title: Broad-spectrum antiviral activity and mechanism of antiviral action of the fluoroquinolone derivative K-12.
abstract: The fluoroquinolone derivatives have been shown to inhibit human immunodeficiency virus (HIV) replication at the transcriptional level. We confirmed the anti-HIV activity of the most potent congener, 8-difluoromethoxy-1-ethyl-6-fluoro-1,4-dihydro-7-[4-(2- methoxyphenyl)-1-piperazinyl]-4-quinolone-3-carboxylic acid (K-12), in both acutely and chronically infected cells. K-12 was active against different strains of HIV-1 (including AZT- and ritonavir-resistant HIV-1 strains), HIV-2 and simian immunodeficiency virus, in MT-4, CEM, C8166 and peripheral blood mononuclear cells. In all of these antiviral assay systems, K-12 showed a similar activity (EC50 0.2-0.6 microM). K-12 inhibited Moloney murine sarcoma virus-induced transformation of C3H/3T3 cells with an EC50 of 6.9 microM. Also, K-12 proved inhibitory to herpesvirus saimiri, human cytomegalovirus, varicella-zoster virus and herpes simplex virus types 1 and 2 (in order of decreasing sensitivity), but was not inhibitory (at subtoxic concentrations) to human herpesvirus type 8 (as evaluated in BCBL-1 cells), vaccinia virus, Sindbis virus, vesicular stomatitis virus, respiratory syncytial virus, Coxsackie virus, Punta Toro virus, parainfluenza virus or reovirus. Time-of-addition experiments and quantitative transactivation bioassays indicated that K-12 inhibits the Tat-mediated transactivation process in HIV-infected cells.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Witvrouw
authors.forename: D
authors.initials: D
authors.lastname: Daelemans
authors.forename: C
authors.initials: C
authors.lastname: Pannecouque
authors.forename: J
authors.initials: J
authors.lastname: Neyts
authors.forename: G
authors.initials: G
authors.lastname: Andrei
authors.forename: R
authors.initials: R
authors.lastname: Snoeck
authors.forename: A M
authors.initials: AM
authors.lastname: Vandamme
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: J
authors.initials: J
authors.lastname: Desmyter
authors.forename: M
authors.initials: M
authors.lastname: Baba
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D024841:Fluoroquinolones; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D016655:HIV Core Protein p24 / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D019829:Nevirapine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D015363:Quinolones / Q000737:chemistry* / Q000494:pharmacology; D012190:Retroviridae / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D014764:Viral Proteins / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D000890:Anti-Infective Agents; D000998:Antiviral Agents; D024841:Fluoroquinolones; D016655:HIV Core Protein p24; C117028:K-12, fluoroquinolone; D010879:Piperazines; D015363:Quinolones; D014764:Viral Proteins; D019829:Nevirapine