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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 3′processing reaction catalysed by HIV-1 integrase.Standard 3′processing assay was performed as reported in materials and methods section using 600 nM IN, 1 pmol of 5′ radiolabelled 21 bp ODN 70/72 mimicking the viral U5 end and increasing concentration of molecules. An example of 3′ processing profile obtained with a selected inhibitory compound (here E-piceatannol (PICE) and the raltegravir (RAL) control molecule is shown in A as well as the position and the structure of the expected 19 bp reaction product. The 19 bp processed product was quantified as reported in materials and methods section and the percentage of 3′ processing is shown in B as the average from at least three independent experiments ± standard deviation (error bars).
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pone-0081184-g004: Effect of stilbene compounds on in vitro 3′processing reaction catalysed by HIV-1 integrase.Standard 3′processing assay was performed as reported in materials and methods section using 600 nM IN, 1 pmol of 5′ radiolabelled 21 bp ODN 70/72 mimicking the viral U5 end and increasing concentration of molecules. An example of 3′ processing profile obtained with a selected inhibitory compound (here E-piceatannol (PICE) and the raltegravir (RAL) control molecule is shown in A as well as the position and the structure of the expected 19 bp reaction product. The 19 bp processed product was quantified as reported in materials and methods section and the percentage of 3′ processing is shown in B as the average from at least three independent experiments ± standard deviation (error bars).

Mentions: As shown in figure 4, only: E-ε-viniferinglucoside, leachianol F, E-piceatannol quadrangularin A and E-resveratrol showed an inhibitory effect on 3′processing, thereby confirming the data in figure 3. The low 3′processing inhibitory effect found for E-scirpusin A and leachianol G compared to their inhibition on concerted integration in the presence of the processed donor suggests that these compounds could be specific to the target capture and/or strand transfer reaction. In contrast, the 3′processing inhibition found for E-ε-viniferin glucoside, E-resveratrol and E-piceatannol compared to their poor effect on the strand transfer reaction reported in figure 3A suggests that they could be more active on the maturation step of the viral end. Again the RAL molecule showed a better 3′processing inhibition property than the selected compounds.


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 3′processing reaction catalysed by HIV-1 integrase.Standard 3′processing assay was performed as reported in materials and methods section using 600 nM IN, 1 pmol of 5′ radiolabelled 21 bp ODN 70/72 mimicking the viral U5 end and increasing concentration of molecules. An example of 3′ processing profile obtained with a selected inhibitory compound (here E-piceatannol (PICE) and the raltegravir (RAL) control molecule is shown in A as well as the position and the structure of the expected 19 bp reaction product. The 19 bp processed product was quantified as reported in materials and methods section and the percentage of 3′ processing is shown in B as the average from at least three independent experiments ± standard deviation (error bars).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0081184-g004: Effect of stilbene compounds on in vitro 3′processing reaction catalysed by HIV-1 integrase.Standard 3′processing assay was performed as reported in materials and methods section using 600 nM IN, 1 pmol of 5′ radiolabelled 21 bp ODN 70/72 mimicking the viral U5 end and increasing concentration of molecules. An example of 3′ processing profile obtained with a selected inhibitory compound (here E-piceatannol (PICE) and the raltegravir (RAL) control molecule is shown in A as well as the position and the structure of the expected 19 bp reaction product. The 19 bp processed product was quantified as reported in materials and methods section and the percentage of 3′ processing is shown in B as the average from at least three independent experiments ± standard deviation (error bars).
Mentions: As shown in figure 4, only: E-ε-viniferinglucoside, leachianol F, E-piceatannol quadrangularin A and E-resveratrol showed an inhibitory effect on 3′processing, thereby confirming the data in figure 3. The low 3′processing inhibitory effect found for E-scirpusin A and leachianol G compared to their inhibition on concerted integration in the presence of the processed donor suggests that these compounds could be specific to the target capture and/or strand transfer reaction. In contrast, the 3′processing inhibition found for E-ε-viniferin glucoside, E-resveratrol and E-piceatannol compared to their poor effect on the strand transfer reaction reported in figure 3A suggests that they could be more active on the maturation step of the viral end. Again the RAL molecule showed a better 3′processing inhibition property than the selected compounds.

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