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.

Author Details

Authors

• D. Díaz-Carballo¹*
• K. Ueberla²*
• V. Kleff³
• S. Ergun³
• S. Malak⁴
• M. Freistuehler⁵
• S. Somogyi⁶
• C. Kücherer⁶
• W. Bardenheuer¹
• D. Strumberg¹

Departments

• ¹ Institute for Molecular Oncology and Experimental Therapeutics, Marienhospital Herne, Ruhr University of Bochum, Herne,
• ² Department of Molecular and Medical Virology, Ruhr University of Bochum, Bochum,
• ³ Institute of Anatomy,
• ⁴ West German Cancer Center,
• ⁵ Department of Ophthalmology, University of Duisburg-Essen, School of Medicine, Essen and
• ⁶ Project HIV Variability and Molecular Epidemiology/P
• ¹ 
• ¹ , Robert Koch Institute, Berlin, Germany
  
  *The two first authors contributed equally to this work.

Address

Dr. D. Diaz-Carballo
Institut für Molekulare Onkologie und Substanzentwicklung
Marienhospital Herne
Katholische Stiftung
Ruhr-Universität Bochum
Düngelstraße 33, 44625 Herne, Germany
Email: [email protected]

Citation