Inhibition of the tax-dependent human T-lymphotropic virus type I replication in persistently infected cells by the fluoroquinolone derivative k-37.

Xin Wang, Hiroshi Miyake, Mika Okamoto, Mineki Saito, Jun-Ichi Fujisawa, Yuetsu Tanaka, Shuji Izumo, Masanori Baba

Division of Human Retroviruses, Third Department of Internal Medicine, Faculty of Medicine, Kagoshima University, Kagoshima, Japan.

Molecular pharmacology 2002 Jun

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In the search for anti-human T-lymphotropic virus type-I (HTLV-I) compounds, we have evaluated several compounds for their inhibitory effects on HTLV-I replication in cell cultures. Among the test compounds, the fluoroquinolone derivative 7-(3,4-dehydro-4-phenyl-1-piperidinyl)-1,4-dihydro-6-fluoro-1-methyl-8- trifluoromethyl-4-oxoquinoline-3-carboxylic acid (K-37) was found to be a potent and selective inhibitor of HTLV-I replication in persistently infected cells, such as MT-2 and MT-4. When the cells were cultured in the presence of various concentrations of the compound, the 50% effective concentrations of K-37 for HTLV-I p19 antigen production were 0.44 and 0.24 microM in MT-2 and MT-4 cells, respectively. K-37 did not affect the viability and proliferation of these cells at these concentrations, and its 50% cytotoxic concentrations to MT-2 and MT-4 cells were 5.7 and 1.1 microM, respectively. The compound also showed selective inhibition of HTLV-I production in peripheral blood mononuclear cells obtained from patients with HTLV-I-associated myelopathy/tropical spastic paraparesis. Quantitative reverse transcription-polymerase chain reaction analysis revealed that K-37 selectively suppressed viral mRNA synthesis in MT-2 cells in a dose-dependent fashion. Furthermore, K-37 could inhibit the endogenous Tax-induced HTLV-I long terminal repeat (LTR)-driven reporter gene expression in MT-2 cells. Western blot analysis confirmed the reduced expression of Tax in MT-2 cells exposed to K-37. In contrast, when Tax was introduced into cells not infected with HTLV-I with a plasmid under the control of human cytomegalovirus promoter, the compound did not affect Tax-induced HTLV-I LTR-driven reporter gene expression. These results suggest that the inhibition occurred at the level of HTLV-I LTR-driven Tax expression.

Citation

Xin Wang, Hiroshi Miyake, Mika Okamoto, Mineki Saito, Jun-Ichi Fujisawa, Yuetsu Tanaka, Shuji Izumo, Masanori Baba. Inhibition of the tax-dependent human T-lymphotropic virus type I replication in persistently infected cells by the fluoroquinolone derivative k-37. Molecular pharmacology. 2002 Jun;61(6):1359-65