Cell-dependent interference of a series of new 6-aminoquinolone derivatives with viral (HIV/CMV) transactivation
Cell-dependent interference of a series of new 6-aminoquinolone derivatives with viral (HIV/CMV) transactivation
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DOI：
10.1093/jac/dki328
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发表时间：
2005-11-01
影响因子：
5.2
通讯作者：
Pannecouque, C
中科院分区：
文献类型：
--
作者：
Stevens, M;Balzarini, J;Pannecouque, C
目的：喹诺酮类衍生物已被证明在转录水平上抑制人类免疫缺陷病毒（HIV）的复制。最近，一系列新的6-氨基喹诺酮类药物与以前报道的喹诺酮类衍生物相比，具有更明显的抗hiv活性。这些有效的6-氨基喹诺酮类药物被进一步评估其广谱抗病毒特性。方法：利用hiv -1潜伏感染细胞系和巨细胞病毒（CMV）感染的成纤维细胞，评价6-氨基喹诺酮类衍生物的抗病毒效力。此外，还进行了不同启动子的绿色荧光蛋白（GFP）转激活实验。结果：化合物完全抑制潜伏感染HIV-1的OM-10.1和U1细胞系中肿瘤坏死因子α (tnf - α)-和phorbol 12-肉豆酸酯13-醋酸酯(PMA)-诱导的HIV-1表达。此外，在两种细胞系中，HIV-1 mRNA的产生以剂量依赖的方式被显著抑制。在相同浓度范围内，化合物抑制pma诱导的OM-10.1细胞的tnf - α释放，但在所有浓度下均允许pma诱导的U1细胞产生tnf - α。6-氨基喹诺酮衍生物不仅抑制tat介导的HIV-1 LTR启动子的转激活，而且还发现以细胞依赖的方式干扰由人CMV早期和人EF-1 α启动子介导的转激活过程。此外，6-氨基喹诺酮衍生物也被发现对成纤维细胞中的巨细胞病毒复制有抑制作用。结论：因此，这类化合物的抗病毒谱似乎不局限于对HIV的特异性抑制，也包括巨细胞病毒。这种广谱活性窗口可能为6-氨基喹诺酮类衍生物的未来应用提供一个有趣的平台。
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.