title: New anti-human immunodeficiency virus type 1 6-aminoquinolones: mechanism of action.
abstract: A 6-aminoquinolone derivative, WM5, which bears a methyl substituent at the N-1 position and a 4-(2-pyridyl)-1-piperazine moiety at position 7 of the bicyclic quinolone ring system, was previously shown to exhibit potent activity against replication of human immunodeficiency virus type 1 (HIV-1) in de novo-infected human lymphoblastoid cells (V. Cecchetti et al., J. Med. Chem. 43:3799-3802, 2000). In this report, we further investigated WM5's mechanism of antiviral activity. WM5 inhibited HIV-1 replication in acutely infected cells as well as in chronically infected cells. The 50% inhibitory concentrations were 0.60 +/- 0.06 and 0.85 +/- 0.05 micro M, respectively. When the effects of WM5 on different steps of the virus life cycle were analyzed, the reverse transcriptase activity and the integrase and protease activities were not impaired. By using a transient trans-complementation assay to examine the activity of WM5 on the replicative potential of HIV-1 in a single round of infection, a sustained inhibition of Tat-mediated long terminal repeat (LTR)-driven transcription (>80% of controls) was obtained in the presence of 5 micro M WM5. Interestingly, the aminoquinolone was found to efficiently complex TAR RNA, with a dissociation constant in the nanomolar range (19 +/- 0.6 nM). These data indicate that WM5 is a promising lead compound for the development of a new class of HIV-1 transcription inhibitors characterized by recognition of viral RNA target(s).
authors.affiliation: Department of Histology, Microbiology and Medical Biotechnologies, Section of Microbiology and Virology, University of Padua, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Parolin
authors.forename: Barbara
authors.initials: B
authors.lastname: Gatto
authors.forename: Claudia
authors.initials: C
authors.lastname: Del Vecchio
authors.forename: Teresa
authors.initials: T
authors.lastname: Pecere
authors.forename: Enzo
authors.initials: E
authors.lastname: Tramontano
authors.forename: Violetta
authors.initials: V
authors.lastname: Cecchetti
authors.forename: Arnaldo
authors.initials: A
authors.lastname: Fravolini
authors.forename: Sara
authors.initials: S
authors.lastname: Masiero
authors.forename: Manlio
authors.initials: M
authors.lastname: Palumbo
authors.forename: Giorgio
authors.initials: G
authors.lastname: Palù
mesh_terms: D000634:Aminoquinolines / Q000378:metabolism / Q000494:pharmacology*; D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology*; D015752:Genes, env / Q000235:genetics; D005816:Genetic Complementation Test; D019427:HIV Integrase / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D016333:HIV Protease / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D015363:Quinolones / Q000378:metabolism / Q000494:pharmacology*; D012367:RNA, Viral / Q000096:biosynthesis / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000634:Aminoquinolines; D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D017320:HIV Protease Inhibitors; D015363:Quinolones; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D019427:HIV Integrase; D054303:HIV Reverse Transcriptase; D016333:HIV Protease