Natural Stilbenoids Isolated from Grapevine Exhibiting Inhibitory Effects against HIV-1 Integrase and Eukaryote MOS1 Transposase In Vitro Activities

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.

Gnetin‐C and other resveratrol oligomers with cancer chemopreventive potential

“…(Cyperaceae) and in some Sophora species (Fabaceae) . Hopeaphenol inhibits topoisomerase IIA and MOS1 transposase . In in vitro studies, this compound inhibited the growth of SK‐MEL‐28 melanoma cells, D‐GBM glioblastoma cells, P‐388 leukemia cells, and the epidermoid carcinoma line KB .…”

Dual and Opposite Effects of hRAD51 Chemical Modulation on HIV-1 Integration

“…As reported in SI4A and [13], P-ter was previously shown to inhibit HIV-1 IN activity with an IC 50 = 47.5 ± 2.5 µM. Since P-ter showed hRAD51 stimulatory effect between 5–20 µM (see SI3) without significantly affecting HIV-1 IN activity, it was tested at concentrations up to 15 µM on hRAD51-mediated IN inhibition.…”

“…Several previously described hRAD51 inhibitors such as RI-1 and A30 [15, 16] were found to alleviate the in vitro integration restriction properties of the recombinase. On the contrary, hRAD51 stimulatory compounds, like the previously reported RS-1 [8] and the newly selected E -pterostilbene purified from grape wine [13], promoted the hRAD51 induced restriction of HIV-1 integration. These results, summarized in SI12, show a strong correlation between the recombination activity of hRAD51 and its ability to inhibit IN.…”

“…To better characterize the mechanism of inhibition, we searched for compounds capable of affecting the hRAD51/DNA binding properties and, thus, the formation of the active nucleofilament. Stilbenes, like DIDS, having previously been shown to affect hRAD51 activity [12], we tested natural stilbenes derivatives recently identified in our laboratory [13] in a hRAD51/DNA interaction assay. As reported in SI2, most of the 22 molecules tested were found to inhibit the hRAD51/DNA association but only one, the E -pterostilbene (P-ter) (chemical structure shown in figure 1A), stimulated binding.…”

“…DIDS previously reported as an hRAD51 inhibitor [12] was purchased from Sigma. E -pterostilbene (P-ter) was extracted from Vitis vinifera leaves (isolation and purification protocols described in [13]). Imatinib was purchased from Selleck chemicals (Euromedex, France).…”