This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gong, Y.-F.
Right arrow Articles by Lin, P.-f.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gong, Y.-F.
Right arrow Articles by Lin, P.-f.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, September 2000, p. 2319-2326, Vol. 44, No. 9
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

In Vitro Resistance Profile of the Human Immunodeficiency Virus Type 1 Protease Inhibitor BMS-232632

Yi-Fei Gong,1 Brett S. Robinson,1 Ronald E. Rose,1 Carol Deminie,1 Timothy P. Spicer,1 David Stock,2 Richard J. Colonno,1 and Pin-fang Lin1,*

Departments of Virology1 and Non-Clinical Statistics,2 Bristol-Myers Squibb Company, Wallingford, Connecticut 06492

Received 7 September 1999/Returned for modification 29 November 1999/Accepted 31 May 2000

BMS-232632 is an azapeptide human immunodeficiency virus (HIV) type 1 (HIV-1) protease inhibitor that displays potent anti-HIV-1 activity (50% effective concentration [EC50], 2.6 to 5.3 nM; EC90, 9 to 15 nM). In vitro passage of HIV-1 RF in the presence of inhibitors showed that BMS-232632 selected for resistant variants more slowly than nelfinavir or ritonavir did. Genotypic and phenotypic analysis of three different HIV strains resistant to BMS-232632 indicated that an N88S substitution in the viral protease appeared first during the selection process in two of the three strains. An I84V change appeared to be an important substitution in the third strain used. Mutations were also observed at the protease cleavage sites following drug selection. The evolution to resistance seemed distinct for each of the three strains used, suggesting multiple pathways to resistance and the importance of the viral genetic background. A cross-resistance study involving five other protease inhibitors indicated that BMS-232632-resistant virus remained sensitive to saquinavir, while it showed various levels (0.1- to 71-fold decrease in sensitivity)-of cross-resistance to nelfinavir, indinavir, ritonavir, and amprenavir. In reciprocal experiments, the BMS-232632 susceptibility of HIV-1 variants selected in the presence of each of the other HIV-1 protease inhibitors showed that the nelfinavir-, saquinavir-, and amprenavir-resistant strains of HIV-1 remained sensitive to BMS-232632, while indinavir- and ritonavir-resistant viruses displayed six- to ninefold changes in BMS-232632 sensitivity. Taken together, our data suggest that BMS-232632 may be a valuable protease inhibitor for use in combination therapy.

* Corresponding author. Mailing address: Bristol-Myers Squibb Co., 5 Research Parkway, Wallingford, CT 06492. Phone: (203) 677-6437. Fax: (203) 677-6088. E-mail: linp{at}bms.com.

Antimicrobial Agents and Chemotherapy, September 2000, p. 2319-2326, Vol. 44, No. 9
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Koh, Y., Das, D., Leschenko, S., Nakata, H., Ogata-Aoki, H., Amano, M., Nakayama, M., Ghosh, A. K., Mitsuya, H. (2009). GRL-02031, a Novel Nonpeptidic Protease Inhibitor (PI) Containing a Stereochemically Defined Fused Cyclopentanyltetrahydrofuran Potent against Multi-PI-Resistant Human Immunodeficiency Virus Type 1 In Vitro. Antimicrob. Agents Chemother. 53: 997-1006 [Abstract] [Full Text]  
  • Dekhtyar, T., Ng, T. I., Lu, L., Masse, S., DeGoey, D. A., Flosi, W. J., Grampovnik, D. J., Klein, L. L., Kempf, D. J., Molla, A. (2008). Characterization of a Novel Human Immunodeficiency Virus Type 1 Protease Inhibitor, A-790742. Antimicrob. Agents Chemother. 52: 1337-1344 [Abstract] [Full Text]  
  • Klei, H. E., Kish, K., Lin, P.-F. M., Guo, Q., Friborg, J., Rose, R. E., Zhang, Y., Goldfarb, V., Langley, D. R., Wittekind, M., Sheriff, S. (2007). X-Ray Crystal Structures of Human Immunodeficiency Virus Type 1 Protease Mutants Complexed with Atazanavir. J. Virol. 81: 9525-9535 [Abstract] [Full Text]  
  • Amano, M., Koh, Y., Das, D., Li, J., Leschenko, S., Wang, Y.-F., Boross, P. I., Weber, I. T., Ghosh, A. K., Mitsuya, H. (2007). A Novel Bis-Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitor (PI), GRL-98065, Is Potent against Multiple-PI-Resistant Human Immunodeficiency Virus In Vitro. Antimicrob. Agents Chemother. 51: 2143-2155 [Abstract] [Full Text]  
  • von Hentig, N., Muller, A., Rottmann, C., Wolf, T., Lutz, T., Klauke, S., Kurowski, M., Oertel, B., Dauer, B., Harder, S., Staszewski, S. (2007). Pharmacokinetics of Saquinavir, Atazanavir, and Ritonavir in a Twice-Daily Boosted Double-Protease Inhibitor Regimen. Antimicrob. Agents Chemother. 51: 1431-1439 [Abstract] [Full Text]  
  • Weinheimer, S., Discotto, L., Friborg, J., Yang, H., Colonno, R. (2005). Atazanavir Signature I50L Resistance Substitution Accounts for Unique Phenotype of Increased Susceptibility to Other Protease Inhibitors in a Variety of Human Immunodeficiency Virus Type 1 Genetic Backbones. Antimicrob. Agents Chemother. 49: 3816-3824 [Abstract] [Full Text]  
  • Orrick, J. J, Steinhart, C. R (2004). Atazanavir. The Annals of Pharmacotherapy 38: 1664-1674 [Abstract] [Full Text]  
  • Cheng, T.-J., Brik, A., Wong, C.-H., Kan, C.-C. (2004). Model System for High-Throughput Screening of Novel Human Immunodeficiency Virus Protease Inhibitors in Escherichia coli. Antimicrob. Agents Chemother. 48: 2437-2447 [Abstract] [Full Text]  
  • Taburet, A.-M., Piketty, C., Chazallon, C., Vincent, I., Gerard, L., Calvez, V., Clavel, F., Aboulker, J.-P., Girard, P.-M. (2004). Interactions between Atazanavir-Ritonavir and Tenofovir in Heavily Pretreated Human Immunodeficiency Virus-Infected Patients. Antimicrob. Agents Chemother. 48: 2091-2096 [Abstract] [Full Text]  
  • Koh, Y., Nakata, H., Maeda, K., Ogata, H., Bilcer, G., Devasamudram, T., Kincaid, J. F., Boross, P., Wang, Y.-F., Tie, Y., Volarath, P., Gaddis, L., Harrison, R. W., Weber, I. T., Ghosh, A. K., Mitsuya, H. (2003). Novel bis-Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitor (PI) UIC-94017 (TMC114) with Potent Activity against Multi-PI-Resistant Human Immunodeficiency Virus In Vitro. Antimicrob. Agents Chemother. 47: 3123-3129 [Abstract] [Full Text]  
  • Lin, P.-F., Blair, W., Wang, T., Spicer, T., Guo, Q., Zhou, N., Gong, Y.-F., Wang, H.-G. H., Rose, R., Yamanaka, G., Robinson, B., Li, C.-B., Fridell, R., Deminie, C., Demers, G., Yang, Z., Zadjura, L., Meanwell, N., Colonno, R. (2003). From the Cover: A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding. Proc. Natl. Acad. Sci. USA 100: 11013-11018 [Abstract] [Full Text]  
  • Colonno, R. J., Thiry, A., Limoli, K., Parkin, N. (2003). Activities of Atazanavir (BMS-232632) against a Large Panel of Human Immunodeficiency Virus Type 1 Clinical Isolates Resistant to One or More Approved Protease Inhibitors. Antimicrob. Agents Chemother. 47: 1324-1333 [Abstract] [Full Text]  
  • Resch, W., Ziermann, R., Parkin, N., Gamarnik, A., Swanstrom, R. (2002). Nelfinavir-Resistant, Amprenavir-Hypersusceptible Strains of Human Immunodeficiency Virus Type 1 Carrying an N88S Mutation in Protease Have Reduced Infectivity, Reduced Replication Capacity, and Reduced Fitness and Process the Gag Polyprotein Precursor Aberrantly. J. Virol. 76: 8659-8666 [Abstract] [Full Text]  
  • Shafer, R. W. (2002). Genotypic Testing for Human Immunodeficiency Virus Type 1 Drug Resistance. Clin. Microbiol. Rev. 15: 247-277 [Abstract] [Full Text]  
  • Maguire, M., Shortino, D., Klein, A., Harris, W., Manohitharajah, V., Tisdale, M., Elston, R., Yeo, J., Randall, S., Xu, F., Parker, H., May, J., Snowden, W. (2002). Emergence of Resistance to Protease Inhibitor Amprenavir in Human Immunodeficiency Virus Type 1-Infected Patients: Selection of Four Alternative Viral Protease Genotypes and Influence of Viral Susceptibility to Coadministered Reverse Transcriptase Nucleoside Inhibitors. Antimicrob. Agents Chemother. 46: 731-738 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»