The Lupane-type Triterpene 30-Oxo-calenduladiol Is a CCR5 Antagonist with Anti-HIV-1 and Anti-chemotactic Activities*

  1. Jonathan Barroso-González‡§,1,
  2. Nabil El Jaber-Vazdekis§,2,
  3. Laura García-Expósito‡,3,
  4. José-David Machado‡,
  5. Rafael Zárate§,4,
  6. Ángel G. Ravelo§,
  7. Ana Estévez-Braun§,5 and
  8. Agustín Valenzuela-Fernández‡,6
  1. From the ‡Laboratorio de Inmunología Celular y Viral, Unidad de Farmacología, Departamento de Medicina Física y Farmacología, Facultad de Medicina, Instituto de Tecnologías Biomédicas, Universidad de La Laguna, 38071 Tenerife,
  2. the §Instituto Universitario de Bio-Orgánica, Universidad de La Laguna, La Laguna, 38206 Tenerife, and
  3. the Instituto Canario de Investigación del Cáncer (ICIC), c/o Hospital Universitario La Candelaria, Carr. El Rosario, 38010 Tenerife, Spain
  1. 5 To whom correspondence may be addressed. Tel.: 34-922-318576; Fax: 34-922-318571; E-mail: aestebra{at}ull.es.
  2. 6 Supported by Fondo Social Europeo (FSE) Grant RYC2002-3018. To whom correspondence may be addressed:
    Laboratorio de Inmunología Celular y Viral, Unidad de Farmacología, Facultad de Medicina, Universidad de La Laguna, Campus de Ofra s/n, La Laguna, 38071 Tenerife, Spain.
    Tel.: 34-922-319351; Fax: 34-922-655995; E-mail: avalenzu{at}ull.es.

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 β-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.

Footnotes

  • ↵1 Supported by associated Fellowship Fundación Canaria de Investigación y Salud (FUNCIS)-PI56/07.

  • ↵2 Supported by a predoctoral fellowship from CajaCanarias.

  • ↵3 Supported by associated Fellowship FIPSE-24661/07.

  • ↵4 Supported Fondo Social Europeo Grant RYC2002-694.

  • ↵* This work was supported in part by Ministerio de Ciencia e Innovación, Spain, Grant SAF2008-01729, Fundación para la Investigación y Prevención del SIDA en España Grants Fundación para la Investigación y Prevención del SIDA en España (FIPSE)-24508/05 and FIPSE-24661/07, Consejería de Industria, Comercio y Nuevas Tecnologías del Gobierno Autónomo de Canarias, Spain, Grant IDT-TF-06/066, and the Fundación Mutua Madrileña, Spain. This work was also supported by the Canary Islands Cancer Research Institute (ICIC), and project SAF 2006-06720 from the Spanish Ministry of Education and Science (MEC).

  • ↵Graphic The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

  • ↵7 The abbreviations used are:

    HIV-1

    human immunodeficiency virus type 1

    VSV-G

    vesicular stomatitis virus G protein

    RANTES

    regulated on activation normal T expressed and secreted

    TIRFM

    total internal reflection fluorescence microscopy

    PE

    phycoerythrin

    MCP-1

    monocyte chemotactic protein 1

    TARC

    thymus- and activation-regulated chemokine

    EGFP

    enhanced green fluorescent protein

    EF

    evanescent field

    IR

    infrared

    mAb

    monoclonal antibody

    PBS

    phosphate-buffered saline

    Env

    envelope.

    • Received January 8, 2009.
    • Revision received April 8, 2009.
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  1. First Published on April 22, 2009, doi: 10.1074/jbc.M109.005835 June 12, 2009 The Journal of Biological Chemistry, 284, 16609-16620.
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