This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Boyer, P L Articles by Hughes, S H Search for Related Content PubMed PubMed Citation Articles by Boyer, P L Articles by Hughes, S H

 Previous Article  |  Next Article 

J Virol. 1993 April; 67(4): 2412-2420

Analysis of nonnucleoside drug-resistant variants of human immunodeficiency virus type 1 reverse transcriptase.

ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Maryland 21702-1201.

ABSTRACT

A number of chemically distinct nonnucleoside inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) have been reported. Several lines of evidence, including the isolation of RT mutants that show cross resistance, suggest that, despite their structural diversity, many of these inhibitors bind to a common site on HIV-1 RT. We have recently reported that, on the basis of analyses of HIV-1/HIV-2 chimeras, the natural product calanolide A may interact with a different site or sites in HIV-1 RT. We have used BspMI cassette mutagenesis to prepare a collection of HIV-1 RT mutants that show resistance to the known members of the general class of nonnucleoside inhibitors. This collection of mutants can be used to determine whether a new drug will show cross resistance with known inhibitors and to define amino acid positions critical for the action of the drugs. The mutants were used to analyze calanolide A, 1H,3H-thiazolo[3,4-a]benzimidazole(4i), and the acyclic nucleoside analog 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine. These analyses suggest that all three drugs interact with HIV-1 RT within the previously defined common binding site for nonnucleoside inhibitors. However, the drugs respond differently to the panel of drug-resistant HIV-1 RTs, indicating that while the binding sites of the drugs overlap they are not identical.

This article has been cited by other articles:

• Buckheit, R. W. Jr., Hartman, T. L., Watson, K. M., Chung, S.-G., Cho, E.-H. (2008). Comparative Evaluation of the Inhibitory Activities of a Series of Pyrimidinedione Congeners That Inhibit Human Immunodeficiency Virus Types 1 and 2. Antimicrob. Agents Chemother. 52: 225-236 [Abstract] [Full Text]  
• Zhang, Z., Walker, M., Xu, W., Shim, J. H., Girardet, J.-L., Hamatake, R. K., Hong, Z. (2006). Novel nonnucleoside inhibitors that select nucleoside inhibitor resistance mutations in human immunodeficiency virus type 1 reverse transcriptase.. Antimicrob. Agents Chemother. 50: 2772-2781 [Abstract] [Full Text]  
• Budihas, S. R., Gorshkova, I., Gaidamakov, S., Wamiru, A., Bona, M. K., Parniak, M. A., Crouch, R. J., McMahon, J. B., Beutler, J. A., Le Grice, S. F. J. (2005). Selective inhibition of HIV-1 reverse transcriptase-associated ribonuclease H activity by hydroxylated tropolones. Nucleic Acids Res 33: 1249-1256 [Abstract] [Full Text]  
• Clavel, F., Hance, A. J. (2004). HIV Drug Resistance. NEJM 350: 1023-1035 [Full Text]  
• Shen, L., Shen, J., Luo, X., Cheng, F., Xu, Y., Chen, K., Arnold, E., Ding, J., Jiang, H. (2003). Steered Molecular Dynamics Simulation on the Binding of NNRTI to HIV-1 RT. Biophys. J 84: 3547-3563 [Abstract] [Full Text]  
• Creagh, T., Ruckle, J. L., Tolbert, D. T., Giltner, J., Eiznhamer, D. A., Dutta, B., Flavin, M. T., Xu, Z.-Q. (2001). Safety and Pharmacokinetics of Single Doses of (+)-Calanolide A, a Novel, Naturally Occurring Nonnucleoside Reverse Transcriptase Inhibitor, in Healthy, Human Immunodeficiency Virus-Negative Human Subjects. Antimicrob. Agents Chemother. 45: 1379-1386 [Abstract] [Full Text]  
• Buckheit, R. W. Jr., Watson, K., Fliakas-Boltz, V., Russell, J., Loftus, T. L., Osterling, M. C., Turpin, J. A., Pallansch, L. A., White, E. L., Lee, J.-W., Lee, S.-H., Oh, J.-W., Kwon, H.-S., Chung, S.-G., Cho, E.-H. (2001). SJ-3366, a Unique and Highly Potent Nonnucleoside Reverse Transcriptase Inhibitor of Human Immunodeficiency Virus Type 1 (HIV-1) That Also Inhibits HIV-2. Antimicrob. Agents Chemother. 45: 393-400 [Abstract] [Full Text]  
• Imamichi, T., Sinha, T., Imamichi, H., Zhang, Y.-M., Metcalf, J. A., Falloon, J., Lane, H. C. (2000). High-Level Resistance to 3'-Azido-3'-Deoxythimidine due to a Deletion in the Reverse Transcriptase Gene of Human Immunodeficiency Virus Type 1. J. Virol. 74: 1023-1028 [Abstract] [Full Text]  
• Buckheit, R. W. Jr., White, E. L., Fliakas-Boltz, V., Russell, J., Stup, T. L., Kinjerski, T. L., Osterling, M. C., Weigand, A., Bader, J. P. (1999). Unique Anti-Human Immunodeficiency Virus Activities of the Nonnucleoside Reverse Transcriptase Inhibitors Calanolide A, Costatolide, and Dihydrocostatolide. Antimicrob. Agents Chemother. 43: 1827-1834 [Abstract] [Full Text]  
• Nissley, D. V., Boyer, P. L., Garfinkel, D. J., Hughes, S. H., Strathern, J. N. (1998). Hybrid Ty1/HIV-1 elements used to detect inhibitors and monitor the activity of HIV-1 reverse transcriptase. Proc. Natl. Acad. Sci. USA 95: 13905-13910 [Abstract] [Full Text]