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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

Cristina Parolin,1 Barbara Gatto,2 Claudia Del Vecchio,1 Teresa Pecere,1 Enzo Tramontano,3 Violetta Cecchetti,4 Arnaldo Fravolini,4 Sara Masiero,1 Manlio Palumbo,2 and Giorgio Palù1*

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).

* Corresponding author. Mailing address: Department of Histology, Microbiology and Medical Biotechnologies, University of Padua, Via A. Gabelli 63, 35121 Padua, Italy. Phone: 39-049-827-2350. Fax: 39-049-827-2355. E-mail: giorgio.palu{at}unipd.it.

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.



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