Potent and selective inhibition of Tat-dependent HIV-1 replication in chronically infected cells by a novel naphthalene derivative JTK-101.
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.
Wang
Xin
X
Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Yamataka
Kazunobu
K
Okamoto
Mika
M
Ikeda
Satoru
S
Baba
Masanori
M
D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D056906:Cyclin T; D042863:Cyclin-Dependent Kinase 9; D016213:Cyclins; D024841:Fluoroquinolones / Q000737:chemistry / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral; D015696:Gene Products, tat / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry* / Q000494:pharmacology*; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
D019380:Anti-HIV Agents; C503684:CCNT1 protein, human; D056906:Cyclin T; D016213:Cyclins; D024841:Fluoroquinolones; D015696:Gene Products, tat; C528436:JTK-101; D009281:Naphthalenes; D014409:Tumor Necrosis Factor-alpha; C411922:fluoroquinoline K-37; D042863:Cyclin-Dependent Kinase 9