymes were also inhibited by compounds 1 and 2. In contrast to the HIV-1 enzyme, the DDDP activities of AMV-RT and MMLV-RT enzymes were significantly reduced by compound 1. Taken together, our results demonstrate that compound 1 is a more effective inhibitor of the viral reverse transcriptases from HIV-1, AMV and MMLV than compound 2. The kinetic behavior analyses of the HIV-1 RT demonstrate that both diterpenes have similar mechanisms of inhibition of RDDP activity.
authors.affiliation: Departamento de Biologia Celular e Molecular/Programa de Neuroimunologia, Instituto de Biologia, Universidade Federal Fluminense, Niterói - RJ, Brasil. helena@biologia.ufrj.br
authors.forename: Helena
authors.initials: H
authors.lastname: de Souza Pereira
authors.forename: Luiz Roberto
authors.initials: LR
authors.lastname: Leão-Ferreira
authors.forename: Nissin
authors.initials: N
authors.lastname: Moussatché
authors.forename: Valéria Laneuville
authors.initials: VL
authors.lastname: Teixeira
authors.forename: Diana Negrão
authors.initials: DN
authors.lastname: Cavalcanti
authors.forename: Luciana Jesus
authors.initials: LJ
authors.lastname: da Costa
authors.forename: Ricardo
authors.initials: R
authors.lastname: Diaz
authors.forename: Izabel Christina
authors.initials: IC
authors.lastname: Frugulhetti
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D009189:Avian Myeloblastosis Virus / Q000201:enzymology; D004259:DNA-Directed DNA Polymerase / Q000187:drug effects; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000187:drug effects* / Q000235:genetics; D008979:Moloney murine leukemia virus / Q000201:enzymology; D000459:Phaeophyceae / Q000737:chemistry*; D012194:RNA-Directed DNA Polymerase / Q000187:drug effects; D011994:Recombinant Proteins / Q000187:drug effects; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D014764:Viral Proteins / Q000187:drug effects
chemical_list: C507328:(6 R)-6-acetoxydichotoma-3,14-diene-1,17-dial; C507327:(6 R)-6-hydroxydichotoma-3,14-diene-1,17-dial; D019380:Anti-HIV Agents; D004224:Diterpenes; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; D014764:Viral Proteins; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase; D004259:DNA-Directed DNA Polymerase