This Article
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 Olmsted, R. A.
Right arrow Articles by Tarpley, W. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Olmsted, R. A.
Right arrow Articles by Tarpley, W. G.

 Previous Article  |  Next Article 

J. Virol., Jun 1996, 3698-3705, Vol 70, No. 6
Copyright © 1996, American Society for Microbiology

(Alkylamino) piperidine bis(heteroaryl)piperizine analogs are potent, broad-spectrum nonnucleoside reverse transcriptase inhibitors of drug- resistant isolates of human immunodeficiency virus type 1 (HIV-1) and select for drug-resistant variants of HIV-1IIIB with reduced replication phenotypes

RA Olmsted, DE Slade, LA Kopta, SM Poppe, TJ Poel, SW Newport, KB Rank, C Biles, RA Morge, TJ Dueweke, Y Yagi, DL Romero, RC Thomas, SK Sharma and WG Tarpley
Cancer and Infectious Diseases Research, Pharmacia & Upjohn, Kalamazoo, Michigan 49001.

The (alkylamino)piperidine bis(heteroaryl)piperizines (AAP-BHAPs) are a new class of human immunodeficiency virus type 1 (HIV-1)-specific inhibitors which were identified by targeted screening of recombinant reverse transcriptase (RT) enzymes carrying key nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-conferring mutations and NNRTI-resistant variants of HIV-1. Phenotypic profiling of the two most potent AAP-BHAPs, U-95133 and U-104489, against in vitro-selected drug- resistant HIV-1 variants carrying the NNRTI resistance-conferring mutation (Tyr->Cys) at position 181 of the HIV-1 RT revealed submicromolar 90% inhibitory concentration estimates for these compounds. Moreover, U-104489 demonstrated potent activity against BHA- P-resistant HIV-1MF harboring the Pro-236->Leu RT substitution and significantly suppressed the replication of clinical isolates of HIV-1 resistant to both delavirdine (BHAP U-90152T) and zidovudine. Biochemical and phenotypic characterization of AAP-BHAPresistant HIV- 1IIIB variants revealed that high-level resistance to the AAP-BHAPs was mediated by a Gly-190->Glu substitution in RT, which had a deleterious effect on the integrity and enzymatic activity of virion-associated RT heterodimers, as well as the replication capacity of these resistant viruses.


This article has been cited by other articles:

  • Dykes, C., Demeter, L. M. (2007). Clinical Significance of Human Immunodeficiency Virus Type 1 Replication Fitness. Clin. Microbiol. Rev. 20: 550-578 [Abstract] [Full Text]  
  • Cases-Gonzalez, C. E., Menendez-Arias, L. (2004). Increased G->A Transition Frequencies Displayed by Primer Grip Mutants of Human Immunodeficiency Virus Type 1 Reverse Transcriptase. J. Virol. 78: 1012-1019 [Abstract] [Full Text]  
  • Huang, W., Gamarnik, A., Limoli, K., Petropoulos, C. J., Whitcomb, J. M. (2002). Amino Acid Substitutions at Position 190 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Increase Susceptibility to Delavirdine and Impair Virus Replication. J. Virol. 77: 1512-1523 [Abstract] [Full Text]  
  • Gutierrez-Rivas, M., Menendez-Arias, L. (2001). A mutation in the primer grip region of HIV-1 reverse transcriptase that confers reduced fidelity of DNA synthesis. Nucleic Acids Res 29: 4963-4972 [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]  
  • Olivares, I., Sánchez-Merino, V., Martínez, M. A., Domingo, E., López-Galíndez, C., Menéndez-Arias, L. (1999). Second-Site Reversion of a Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutant That Restores Enzyme Function and Replication Capacity. J. Virol. 73: 6293-6298 [Abstract] [Full Text]  
  • Argyris, E. G., Vanderkooi, J. M., Venkateswaran, P. S., Kay, B. K., Paterson, Y. (1999). The Connection Domain Is Implicated in Metalloporphyrin Binding and Inhibition of HIV Reverse Transcriptase. J. Biol. Chem. 274: 1549-1556 [Abstract] [Full Text]  
  • Huang, M., Zensen, R., Cho, M., Martin, M. A. (1998). Construction and Characterization of a Temperature-Sensitive Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutant. J. Virol. 72: 2047-2054 [Abstract] [Full Text]  
  • Boyer, P. L., Gao, H.-Q., Hughes, S. H. (1998). A Mutation at Position 190 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Interacts with Mutations at Positions 74 and 75 via the Template Primer. Antimicrob. Agents Chemother. 42: 447-452 [Abstract] [Full Text]  
  • Esnouf, R. M., Ren, J., Hopkins, A. L., Ross, C. K., Jones, E. Y., Stammers, D. K., Stuart, D. I. (1997). Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this nonnucleoside inhibitor. Proc. Natl. Acad. Sci. USA 94: 3984-3989 [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»