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Antimicrobial Agents and Chemotherapy, September 2003, p. 2951-2957, Vol. 47, No. 9
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.9.2951-2957.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Inhibition of Human Immunodeficiency Virus by a New Class of Pyridine Oxide Derivatives

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

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

Received 9 January 2003/ Returned for modification 14 April 2003/ Accepted 10 June 2003

A new class of pyridine oxide derivatives as inhibitors of human immunodeficiency virus type 1 (HIV-1) and/or HIV-2 replication in cell culture has been identified. The compounds, which specifically inhibit HIV-1, behave as typical nonnucleoside reverse transcriptase inhibitors (NNRTIs). The most active congener of this group, JPL-133 (UC-B3096), has a 50% effective concentration of 0.05 µg/ml for HIV-1(IIIB) with a selectivity index of approximately 760 in CEM cell cultures. However, the cytostatic activity of most pyridine oxide derivatives highly depended on the nature of the cell line. All compounds, including those pyridine oxide derivatives that inhibit both HIV-1 and HIV-2 replication, select for NNRTI-characteristic mutations in the HIV-1 reverse transcriptase of HIV-infected cell cultures (i.e., Lys103Asn, Val108Ile, Glu138Lys, Tyr181Cys and Tyr188His). These amino acid mutations emerged mostly through transition of guanine to adenine or adenine to guanine in the corresponding codons of the reverse transcriptase (RT) gene. The HIV-1-specific pyridine oxide derivatives lost their antiviral activity against HIV-1 strains containing these mutations in the RT. However, most compounds retained pronounced antiviral potency against virus strains that contained other NNRTI-characteristic RT mutations, such as Leu100Ile and Val179Asp. Furthermore, the complete lack of inhibitory activity of the pyridine oxide derivatives against recombinant HIV-2 RT and partial retention of anti-HIV-1 activity against HIV-1 strains that contain a variety of HIV-1-characteristic mutations suggest that the pyridine oxide derivatives must have a second target of antiviral action independent from HIV-1 RT.

* Corresponding author. Mailing address: Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium. Phone: 32 16 337341. Fax: 32 16 337340. E-mail: jan.balzarini{at}rega.kuleuven.ac.be.

Antimicrobial Agents and Chemotherapy, September 2003, p. 2951-2957, Vol. 47, No. 9
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.9.2951-2957.2003
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]  
  • 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]  
  • Stevens, M., Pannecouque, C., De Clercq, E., Balzarini, J. (2003). Novel Human Immunodeficiency Virus (HIV) Inhibitors That Have a Dual Mode of Anti-HIV Action. Antimicrob. Agents Chemother. 47: 3109-3116 [Abstract] [Full Text]  


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