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Antimicrobial Agents and Chemotherapy, August 2006, p. 2772-2781, Vol. 50, No. 8
0066-4804/06/$08.00+0     doi:10.1128/AAC.00127-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Novel Nonnucleoside Inhibitors That Select Nucleoside Inhibitor Resistance Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase

Zhijun Zhang,* Michelle Walker, Wen Xu, Jae Hoon Shim, Jean-Luc Girardet, Robert K. Hamatake, and Zhi Hong

Drug Discovery, Valeant Research & Development, 3300 Hyland Avenue, Costa Mesa, California 92626

Received 31 January 2006/ Returned for modification 11 April 2006/ Accepted 25 May 2006

Mutations in and around the catalytic site of the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) are associated with resistance to nucleoside RT inhibitors (NRTIs), whereas changes in the hydrophobic pocket of the RT are attributed to nonnucleoside RT inhibitor (NNRTI) resistance. In this study, we report a novel series of nonnucleoside inhibitors of HIV-1, exemplified by VRX-329747 and VRX-413638, which inhibit both NNRTI- and NRTI-resistant HIV-1 isolates. Enzymatic studies indicated that these compounds are HIV-1 RT inhibitors. Surprisingly, however, following prolonged (6 months) tissue culture selection, this series of nonnucleoside inhibitors did not select NNRTI-resistant mutations in HIV-1 RT. Rather, four mutations (M41L, A62T/V, V118I, and M184V) known to cause resistance to NRTIs and two additional novel mutations (S68N and G112S) adjacent to the catalytic site of the enzyme were selected. Although the M184V mutation appears to be the initial mutation to establish resistance, this mutation alone confers only a two- to fourfold decrease in susceptibility to VRX-329747 and VRX-413638. At least two additional mutations must accumulate for significant resistance. Moreover, while VRX-329747-selected viruses are resistant to lamivudine and emtricitabine due to the M184V mutation, they remain susceptible to zidovudine, stavudine, dideoxyinosine, abacavir, tenofovir, and efavirenz. These results directly demonstrate that VRX-329747 and VRX-413638 are novel nonnucleoside inhibitors of HIV-1 RT with the potential to augment current therapies.

* Corresponding author. Mailing address: Drug Discovery, Valeant Research & Development, 3300 Hyland Avenue, Costa Mesa, CA 92626. Phone: (714) 545-0100. Fax: (714) 668-3141. E-mail: zzhang{at}valeant.com.

Antimicrobial Agents and Chemotherapy, August 2006, p. 2772-2781, Vol. 50, No. 8
0066-4804/06/$08.00+0     doi:10.1128/AAC.00127-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Xu, H., Quan, Y., Brenner, B. G., Bar-Magen, T., Oliveira, M., Schader, S. M., Wainberg, M. A. (2009). Human Immunodeficiency Virus Type 1 Recombinant Reverse Transcriptase Enzymes Containing the G190A and Y181C Resistance Mutations Remain Sensitive to Etravirine. Antimicrob. Agents Chemother. 53: 4667-4672 [Abstract] [Full Text]  
  • Ehteshami, M., Scarth, B. J., Tchesnokov, E. P., Dash, C., Le Grice, S. F. J., Hallenberger, S., Jochmans, D., Gotte, M. (2008). Mutations M184V and Y115F in HIV-1 Reverse Transcriptase Discriminate against "Nucleotide-competing Reverse Transcriptase Inhibitors". J. Biol. Chem. 283: 29904-29911 [Abstract] [Full Text]  
  • Zhang, Z., Xu, W., Koh, Y.-H., Shim, J. H., Girardet, J.-L., Yeh, L.-T., Hamatake, R. K., Hong, Z. (2007). A Novel Nonnucleoside Analogue That Inhibits Human Immunodeficiency Virus Type 1 Isolates Resistant to Current Nonnucleoside Reverse Transcriptase Inhibitors. Antimicrob. Agents Chemother. 51: 429-437 [Abstract] [Full Text]  


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