title: 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.affiliation: 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; Instituto Universitario de Bio-Orgánica, Universidad de La Laguna, La Laguna, 38206 Tenerife; Instituto Canario de Investigación del Cáncer (ICIC), c/o Hospital Universitario La Candelaria, Carr. El Rosario, 38010 Tenerife, Spain.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Barroso-González
authors.affiliation: Instituto Universitario de Bio-Orgánica, Universidad de La Laguna, La Laguna, 38206 Tenerife; Instituto Canario de Investigación del Cáncer (ICIC), c/o Hospital Universitario La Candelaria, Carr. El Rosario, 38010 Tenerife, Spain.
authors.forename: Nabil
authors.initials: N
authors.lastname: El Jaber-Vazdekis
authors.affiliation: 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; Instituto Canario de Investigación del Cáncer (ICIC), c/o Hospital Universitario La Candelaria, Carr. El Rosario, 38010 Tenerife, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: García-Expósito
authors.affiliation: 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.
authors.forename: José-David
authors.initials: JD
authors.lastname: Machado
authors.affiliation: Instituto Universitario de Bio-Orgánica, Universidad de La Laguna, La Laguna, 38206 Tenerife; Instituto Canario de Investigación del Cáncer (ICIC), c/o Hospital Universitario La Candelaria, Carr. El Rosario, 38010 Tenerife, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Zárate
authors.affiliation: Instituto Universitario de Bio-Orgánica, Universidad de La Laguna, La Laguna, 38206 Tenerife; Instituto Canario de Investigación del Cáncer (ICIC), c/o Hospital Universitario La Candelaria, Carr. El Rosario, 38010 Tenerife, Spain.
authors.forename: Ángel G
authors.initials: ÁG
authors.lastname: Ravelo
authors.affiliation: Instituto Universitario de Bio-Orgánica, Universidad de La Laguna, La Laguna, 38206 Tenerife; Instituto Canario de Investigación del Cáncer (ICIC), c/o Hospital Universitario La Candelaria, Carr. El Rosario, 38010 Tenerife, Spain. Electronic address: aestebra@ull.es.
authors.forename: Ana
authors.initials: A
authors.lastname: Estévez-Braun
authors.affiliation: 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; Instituto Canario de Investigación del Cáncer (ICIC), c/o Hospital Universitario La Candelaria, Carr. El Rosario, 38010 Tenerife, Spain. Electronic address: avalenzu@ull.es.
authors.forename: Agustín
authors.initials: A
authors.lastname: Valenzuela-Fernández
mesh_terms: D001667:Binding, Competitive / Q000187:drug effects; D065100:CCR5 Receptor Antagonists; D002118:Calcium / Q000378:metabolism; D002459:Cell Fusion; D018946:Chemokine CCL5 / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism; D015195:Drug Design; D005434:Flow Cytometry; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development; D006367:HeLa Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D054389:Receptors, CCR1 / Q000378:metabolism; D054390:Receptors, CCR2 / Q000378:metabolism; D054397:Receptors, CCR3 / Q000378:metabolism; D054398:Receptors, CCR4 / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C542876:30-oxo-calenduladiol; C515300:CCR1 protein, human; C515350:CCR3 protein, human; C515354:CCR4 protein, human; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D054397:Receptors, CCR3; D054398:Receptors, CCR4; D019713:Receptors, CCR5; D014315:Triterpenes; D002118:Calcium