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: Eugene Boon Beng Ong, Nobumoto Watanabe, Akiko Saito, Yushi Futamura, Khaled Hussein Abd El Galil, Atsushi Koito, Nazalan Najimudin, Hiroyuki Osada
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 286 Issue 16 Pg. 14049-56 (Apr 22 2011) ISSN: 1083-351X [Electronic] United States
• PMID: 21357691 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-HIV Agents
• Carbamates
• Coumarins
• vipirinin
• vpr Gene Products, Human Immunodeficiency Virus
• Glutamine
• Glutamic Acid
• coumarin

Topics

• Anti-HIV Agents (pharmacology)
• Binding Sites
• Binding, Competitive
• Carbamates (pharmacology)
• Coumarins (chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Drug Design
• Glutamic Acid (chemistry)
• Glutamine (chemistry)
• Humans
• Macrophages (cytology)
• Mutation
• Protein Binding
• Protein Structure, Tertiary
• Structure-Activity Relationship
• vpr Gene Products, Human Immunodeficiency Virus (antagonists & inhibitors, chemistry)