title: Inhibition of the tax-dependent human T-lymphotropic virus type I replication in persistently infected cells by the fluoroquinolone derivative k-37.
abstract: 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.
authors.affiliation: Division of Human Retroviruses, Third Department of Internal Medicine, Faculty of Medicine, Kagoshima University, Kagoshima, Japan.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyake
authors.forename: Mika
authors.initials: M
authors.lastname: Okamoto
authors.forename: Mineki
authors.initials: M
authors.lastname: Saito
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Fujisawa
authors.forename: Yuetsu
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Shuji
authors.initials: S
authors.lastname: Izumo
authors.forename: Masanori
authors.initials: M
authors.lastname: Baba
mesh_terms: D000890:Anti-Infective Agents; D000956:Antigens, Viral / Q000096:biosynthesis / Q000235:genetics; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D024841:Fluoroquinolones / Q000737:chemistry / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D016356:Gene Products, tax / Q000502:physiology*; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D008826:Microbial Sensitivity Tests; D010880:Piperidines / Q000494:pharmacology*; D012367:RNA, Viral / Q000187:drug effects / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000890:Anti-Infective Agents; D000956:Antigens, Viral; D000998:Antiviral Agents; D024841:Fluoroquinolones; D016356:Gene Products, tax; D010880:Piperidines; D012367:RNA, Viral; C411922:fluoroquinoline K-37