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Antimicrobial Agents and Chemotherapy, October 2003, p. 3109-3116, Vol. 47, No. 10
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.10.3109-3116.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Novel Human Immunodeficiency Virus (HIV) Inhibitors That Have a Dual Mode of Anti-HIV Action

Miguel Stevens, Christophe Pannecouque, Erik De Clercq, and Jan Balzarini*

Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium

Received 3 March 2003/ Returned for modification 27 May 2003/ Accepted 24 June 2003

We have found that novel pyridine oxide derivatives are inhibitors of a wide range of human immunodeficiency virus (HIV) type 1 (HIV-1) and HIV-2 strains in CEM cell cultures. Some of the compounds showed inhibitory activities against recombinant HIV-1 reverse transcriptase (RT), whereas others were totally inactive against this viral protein in vitro. Partial retention of anti-HIV-1 activity against virus strains that contain a variety of mutations characteristic of those for resistance to nonnucleoside RT inhibitors and a lack of inhibitory activity against recombinant HIV-2 RT suggested that these pyridine oxide derivatives possess a mode of antiviral action independent from HIV RT inhibition. Time-of-addition experiments revealed that these pyridine oxide derivatives interact at a postintegration step in the replication cycle of HIV. Furthermore, it was shown that these compounds are active not only in acutely HIV-1-infected cells but also in chronically HIV-infected cells. A dose-dependent inhibition of virus particle release and viral protein expression was observed upon exposure to the pyridine oxide derivatives. Finally, inhibition of HIV-1 long terminal repeat-mediated green fluorescence protein expression in quantitative transactivation bioassays indicated that the additional target of action of the pyridine oxide derivatives may be located at the level of HIV gene expression.

* Corresponding author. Mailing address: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. Phone: 0032 16 33 73 41. Fax: 0032 16 33 73 40. E-mail: jan.balzarini{at}rega.kuleuven.ac.be.

Antimicrobial Agents and Chemotherapy, October 2003, p. 3109-3116, Vol. 47, No. 10
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.10.3109-3116.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Balzarini, J., Keyaerts, E., Vijgen, L., Vandermeer, F., Stevens, M., De Clercq, E., Egberink, H., Van Ranst, M. (2006). Pyridine N-oxide derivatives are inhibitory to the human SARS and feline infectious peritonitis coronavirus in cell culture. J Antimicrob Chemother 57: 472-481 [Abstract] [Full Text]  
  • Stevens, M., Balzarini, J., Tabarrini, O., Andrei, G., Snoeck, R., Cecchetti, V., Fravolini, A., De Clercq, E., Pannecouque, C. (2005). Cell-dependent interference of a series of new 6-aminoquinolone derivatives with viral (HIV/CMV) transactivation. J Antimicrob Chemother 56: 847-855 [Abstract] [Full Text]  
  • Balzarini, J., Stevens, M., De Clercq, E., Schols, D., Pannecouque, C. (2005). Pyridine N-oxide derivatives: unusual anti-HIV compounds with multiple mechanisms of antiviral action. J Antimicrob Chemother 55: 135-138 [Abstract] [Full Text]  


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