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JAC Advance Access originally published online on September 8, 2005
Journal of Antimicrobial Chemotherapy 2005 56(5):847-855; doi:10.1093/jac/dki328
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Cell-dependent interference of a series of new 6-aminoquinolone derivatives with viral (HIV/CMV) transactivation

Miguel Stevens1,*, Jan Balzarini1, Oriana Tabarrini2, Graciela Andrei1, Robert Snoeck1, Violetta Cecchetti2, Arnaldo Fravolini2, Erik De Clercq1 and Christophe Pannecouque1

1 Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium; 2 Department of Chemistry and Technology of Drugs, University of Perugia, Via del Liceo, 06123 Perugia, Italy

Received 29 June 2005; returned 12 June 2005; revised 10 August 2005; accepted 19 August 2005

* Corresponding author. Tel: +32-16-332171; Fax: +32-16-332131; E-mail: Miguel.Stevens{at}med.kuleuven.be

Objectives: Quinolone derivatives have been shown to inhibit human immunodeficiency virus (HIV) replication at the transcriptional level. Recently, a series of new 6-aminoquinolones that are endowed with more pronounced anti-HIV activities compared with the formerly reported quinolone derivatives have been published. These potent 6-aminoquinolones were further evaluated for their broad-spectrum antiviral properties.

Methods: Latently HIV-1-infected cell lines as well as cytomegalovirus (CMV)-infected fibroblasts were used to evaluate the antiviral potency of the 6-aminoquinolone derivatives. Additionally green fluorescent protein (GFP) transactivation experiments using different promoters were conducted.

Results: The compounds completely suppressed tumour necrosis factor alpha (TNF-{alpha})- and phorbol 12-myristate 13-acetate (PMA)-induced HIV-1 expression in latently HIV-1-infected OM-10.1 and U1 cell lines at non-toxic concentrations. In addition, HIV-1 mRNA production was dramatically suppressed in both cell lines in a dose-dependent manner. In the same concentration range, the compounds inhibited TNF-{alpha} release from PMA-induced OM-10.1 cells but allowed TNF-{alpha} production from PMA-induced U1 cells at all concentrations tested. The 6-aminoquinolone derivatives were not only inhibitory to the Tat-mediated transactivation of the HIV-1 LTR promoter, but were also found to interfere in a cell-dependent way with the transactivation process mediated from the human CMV immediate early and the human EF-1{alpha} promoter. Additionally, the 6-aminoquinolone derivatives were also found to be inhibitory to CMV replication in fibroblast cells.

Conclusions: It thus appears that the antiviral spectrum of this class of compounds is not confined to the specific inhibition of HIV but encompasses CMV as well. This broad-spectrum activity window might provide an interesting platform for future applications for the 6-aminoquinolone derivatives.

Keywords: Tat , TAR , latency


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