title: The fungal metabolite galiellalactone interferes with the nuclear import of NF-κB and inhibits HIV-1 replication.
abstract: Galiellalactone (GL) is a metabolite produced by the fungus Galiella rufa that presents antitumor and immunomodulatory activities. GL interferes with the binding to DNA of signal transducer and activator of transcription (STAT)-3 and also inhibits other signal pathways such as NF-κB, but the mechanism of action in this pathway remains unknown. In this study we report that GL inhibits vesicular stomatitis virus-recombinant HIV-1 infection and the NF-κB-dependent transcriptional activity of the HIV-LTR promoter. We found that GL prevents the binding of NF-κB to DNA but neither affects the phosphorylation and degradation of NF-κB inhibitory protein, IκBα, nor the phosphorylation and acetylation of the NF-κB p65 subunit. However, GL prevents the association of p65 with the importin α3 impairing the nuclear translocation of this transcription factor. Using a biotinylated probe we found that GL binds to p65 but not to importin α3. Therefore, GL is a dual NF-κB/STAT3 inhibitor that could serve as a lead compound for the development of novel drugs against HIV-1, cancer and inflammatory diseases.
authors.affiliation: Maimónides Institute for Research in Biomedicine of Córdoba, Reina Sofía University Hospital, University of Córdoba, Spain.
authors.forename: Moisés
authors.initials: M
authors.lastname: Pérez
authors.affiliation: Maimónides Institute for Research in Biomedicine of Córdoba, Reina Sofía University Hospital, University of Córdoba, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Soler-Torronteras
authors.affiliation: Maimónides Institute for Research in Biomedicine of Córdoba, Reina Sofía University Hospital, University of Córdoba, Spain.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Collado
authors.affiliation: Maimónides Institute for Research in Biomedicine of Córdoba, Reina Sofía University Hospital, University of Córdoba, Spain.
authors.forename: Carmen G
authors.initials: CG
authors.lastname: Limones
authors.affiliation: Division of Urological Cancers, Department of Clinical Sciences, Lund University, Sweden.
authors.forename: Rebecka
authors.initials: R
authors.lastname: Hellsten
authors.affiliation: Division of Organic Chemistry, Lund University, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Johansson
authors.affiliation: Division of Organic Chemistry, Lund University, Sweden.
authors.forename: Olov
authors.initials: O
authors.lastname: Sterner
authors.affiliation: Division of Urological Cancers, Department of Clinical Sciences, Lund University, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Bjartell
authors.affiliation: Maimónides Institute for Research in Biomedicine of Córdoba, Reina Sofía University Hospital, University of Córdoba, Spain.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Calzado
authors.affiliation: Maimónides Institute for Research in Biomedicine of Córdoba, Reina Sofía University Hospital, University of Córdoba, Spain. Electronic address: fi1muble@uco.es.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Muñoz
mesh_terms: D001203:Ascomycota / Q000737:chemistry*; D001692:Biological Transport / Q000187:drug effects*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007783:Lactones / Q000302:isolation & purification / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects*; D028901:alpha Karyopherins / Q000378:metabolism
chemical_list: C106259:KPNA4 protein, human; D007783:Lactones; D016328:NF-kappa B; D028901:alpha Karyopherins; C416043:galiellalactone
keywords: Galiellalactone; HIV-1; Importins; LTR; NF-κB