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Antimicrobial Agents and Chemotherapy, March 2003, p. 889-896, Vol. 47, No. 3
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.3.889-896.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

New Anti-Human Immunodeficiency Virus Type 1 6-Aminoquinolones: Mechanism of Action

Department of Histology, Microbiology and Medical Biotechnologies, Section of Microbiology and Virology,¹ Department of Pharmaceutical Sciences, University of Padua, 35121 Padua,² Department of Experimental Biology, University of Cagliari, 09042 Cagliari,³ Department of Pharmaceutical Chemistry and Technology, University of Perugia, 06123 Perugia, Italy⁴

Received 14 August 2002/ Returned for modification 15 November 2002/ Accepted 19 December 2002

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).

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