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

dc.contributor.author	ONG, EUGENE BOON BENG
dc.date.accessioned	2018-08-03T07:22:05Z
dc.date.available	2018-08-03T07:22:05Z
dc.date.issued	2011-05
dc.description.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.	en_US
dc.identifier.uri	http://hdl.handle.net/123456789/6170
dc.language.iso	en	en_US
dc.publisher	Universiti Sains Malaysia	en_US
dc.subject	Screening for small molecule inhibitors of HIV-1 VPR	en_US
dc.subject	discovery of vipirinin and its use as a bioprobe	en_US
dc.title	Screening For Small Molecule Inhibitors Of HIV-1 VPR: Discovery Of Vipirinin And Its Use As A Bioprobe	en_US
dc.type	Thesis	en_US