Screening For Small Molecule Inhibitors Of HIV-1 VPR: Discovery Of Vipirinin And Its Use As A Bioprobe

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Date
2011-05
Authors
ONG, EUGENE BOON BENG
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Universiti Sains Malaysia
Abstract
The human immunodeficiency virus 1 (HIV-1) viral protein R (Vpr) is an accessory protein that has been known to have multiple roles in HIV-1 pathogenesis. Here, a high-throughput screening (HTS) system was developed to screen chemical libraries in RIKEN Natural Products Depository (NPDepo). Through HTS, NPD4456, a 3-phenyl coumarin based compound, was identified to be an inhibitor of the cell cycle arrest activity of Vpr in yeast. The minimal pharmacophore of the inhibitor was determined through a structure-activity relationship study and more potent derivatives were produced. The Vpr inhibitors were used as bioprobes to explore a panel of single point alanine mutants of Vpr and the hydrophobic region about residues E25 and Q65 of the Vpr protein was found to be potentially involved in the binding of the inhibitor. Docking models predicted that the inhibitors were able to bind to a hydrophobic pocket in the same region. Direct binding of Vpr to the inhibitor was detected in a pull-down assay with compound-immobilized beads and the protein was observed to bind in a competitive manner. The inhibitors were also found be able to inhibit Vpr-dependent viral infection of human macrophages. Taken together, these findings delineated a convenient approach to explore a probable drug targeting site on Vpr using small molecule inhibitors.
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Screening for small molecule inhibitors of HIV-1 VPR , discovery of vipirinin and its use as a bioprobe
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