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JAC Advance Access published online on September 8, 2005
Journal of Antimicrobial Chemotherapy, 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
Received June 29, 2005
Revised August 10, 2005
Accepted August 19, 2005

Original article

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

Miguel Stevens 1*, Jan Balzarini 1, Oriana Tabarrini 2, Graciela Andrei 1, Robert Snoeck 1, Violetta Cecchetti 2, Arnaldo Fravolini 2, Erik De Clercq 1, and Christophe Pannecouque 1

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

* To whom correspondence should be addressed.
Miguel Stevens, E-mail: Miguel.Stevens{at}med.kuleuven.be


  Abstract

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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