RESUMO
HIV-1 infection is a global epidemic whose treatment is limited majorly by viral resistance and adverse effects. Natural products from algae have been studied for many years, including antiviral, being an alternative to anti-HIV drug design. Since the isolation of natural products can be a hurdle, molecular modeling is an important tool to study these compounds. Herein, structure-activity relationship, molecular docking, and molecular dynamic studies were performed to direct the studies of ten marine natural products with anti-HIV activity. In the structure-activity relationship, descriptors were identified associating the anti-HIV activity of five diterpenes with possible action on the reverse transcriptase allosteric site. These diterpenes were evaluated by molecular docking, and it was identified that only dolabelladienetriol interacted in the allosteric site. Molecular dynamics suggested that the dolabelladienetriol might interfere with the viral RNA binding to HIV-1 RT by inducing a conformational change of the enzyme. Also, in silico ADMET simulations predicts that the dolabelladienetriol present a high potential to be successfully developed as a drug. Thus, applying in silico approaches was possible to suggest potential anti-HIV compounds derived from marine natural products.Communicated by Ramaswamy H. Sarma.
Assuntos
Fármacos Anti-HIV , Produtos Biológicos , Diterpenos , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Produtos Biológicos/farmacologia , Diterpenos/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade , Relação Estrutura-AtividadeRESUMO
The antiviral effect of the CH(2)Cl(2)/MeOH-soluble fraction from the alga Dictyota menstrualis on HIV-1 replication was evaluated in vitro. The antiretroviral activity was attributed to two diterpenes: (6R)-6-hydroxydichotoma-3,14-diene-1,17-dial, named Da-1, and (6R)-6-acetoxi-dichotoma-3,14-diene-1,17-dial, named AcDa-1. Da-1 or AcDa-1 were added to the culture medium of HIV-1-infected PM-1 cells at different times post-infection or during virus adsorption/penetration. The results indicated that the compounds affected an early step of the virus replicative cycle. Virus binding and entry into the host cells were evaluated in the presence of each diterpene, but no inhibitory effect was observed. To evaluate provirus DNA synthesis/integration into the host genome, the viral protease coding sequence was amplified from total cellular DNA. Proviral DNA was not detected in infected cells incubated with the diterpenes. To investigate the effect of the diterpenes on the reverse transcription of the viral genomic RNA, the recombinant HIV-1 reverse transcriptase (RT) was assayed in vitro in the presence of each diterpene. Da-1 and AcDa-1 inhibited the RNA-dependent DNA-polymerase activity of HIV-1 RT in a dose-dependent manner. Taken together, our results demonstrate that both diterpenes inhibit HIV-1 RT and consequently virus replication.
Assuntos
Fármacos Anti-HIV/isolamento & purificação , Fármacos Anti-HIV/farmacologia , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , HIV-1/efeitos dos fármacos , Phaeophyceae/química , Adsorção , Fármacos Anti-HIV/química , Brasil , Linhagem Celular , DNA Viral/biossíntese , Diterpenos/química , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/fisiologia , Humanos , Estrutura Molecular , Provírus/efeitos dos fármacos , Provírus/fisiologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/isolamento & purificação , Inibidores da Transcriptase Reversa/farmacologia , Replicação Viral/efeitos dos fármacosRESUMO
Laboratory and field experiments were performed to assess the ecological roles of natural products produced by the Brazilian red seaweed Laurencia obtusa. Laboratory assays revealed that the natural concentration of the crude organic extract of L. obtusa significantly inhibited feeding by two herbivores: the crab Pachygrapsus transversus and the sea urchin Lytechinus variegatus. It was verified that this chemically defensive action was due to halogenated sesquiterpenoid elatol, found to be the major natural product of this red seaweed. In addition, it was verified that the antifouling property of the chemicals produced by L. obtusa could make this red alga less attractive for fish grazing. Direct protection against two herbivore species and indirect protection against herbivory by fouling inibition constitute evidence that the major natural product from Brazilian L. obtusa plays multiple environmental roles, thereby increasing the adaptive value of these metabolites. On the other hand, the evidence reinforces the idea that marine natural products may have different functions in the sea.
Assuntos
Animais , Alga Marinha , Adaptação Fisiológica , Brasil , Ecossistema , Ouriços-do-MarRESUMO
Laboratory and field experiments were performed to assess the ecological roles of natural products produced by the Brazilian red seaweed Laurencia obtusa. Laboratory assays revealed that the natural concentration of the crude organic extract of L. obtusa significantly inhibited feeding by two herbivores: the crab Pachygrapsus transversus and the sea urchin Lytechinus variegatus. It was verified that this chemically defensive action was due to halogenated sesquiterpenoid elatol, found to be the major natural product of this red seaweed. In addition, it was verified that the antifouling property of the chemicals produced by L. obtusa could make this red alga less attractive for fish grazing. Direct protection against two herbivore species and indirect protection against herbivory by fouling inibition constitute evidence that the major natural product from Brazilian L. obtusa plays multiple environmental roles, thereby increasing the adaptive value of these metabolites. On the other hand, the evidence reinforces the idea that marine natural products may have different functions in the sea.
Assuntos
Laurencia/química , Alga Marinha/química , Adaptação Fisiológica , Animais , Brasil , Decápodes/efeitos dos fármacos , Ecossistema , Ouriços-do-Mar/efeitos dos fármacosRESUMO
Seaweed preference by the Brazilian endemic gastropod Astraea latispina was examined in the laboratory to evaluate the role of secondary metabolites in determining food choice. Of three species of seaweeds examined, Plocamium brasiliense was highly preferred; less so were Sargassum furcatum and Dictyota cervicornis were preferred less. Extracts and/or pure major metabolites of the two potentially chemically-defended seaweeds (P. brasiliense and D. cervicornis) were tested as feeding deterrents against A. latispina. Algal extract assays demonstrated that three concentrations of crude organic extract of the red alga P. brasiliense (50%, 100%: natural concentration, and 200% of dry weight: dw) did not affect feeding of this gastropod. In contrast, the three concentrations of crude organic extract of the brown alga D. cervicornis (50%, 100% and 200% dw) inhibited feeding by A. latispina. The chemical deterrent property of D. cervicornis extract against the gastropod A. latispina occurred due to a mixture of the secodolastane diterpenes isolinearol/linearol (4:1--0.08% dry weight). This is the first report showing that Dictyota cervicornis produces a chemical defense against herbivores using secodolastane diterpenoid. In addition, these results widen the action spectrum of secondary metabolites found in seaweed belonging to this brown algal genus.
Assuntos
Preferências Alimentares/fisiologia , Moluscos/fisiologia , Alga Marinha/química , Animais , Brasil , Comportamento Alimentar , Extratos VegetaisRESUMO
Seaweed preference by the Brazilian endemic gastropod Astraea latispina was examined in the laboratory to evaluate the role of secondary metabolites in determining food choice. Of three species of seaweeds examined, Plocamium brasiliense was highly preferred; less so were Sargassum furcatum and Dictyota cervicornis were preferred less. Extracts and/or pure major metabolites of the two potentially chemically-defended seaweeds (P. brasiliense and D. cervicornis) were tested as feeding deterrents against A. latispina. Algal extract assays demonstrated that three concentrations of crude organic extract of the red alga P. brasiliense (50 percent, 100 percent: natural concentration, and 200 percent of dry weight: dw) did not affect feeding of this gastropod. In contrast, the three concentrations of crude organic extract of the brown alga D. cervicornis (50 percent, 100 percent and 200 percent dw) inhibited feeding by A. latispina. The chemical deterrent property of D. cervicornis extract against the gastropod A. latispina occurred due to a mixture of the secodolastane diterpenes isolinearol/linearol (4:1 -- 0.08 percent dry weight). This is the first report showing that Dictyota cervicornis produces a chemical defense against herbivores using secodolastane diterpenoid. In addition, these results widen the action spectrum of secondary metabolites found in seaweed belonging to this brown algal genus
Assuntos
Animais , Preferências Alimentares , Moluscos , Alga Marinha , Brasil , Comportamento Alimentar , Extratos VegetaisRESUMO
Recent studies have show that small marine herbivores with limited mobility (mesograzers) often feed on macroalgae chemically defended against fishes or sea-urchins. In order to verify the involved mechanisms of chemotaxis or chemical defense into this process in Brazilian littoral, two species of brown alga Dictyota menstrualis and Dictyota mertensii were studied against the limited mobility herbivores, the amphipod Parhyale hawaiensis and the crab Pachygrapsus transversus. These two species were studied in order to verify the action of their crude extracts in the defense and chemotaxis processes related to limited mobility of these herbivores. Feeding preference assays revealed that P. hawaiensis do not eaten these Dictyota species. P. transversus do not eaten D. menstrualis either, but consumed large amounts of D. mertensii. Chemical deterrence assays showed that extracts of these species act as feeding deterrent to both species of herbivores. In addition, chemotaxis assays demonstrated that both herbivores are significantly negative chemotactic probably due to the presence of complementary metabolites into artificial foods. Considering that both Dictyota species exhibit active extracts against these small herbivores, we suppose that the non-occurrence of these herbivore species in close relationship with the seaweeds D. menstrualis and D. mertensii may explain the defense action of both extracts related to these mesograzers
Assuntos
Animais , Braquiúros , Fatores Quimiotáticos , Quimiotaxia/fisiologia , Comportamento Alimentar/efeitos dos fármacos , Extratos Vegetais/farmacologia , Alga Marinha/química , Análise de Variância , Estudos de Casos e Controles , Mecanismos de DefesaRESUMO
Recent studies have show that small marine herbivores with limited mobility (mesograzers) often feed on macroalgae chemically defended against fishes or sea-urchins. In order to verify the involved mechanisms of chemotaxis or chemical defense into this process in Brazilian littoral, two species of brown alga Dictyota menstrualis and Dictyota mertensii were studied against the limited mobility herbivores, the amphipod Parhyale hawaiensis and the crab Pachygrapsus transversus. These two species were studied in order to verify the action of their crude extracts in the defense and chemotaxis processes related to limited mobility of these herbivores. Feeding preference assays revealed that P. hawaiensis do not eaten these Dictyota species. P. transversus do not eaten D. menstrualis either, but consumed large amounts of D. mertensii. Chemical deterrent assays showed that extracts of these species act as feeding deterrent to both species of herbivores. In addition, chemotaxis assays demonstrated that both herbivores are significantly negative chemotactic probably due to the presence of complementary metabolites into artificial foods. Considering that both Dictyota species exhibit active extracts against these small herbivores, we suppose that the non-occurrence of these herbivore species in close relationship with the seaweeds D. menstrualis and D. mertensii may explain the defense action of both extracts related to these mesograzers.