Cell-dependent interference of a series of new 6-aminoquinolone derivatives with viral (HIV/CMV) transactivation.
OBJECTIVE
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-1alpha 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.
Stevens
Miguel
M
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium. Miguel.Stevens@med.kuleuven.de
Balzarini
Jan
J
Tabarrini
Oriana
O
Andrei
Graciela
G
Snoeck
Robert
R
Cecchetti
Violetta
V
Fravolini
Arnaldo
A
De Clercq
Erik
E
Pannecouque
Christophe
C
D000634:Aminoquinolines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects* / Q000502:physiology; D017781:Genes, Immediate-Early; D049452:Green Fluorescent Proteins / Q000032:analysis; D006678:HIV / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D016325:HIV Long Terminal Repeat; D006801:Humans; D051379:Mice; D020648:Peptide Elongation Factor 1 / Q000235:genetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D012367:RNA, Viral / Q000032:analysis; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014775:Virus Activation; D017735:Virus Latency; D014779:Virus Replication / Q000187:drug effects
D000634:Aminoquinolines; D000998:Antiviral Agents; D020648:Peptide Elongation Factor 1; D012333:RNA, Messenger; D012367:RNA, Viral; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins; C016658:phorbolol myristate acetate; C025152:aminoquinolone; D013755:Tetradecanoylphorbol Acetate