Open AccessNew Anti-Human Immunodeficiency Virus Type 1 6-Aminoquinolones: Mechanism of Action
Author(s) -
Cristina Parolin,
Barbara Gatto,
Claudia Del Vecchio,
Teresa Pecere,
Enzo Tramontano,
Violetta Cecchetti,
Arnaldo Fravolini,
Sara Masiero,
Manlio Palumbo,
Giorgio Palù
Publication year - 2003
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.47.3.889-896.2003
Subject(s) - reverse transcriptase , integrase inhibitor , viral replication , biology , transcription (linguistics) , mechanism of action , microbiology and biotechnology , integrase , virology , rna , virus , chemistry , in vitro , biochemistry , human immunodeficiency virus (hiv) , viral load , linguistics , philosophy , gene , antiretroviral therapy
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).