The lupane-type triterpene 30-oxo-calenduladiol is a CCR5 antagonist with anti-HIV-1 and anti-chemotactic activities.

Abstract

The existence of drug-resistant human immunodeficiency virus (HIV) viruses in patients receiving antiretroviral treatment urgently requires the characterization and development of new antiretroviral drugs designed to inhibit resistant viruses and to complement the existing antiretroviral strategies against AIDS. We assayed several natural or semi-synthetic lupane-type pentacyclic triterpenes in their ability to inhibit HIV-1 infection in permissive cells. We observed that the 30-oxo-calenduladiol triterpene, compound 1, specifically impaired R5-tropic HIV-1 envelope-mediated viral infection and cell fusion in permissive cells, without affecting X4-tropic virus. This lupane derivative competed for the binding of a specific anti-CCR5 monoclonal antibody or the natural CCL5 chemokine to the CCR5 viral coreceptor with high affinity. 30-oxo-calenduladiol seems not to interact with the CD4 antigen, the main HIV receptor, or the CXCR4 viral coreceptor. Our results suggest that compound 1 is a specific CCR5 antagonist, because it binds to the CCR5 receptor without triggering cell signaling or receptor internalization, and inhibits RANTES (regulated on activation normal T cell expressed and secreted)-mediated CCR5 internalization, intracellular calcium mobilization, and cell chemotaxis. Furthermore, compound 1 appeared not to interact with beta-chemokine receptors CCR1, CCR2b, CCR3, or CCR4. Thereby, the 30-oxo-calenduladiol-associated anti-HIV-1 activity against R5-tropic virus appears to rely on the selective occupancy of the CCR5 receptor to inhibit CCR5-mediated HIV-1 infection. Therefore, it is plausible that the chemical structure of 30-oxo-calenduladiol or other related dihydroxylated lupane-type triterpenes could represent a good model to develop more potent anti-HIV-1 molecules to inhibit viral infection by interfering with early fusion and entry steps in the HIV life cycle.

• Authors: Jonathan Barroso-González, Nabil El Jaber-Vazdekis, Laura García-Expósito, José-David Machado, Rafael Zárate, Ángel G Ravelo, Ana Estévez-Braun, Agustín Valenzuela-Fernández
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 284 Issue 24 Pg. 16609-16620 (Jun 12 2009) ISSN: 0021-9258 [Print] United States
• PMID: 19386595 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 30-oxo-calenduladiol
• CCR1 protein, human
• CCR3 protein, human
• CCR4 protein, human
• CCR5 Receptor Antagonists
• Chemokine CCL5
• Receptors, CCR1
• Receptors, CCR2
• Receptors, CCR3
• Receptors, CCR4
• Receptors, CCR5
• Triterpenes
• Calcium

Topics

• Binding, Competitive (drug effects)
• CCR5 Receptor Antagonists
• Calcium (metabolism)
• Cell Fusion
• Chemokine CCL5 (metabolism)
• Chemotaxis (drug effects)
• Cytosol (metabolism)
• Drug Design
• Flow Cytometry
• HIV Infections (drug therapy, immunology)
• HIV-1 (drug effects, growth & development)
• HeLa Cells
• Humans
• Microscopy, Fluorescence
• Receptors, CCR1 (metabolism)
• Receptors, CCR2 (metabolism)
• Receptors, CCR3 (metabolism)
• Receptors, CCR4 (metabolism)
• Receptors, CCR5 (metabolism)
• Triterpenes (chemistry, pharmacology)