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.
Highlights
DNA mobility is a crucial mechanism involved in genome evolution and in many vital cellular functions such as replication, transcription and the processes of viral and bacterial infection
The primary objectives of the study were to investigate the isolation of new lead compounds deriving from resveratrol and to evaluate their in vitro activity in HIV-1 IN and MOS-1 transposase inhibitory assays for further modelling of new agents active against HIV-1 integrase
Fractionation of crude stilbenoid extract was performed by centrifugal partition chromatography (CPC) using adapted Arizona solvent systems [18]
Summary
DNA mobility is a crucial mechanism involved in genome evolution and in many vital cellular functions such as replication, transcription and the processes of viral and bacterial infection. Polynucleotidyl transferases are involved in the cleavage and paste process of a wide variety of DNA products This family includes several enzymes sharing similar functions (cleavage and strand transfer) but interacting with a variety of different DNA fragments through different mechanisms. These enzymes are known as the DDE/ DDD enzymes, according to the amino acid triad involved in the catalytic functions. The nucleophilic substitution reactions are assisted by divalent metal cofactors [1], generally a pair of divalent metal cations (Mg++ or Mn++) that are thought to be coordinated by three carboxylates of the catalytic core Both transposases and integrases are DDE/DDD enzymes
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