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Natural stilbenoids isolated from grapevine exhibiting inhibitory effects against HIV-1 integrase and eukaryote MOS1 transposase in vitro activities.

Pflieger A, Waffo Teguo P, Papastamoulis Y, Chaignepain S, Subra F, Munir S, Delelis O, Lesbats P, Calmels C, Andreola ML, Merillon JM, Auge-Gouillou C, Parissi V - PLoS ONE (2013)

Bottom Line: Some of the molecules were found to be active against both proteins while others were specific for one of the two models.Comparison of the differential effects of the molecules suggested that the compounds could target specific intermediate nucleocomplexes of the reactions.Additionally E-pterostilbene was found active on the early lentiviral replication steps in lentiviruses transduced cells.

View Article: PubMed Central - PubMed

Affiliation: Université François Rabelais de Tours, EA 6306, UFR Sciences Pharmaceutiques, Parc Grandmont, Tours, France.

ABSTRACT
Polynucleotidyl transferases are enzymes involved in several DNA mobility mechanisms in prokaryotes and eukaryotes. Some of them such as retroviral integrases are crucial for pathogenous processes and are therefore good candidates for therapeutic approaches. To identify new therapeutic compounds and new tools for investigating the common functional features of these proteins, we addressed the inhibition properties of natural stilbenoids deriving from resveratrol on two models: the HIV-1 integrase and the eukaryote MOS-1 transposase. Two resveratrol dimers, leachianol F and G, were isolated for the first time in Vitis along with fourteen known stilbenoids: E-resveratrol, E-piceid, E-pterostilbene, E-piceatannol, (+)-E-ε-viniferin, E-ε-viniferinglucoside, E-scirpusin A, quadragularin A, ampelopsin A, pallidol, E-miyabenol C, E-vitisin B, hopeaphenol, and isohopeaphenol and were purified from stalks of Vitis vinifera (Vitaceae), and moracin M from stem bark of Milliciaexelsa (Moraceae). These compounds were tested in in vitro and in vivo assays reproducing the activity of both enzymes. Several molecules presented significant inhibition on both systems. Some of the molecules were found to be active against both proteins while others were specific for one of the two models. Comparison of the differential effects of the molecules suggested that the compounds could target specific intermediate nucleocomplexes of the reactions. Additionally E-pterostilbene was found active on the early lentiviral replication steps in lentiviruses transduced cells. Consequently, in addition to representing new original lead compounds for further modelling of new active agents against HIV-1 integrase, these molecules could be good tools for identifying such reaction intermediates in DNA mobility processes.

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Effect of stilbene compounds on in vitro HIV-1 concerted integration.Concerted integration assays were performed using 600(A) or unprocessed (B) donor DNA incubated with increasing concentration of compounds. The integration products were quantified as reported in materials and methods section and the percentage of integration is shown as the means from at least three independent experiments ± standard deviation (error bars). We also reported the inhibitory effect observed with raltegravir (RAL).
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pone-0081184-g003: Effect of stilbene compounds on in vitro HIV-1 concerted integration.Concerted integration assays were performed using 600(A) or unprocessed (B) donor DNA incubated with increasing concentration of compounds. The integration products were quantified as reported in materials and methods section and the percentage of integration is shown as the means from at least three independent experiments ± standard deviation (error bars). We also reported the inhibitory effect observed with raltegravir (RAL).

Mentions: The data in figures 3A and 3B confirm the first selection since leachianol G, leachianol F, quadrangularin A, E-scirpusin A, pallidol, E-piceid and E-pterostilbene inhibited both activities with various efficiencies (the best inhibition was observed with leachianol G and leachianol F, reaching 30–60% inhibition at 50 µM). Interestingly, some molecules exhibited specificities for one reaction over the other. For example, E-ε-viniferin glucoside, E-resveratrol and E-piceatannol were found to inhibit integration from the unprocessed substrate without having any detectable effect on the processed DNA, and quadrangularin A was a better inhibitor of integration from unprocessed than from processed DNA. The raltegravir molecule was always found better inhibitor than the selected compounds. However under our conditions some molecules showed inhibitory efficiencies close to raltegravir (leachianol G, leachianol F and E-pterostilbene). Since these results suggested a differential effect of the molecules on the 3′processing steps compared to the strand transfer reaction monitored when using the pre-processed donor, we analysed the molecules in an independent 3′processing assay.


Natural stilbenoids isolated from grapevine exhibiting inhibitory effects against HIV-1 integrase and eukaryote MOS1 transposase in vitro activities.

Pflieger A, Waffo Teguo P, Papastamoulis Y, Chaignepain S, Subra F, Munir S, Delelis O, Lesbats P, Calmels C, Andreola ML, Merillon JM, Auge-Gouillou C, Parissi V - PLoS ONE (2013)

Effect of stilbene compounds on in vitro HIV-1 concerted integration.Concerted integration assays were performed using 600(A) or unprocessed (B) donor DNA incubated with increasing concentration of compounds. The integration products were quantified as reported in materials and methods section and the percentage of integration is shown as the means from at least three independent experiments ± standard deviation (error bars). We also reported the inhibitory effect observed with raltegravir (RAL).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3842960&req=5

pone-0081184-g003: Effect of stilbene compounds on in vitro HIV-1 concerted integration.Concerted integration assays were performed using 600(A) or unprocessed (B) donor DNA incubated with increasing concentration of compounds. The integration products were quantified as reported in materials and methods section and the percentage of integration is shown as the means from at least three independent experiments ± standard deviation (error bars). We also reported the inhibitory effect observed with raltegravir (RAL).
Mentions: The data in figures 3A and 3B confirm the first selection since leachianol G, leachianol F, quadrangularin A, E-scirpusin A, pallidol, E-piceid and E-pterostilbene inhibited both activities with various efficiencies (the best inhibition was observed with leachianol G and leachianol F, reaching 30–60% inhibition at 50 µM). Interestingly, some molecules exhibited specificities for one reaction over the other. For example, E-ε-viniferin glucoside, E-resveratrol and E-piceatannol were found to inhibit integration from the unprocessed substrate without having any detectable effect on the processed DNA, and quadrangularin A was a better inhibitor of integration from unprocessed than from processed DNA. The raltegravir molecule was always found better inhibitor than the selected compounds. However under our conditions some molecules showed inhibitory efficiencies close to raltegravir (leachianol G, leachianol F and E-pterostilbene). Since these results suggested a differential effect of the molecules on the 3′processing steps compared to the strand transfer reaction monitored when using the pre-processed donor, we analysed the molecules in an independent 3′processing assay.

Bottom Line: Some of the molecules were found to be active against both proteins while others were specific for one of the two models.Comparison of the differential effects of the molecules suggested that the compounds could target specific intermediate nucleocomplexes of the reactions.Additionally E-pterostilbene was found active on the early lentiviral replication steps in lentiviruses transduced cells.

View Article: PubMed Central - PubMed

Affiliation: Université François Rabelais de Tours, EA 6306, UFR Sciences Pharmaceutiques, Parc Grandmont, Tours, France.

ABSTRACT
Polynucleotidyl transferases are enzymes involved in several DNA mobility mechanisms in prokaryotes and eukaryotes. Some of them such as retroviral integrases are crucial for pathogenous processes and are therefore good candidates for therapeutic approaches. To identify new therapeutic compounds and new tools for investigating the common functional features of these proteins, we addressed the inhibition properties of natural stilbenoids deriving from resveratrol on two models: the HIV-1 integrase and the eukaryote MOS-1 transposase. Two resveratrol dimers, leachianol F and G, were isolated for the first time in Vitis along with fourteen known stilbenoids: E-resveratrol, E-piceid, E-pterostilbene, E-piceatannol, (+)-E-ε-viniferin, E-ε-viniferinglucoside, E-scirpusin A, quadragularin A, ampelopsin A, pallidol, E-miyabenol C, E-vitisin B, hopeaphenol, and isohopeaphenol and were purified from stalks of Vitis vinifera (Vitaceae), and moracin M from stem bark of Milliciaexelsa (Moraceae). These compounds were tested in in vitro and in vivo assays reproducing the activity of both enzymes. Several molecules presented significant inhibition on both systems. Some of the molecules were found to be active against both proteins while others were specific for one of the two models. Comparison of the differential effects of the molecules suggested that the compounds could target specific intermediate nucleocomplexes of the reactions. Additionally E-pterostilbene was found active on the early lentiviral replication steps in lentiviruses transduced cells. Consequently, in addition to representing new original lead compounds for further modelling of new active agents against HIV-1 integrase, these molecules could be good tools for identifying such reaction intermediates in DNA mobility processes.

Show MeSH