title: Antiretroviral activity of two polyisoprenylated acylphloroglucinols, 7-epi-nemorosone and plukenetione A, isolated from Caribbean propolis.
abstract: OBJECTIVE
  Polyisoprenylated acylphloroglucinols have recently emerged as antitumoral agents. This study aims at elucidating the antiretroviral activity of two such compounds which were isolated from Caribbean propolis: 7-epi-nemorosone and plukenetione A, the structure of which is based on an adamantane moiety. Plukenetione A is for the first time shown to have antiretroviral activity.
  
  
  METHODS
  The isolation of both small molecules was carried out using RP-HPLC. Their antiretroviral activity was studied based on lentiviral particles produced in HEK293T cells from the SIV-based vector VLDBH; their cytotoxicity was monitored by MTT proliferation assay. The antiviral activity of 7-epi-nemorosone was studied in CEMx174-SEAP infected with the HIV-1-strain pNL4.3wt. Reverse transcriptase inhibition was determined by a standard two-step RT-PCR using MMLV RT.
  
  
  RESULTS
  7-epi-nemorosone and plukenetione A were found to be potent antilentiviral agents in the employed system, inhibiting viral infection at concentrations below 1 µM/2 µM, respectively. Whereas 7-epi-nemorosone was not able to inhibit the reverse transcriptase in vitro (IC50 > 25 µM), plukenetione A effectively inhibited its enzymatic activity at an IC50 of 1.75 µM.
  
  
  CONCLUSIONS
  Despite 7-epi-nemorosone and plukenetione A sharing some structural core elements, the mechanism of action involved in their antiretroviral activity seems to be different. We propose that 7-epi-nemorosone inhibits the viral replication by interrupting the Akt/PKB signaling cascade, as was demonstrated previously in various cell lines. Since plukenetione A effectively inhibits the enzymatic activity of MMLV reverse transcriptase at concentrations that show antilentiviral activity, we suggest that this small molecule acts by interfering with the enzyme's catalytic site.
authors.affiliation: Institute for Molecular Oncology and Experimental Therapeutics, Marienhospital Herne, Ruhr University of Bochum, Herne, Germany. david.diaz-carballo@marienhospital-herne.de
authors.forename: D
authors.initials: D
authors.lastname: Díaz-Carballo
authors.forename: K
authors.initials: K
authors.lastname: Ueberla
authors.forename: V
authors.initials: V
authors.lastname: Kleff
authors.forename: S
authors.initials: S
authors.lastname: Ergun
authors.forename: S
authors.initials: S
authors.lastname: Malak
authors.forename: M
authors.initials: M
authors.lastname: Freistuehler
authors.forename: S
authors.initials: S
authors.lastname: Somogyi
authors.forename: C
authors.initials: C
authors.lastname: Kücherer
authors.forename: W
authors.initials: W
authors.lastname: Bardenheuer
authors.forename: D
authors.initials: D
authors.lastname: Strumberg
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001577:Benzophenones / Q000737:chemistry / Q000494:pharmacology*; D017691:Caribbean Region; D002478:Cells, Cultured; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D016086:Lentivirus / Q000187:drug effects*; D011083:Polycyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D011429:Propolis / Q000737:chemistry*
chemical_list: D000998:Antiviral Agents; D001577:Benzophenones; D011083:Polycyclic Compounds; C437463:nemorosone; C534123:plukenetione A; D011429:Propolis