title: Vipirinin, a coumarin-based HIV-1 Vpr inhibitor, interacts with a hydrophobic region of VPR.
abstract: The human immunodeficiency virus 1 (HIV-1) viral protein R (Vpr) is an accessory protein that has been shown to have multiple roles in HIV-1 pathogenesis. By screening chemical libraries in the RIKEN Natural Products Depository, we identified a 3-phenyl coumarin-based compound that inhibited the cell cycle arrest activity of Vpr in yeast and Vpr-dependent viral infection of human macrophages. We determined its minimal pharmacophore through a structure-activity relationship study and produced more potent derivatives. We detected direct binding, and by assaying a panel of Vpr mutants, we found the hydrophobic region about residues Glu-25 and Gln-65 to be potentially involved in the binding of the inhibitor. Our findings exposed a targeting site on Vpr and delineated a convenient approach to explore other targeting sites on the protein using small molecule inhibitors as bioprobes.
authors.affiliation: From the Chemical Biology Core Facility, Chemical Biology Department, RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
authors.forename: Eugene Boon Beng
authors.initials: EB
authors.lastname: Ong
authors.forename: Nobumoto
authors.initials: N
authors.lastname: Watanabe
authors.forename: Akiko
authors.initials: A
authors.lastname: Saito
authors.forename: Yushi
authors.initials: Y
authors.lastname: Futamura
authors.forename: Khaled Hussein
authors.initials: KH
authors.lastname: Abd El Galil
authors.forename: Atsushi
authors.initials: A
authors.lastname: Koito
authors.forename: Nazalan
authors.initials: N
authors.lastname: Najimudin
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D001665:Binding Sites; D001667:Binding, Competitive; D002219:Carbamates / Q000494:pharmacology*; D003374:Coumarins / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D018698:Glutamic Acid / Q000737:chemistry; D005973:Glutamine / Q000737:chemistry; D006801:Humans; D008264:Macrophages / Q000166:cytology; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D019380:Anti-HIV Agents; D002219:Carbamates; D003374:Coumarins; C558926:vipirinin; D054325:vpr Gene Products, Human Immunodeficiency Virus; D005973:Glutamine; D018698:Glutamic Acid; C030123:coumarin