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Antiretroviral activity of two polyisoprenylated acylphloroglucinols, 7-epi-nemorosone and plukenetione A, isolated from Caribbean propolis.

Abstract

OBJECTIVES

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.

MATERIAL AND 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.

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  • Authors+Show Affiliations

    ,

    Institute for Molecular Oncology and Experimental Therapeutics, Marienhospital Herne, Ruhr University of Bochum, Herne, Germany. david.diaz-carballo@marienhospital-herne.de

    , , , , , , , ,

    Source

    MeSH

    Antiviral Agents
    Benzophenones
    Caribbean Region
    Cells, Cultured
    HIV-1
    Humans
    Lentivirus
    Polycyclic Compounds
    Propolis

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    20875373

    Citation

    TY - JOUR T1 - Antiretroviral activity of two polyisoprenylated acylphloroglucinols, 7-epi-nemorosone and plukenetione A, isolated from Caribbean propolis. AU - Díaz-Carballo,D, AU - Ueberla,K, AU - Kleff,V, AU - Ergun,S, AU - Malak,S, AU - Freistuehler,M, AU - Somogyi,S, AU - Kücherer,C, AU - Bardenheuer,W, AU - Strumberg,D, PY - 2010/9/30/entrez PY - 2010/9/30/pubmed PY - 2010/11/17/medline SP - 670 EP - 7 JF - International journal of clinical pharmacology and therapeutics JO - Int J Clin Pharmacol Ther VL - 48 IS - 10 N2 - OBJECTIVES: 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. MATERIAL AND 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. SN - 0946-1965 UR - https://www.unboundmedicine.com/medline/citation/20875373/full_citation/Antiretroviral_activity_of_two_polyisoprenylated_acylphloroglucinols_7_epi_nemorosone_and_plukenetione_A_isolated_from_Caribbean_propolis_ L2 - http://www.dustri.com/nc/journals-in-english.html?artId=###ARTID### ER -