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 μM, 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 μM 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).
New Anti-Human Immunodeficency Virus Type 1 6-Aminoquinolones: Mechanism of Action
CECCHETTI, Violetta;FRAVOLINI, Arnaldo;
2003
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 μM, 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 μM 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).I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
