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Journal of Virology, June 2004, p. 5728-5736, Vol. 78, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.11.5728-5736.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Styrylquinolines, Integrase Inhibitors Acting Prior to Integration: a New Mechanism of Action for Anti-Integrase Agents

Sabine Bonnenfant,1,2 Claire Marie Thomas,1 Claudio Vita,3 Frédéric Subra,4 Eric Deprez,4 Fatima Zouhiri,1 Didier Desmaële,5 Jean d'Angelo,5 Jean François Mouscadet,4 and Hervé Leh1*

BioalliancePharma, 75015 Paris,1 INSERM U552, 75018 Paris,2 LBPA, CNRS UMR 8113, Ecole Normale Supérieure de Cachan, 94235 Cachan,4 Unité de Chimie Organique, UPRES-A CNRS 8076, Centre d'Études Pharmaceutiques, Université Paris-Sud, 92296 ChÂtenay-Malabry,5 Département d'Ingénierie et d'Etudes des Protéines, CEA Saclay, Gif-sur-Yvette, France3

Received 21 October 2003/ Accepted 30 January 2004

We have previously shown that styrylquinolines (SQLs) are integrase inhibitors in vitro. They compete with the long terminal repeat substrate for integrase. Here, we describe the cellular mode of action of these molecules. We show that SQLs do not interfere with virus entry. In fact, concentrations of up to 20 times the 50% inhibitory concentration did not inhibit cell-to-cell fusion or affect the interaction between GP120 and CD4 in vitro. Moreover, the pseudotype of the retrovirus envelope did not affect drug activity. Quantitative reverse transcription PCR experiments showed that SQLs do not inhibit the entry of the genomic RNA. In contrast, the treatment of human immunodeficiency virus type 1-infected cells with SQLs reduced the amount of the late cDNA, suggesting for the first time that integrase targeting molecules may affect the accumulation of DNA during reverse transcription. The cellular target of SQLs was confirmed by the appearance of mutations in the integrase gene when viruses were grown in the presence of increasing concentrations of SQLs. Finally, these mutations led to SQL-resistant viruses when introduced into the wild-type sequence. In contrast, SQLs were fully active against reverse transcriptase inhibitor- and diketo acid-resistant viruses, positioning SQLs as a second group of anti-integrase compounds.

* Corresponding author. Mailing address: BioalliancePharma, 59 Boulevard M. Valin, 75015 Paris, France. Phone: 33 1 47 40 76 74. Fax: 33 1 47 40 76 71. E-mail: leh{at}lbpa.ens-cachan.fr.

Journal of Virology, June 2004, p. 5728-5736, Vol. 78, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.11.5728-5736.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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