Wang Xin, Yamataka Kazunobu, Okamoto Mika, Ikeda Satoru, Baba Masanori
Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Antivir Chem Chemother. 2007;18(4):201-11. doi: 10.1177/095632020701800404.
In search for effective human immunodeficiency virus type 1 (HIV-1) transcription inhibitors, we have evaluated more than 100,000 compounds for their inhibitory effects on HIV-1 long terminal repeat (LTR)-driven reporter gene expression, and identified a novel naphthalene derivative, JTK-101. This compound could suppress tumour necrosis factor (TNF)-alpha-induced HIV-1 production in latently infected OM-10.1 cells at nanomolar concentrations. JTK-101 could also potently inhibit constitutive HIV-1 production in MOTL-4/IIIB. However, the antiviral activity of JTK-101 was found to be much weaker in acutely infected cells and the chronically infected cells U937/IIIB cells than in OM-10.1 and MOLT-4/IIIB cells. JTK-101 selectively suppressed TNF-alpha-induced HIV-1 mRNA synthesis in OM-10.1 cells in a dose-dependent fashion. JTK-101 modestly inhibited TNF-alpha-induced HIV-1 LTR-driven reporter gene expression, but potently inhibited Tat-induced gene expression. Immunoblot analysis revealed that low-level expression of the Tat cofactors CDK9 and cyclin T1 might contribute to the diminished antiviral activity in U937/IIIB cells. Furthermore, JTK-101 could not inhibit HIV-1 replication in chronically infected monocytes/macrophages, in which CDK9 and cyclin T1 were undetectable. These results suggest that JTK-101 exerts its anti-HIV-1 activity through the inhibition of known or unknown Tat cofactors, presumably CDK9/cyclin T1.
为了寻找有效的1型人类免疫缺陷病毒（HIV-1）转录抑制剂，我们评估了超过100,000种化合物对HIV-1长末端重复序列（LTR）驱动的报告基因表达的抑制作用，并鉴定出一种新型萘衍生物JTK-101。该化合物能够在纳摩尔浓度下抑制肿瘤坏死因子（TNF）-α诱导的潜伏感染OM-10.1细胞中HIV-1的产生。JTK-101还能有效抑制MOTL-4/IIIB细胞中组成性HIV-1的产生。然而，发现JTK-101在急性感染细胞以及慢性感染的U937/IIIB细胞中的抗病毒活性比在OM-10.1和MOLT-4/IIIB细胞中弱得多。JTK-101以剂量依赖的方式选择性抑制OM-10.1细胞中TNF-α诱导的HIV-1 mRNA合成。JTK-101适度抑制TNF-α诱导的HIV-1 LTR驱动的报告基因表达，但有效抑制Tat诱导的基因表达。免疫印迹分析表明，Tat辅因子CDK9和细胞周期蛋白T1的低水平表达可能导致U937/IIIB细胞中抗病毒活性降低。此外，JTK-101不能抑制慢性感染单核细胞/巨噬细胞中的HIV-1复制，在这些细胞中检测不到CDK9和细胞周期蛋白T1。这些结果表明，JTK-101通过抑制已知或未知的Tat辅因子（可能是CDK9/细胞周期蛋白T1）发挥其抗HIV-1活性。
