Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 7 December 1990:
Vol. 250. no. 4986, pp. 1411 - 1413
DOI: 10.1126/science.1701568
Prev | Table of Contents | Next

Articles

Science, Vol 250, Issue 4986, 1411-1413
Copyright © 1990 by American Association for the Advancement of Science

articles

Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor

VJ Merluzzi, KD Hargrave, M Labadia, K Grozinger, M Skoog, JC Wu, CK Shih, K Eckner, S Hattox, J Adams, and al. et

Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877.

A series of dipyridodiazepinones have been shown to be potent inhibitors of human immunodeficiency virus-1 (HIV-1) reverse transcriptase (RT). One compound, BI-RG-587, had a Ki of 200 nanomolar for inhibition of HIV-1 RT that was noncompetitive with respect to deoxyguanosine triphosphate. BI-RG-587 was specific for HIV-1 RT, having no effect on feline and simian RT or any mammalian DNA polymerases. BI-RG-587 inhibited HIV-1 replication in vitro as demonstrated by in situ hybridization, inhibition of protein p24 production, and the lack of syncytia formation in cultured human T cell lines and freshly isolated human peripheral blood lymphocytes. Cytotoxicity studies of BI-RG-587 on human cells showed a high therapeutic index (greater than 8000) in culture.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Cytotoxicological Analysis of a gp120 Binding Aptamer with Cross-Clade Human Immunodeficiency Virus Type 1 Entry Inhibition Properties: Comparison to Conventional Antiretrovirals.
W. R. L. de Campos, D. Coopusamy, L. Morris, B. M. Mayosi, and M. Khati (2009)
Antimicrob. Agents Chemother. 53, 3056-3064
   Abstract »    Full Text »    PDF »
Inhibition of Human Immunodeficiency Virus Type 1 Infection by the Candidate Microbicide Dapivirine, a Nonnucleoside Reverse Transcriptase Inhibitor.
P. Fletcher, S. Harman, H. Azijn, N. Armanasco, P. Manlow, D. Perumal, M.-P. de Bethune, J. Nuttall, J. Romano, and R. Shattock (2009)
Antimicrob. Agents Chemother. 53, 487-495
   Abstract »    Full Text »    PDF »
Reverse transcription of the HIV-1 pandemic.
A. Basavapathruni and K. S. Anderson (2007)
FASEB J 21, 3795-3808
   Abstract »    Full Text »    PDF »
Antiretroviral Drugs.
D. Warnke, J. Barreto, and Z. Temesgen (2007)
J. Clin. Pharmacol. 47, 1570-1579
   Abstract »    Full Text »    PDF »
Characterization of a Replication-Competent, Integrase-Defective Human Immunodeficiency Virus (HIV)/Simian Virus 40 Chimera as a Powerful Tool for the Discovery and Validation of HIV Integrase Inhibitors.
D. Daelemans, R. Lu, E. De Clercq, and A. Engelman (2007)
J. Virol. 81, 4381-4385
   Abstract »    Full Text »    PDF »
Closing of the Fingers Domain Generates Motor Forces in the HIV Reverse Transcriptase.
H. Lu, J. Macosko, D. Habel-Rodriguez, R. W. Keller, J. A. Brozik, and D. J. Keller (2004)
J. Biol. Chem. 279, 54529-54532
   Abstract »    Full Text »    PDF »
Diversity-oriented solid-phase synthesis and biological evaluation of oligonucleotide hairpins as HIV-1 RT RNase H inhibitors.
R. N. Hannoush, K.-L. Min, and M. J. Damha (2004)
Nucleic Acids Res. 32, 6164-6175
   Abstract »    Full Text »    PDF »
Structure of HIV-1 reverse transcriptase bound to an inhibitor active against mutant reverse transcriptases resistant to other nonnucleoside inhibitors.
J. D. Pata, W. G. Stirtan, S. W. Goldstein, and T. A. Steitz (2004)
PNAS 101, 10548-10553
   Abstract »    Full Text »    PDF »
Defining a Molecular Mechanism of Synergy between Nucleoside and Nonnucleoside AIDS Drugs.
A. Basavapathruni, C. M. Bailey, and K. S. Anderson (2004)
J. Biol. Chem. 279, 6221-6224
   Abstract »    Full Text »    PDF »
Specific inhibitors of HCV polymerase identified using an NS5B with lower affinity for template/primer substrate.
G. McKercher, P. L. Beaulieu, D. Lamarre, S. LaPlante, S. Lefebvre, C. Pellerin, L. Thauvette, and G. Kukolj (2004)
Nucleic Acids Res. 32, 422-431
   Abstract »    Full Text »    PDF »
Non-nucleoside Inhibitors of HIV-1 Reverse Transcriptase Inhibit Phosphorolysis and Resensitize the 3'-Azido-3'-deoxythymidine (AZT)-resistant Polymerase to AZT-5'-triphosphate.
L. Odriozola, C. Cruchaga, M. Andreola, V. Dolle, C. H. Nguyen, L. Tarrago-Litvak, A. Perez-Mediavilla, and J. J. Martinez-Irujo (2003)
J. Biol. Chem. 278, 42710-42716
   Abstract »    Full Text »    PDF »
The Y181C Substitution in 3'-Azido-3'-deoxythymidine-resistant Human Immunodeficiency Virus, Type 1, Reverse Transcriptase Suppresses the ATP-mediated Repair of the 3'-Azido-3'-deoxythymidine 5'-Monophosphate-terminated Primer.
B. Selmi, J. Deval, K. Alvarez, J. Boretto, S. Sarfati, C. Guerreiro, and B. Canard (2003)
J. Biol. Chem. 278, 40464-40472
   Abstract »    Full Text »    PDF »
From the Cover: Nonnucleoside reverse transcriptase inhibitors are chemical enhancers of dimerization of the HIV type 1 reverse transcriptase.
G. Tachedjian, M. Orlova, S. G. Sarafianos, E. Arnold, and S. P. Goff (2001)
PNAS 98, 7188-7193
   Abstract »    Full Text »    PDF »
Phenylethylthiazolylthiourea (PETT) Non-nucleoside Inhibitors of HIV-1 and HIV-2 Reverse Transcriptases. STRUCTURAL AND BIOCHEMICAL ANALYSES.
J. Ren, J. Diprose, J. Warren, R. M. Esnouf, L. E. Bird, S. Ikemizu, M. Slater, J. Milton, J. Balzarini, D. I. Stuart, et al. (2000)
J. Biol. Chem. 275, 5633-5639
   Abstract »    Full Text »    PDF »
Safety Assessment, In Vitro and In Vivo, and Pharmacokinetics of Emivirine, a Potent and Selective Nonnucleoside Reverse Transcriptase Inhibitor of Human Immunodeficiency Virus Type 1.
G. M. Szczech, P. Furman, G. R. Painter, D. W. Barry, K. Borroto-Esoda, T. B. Grizzle, M. R. Blum, J.-P. Sommadossi, R. Endoh, T. Niwa, et al. (2000)
Antimicrob. Agents Chemother. 44, 123-130
   Abstract »    Full Text »
High-Level Resistance to 3'-Azido-3'-Deoxythimidine due to a Deletion in the Reverse Transcriptase Gene of Human Immunodeficiency Virus Type 1.
T. Imamichi, T. Sinha, H. Imamichi, Y.-M. Zhang, J. A. Metcalf, J. Falloon, and H. C. Lane (2000)
J. Virol. 74, 1023-1028
   Abstract »    Full Text »
Biotransformation of Nevirapine, a Non-nucleoside HIV-1 Reverse Transcriptase Inhibitor, in Mice, Rats, Rabbits, Dogs, Monkeys, and Chimpanzees.
P. S. Riska, D. P. Joseph, R. M. Dinallo, W. C. Davidson, J. J. Keirns, and S. E. Hattox (1999)
Drug Metab. Dispos. 27, 1434-1447
   Abstract »    Full Text »
Disposition and Biotransformation of the Antiretroviral Drug Nevirapine in Humans.
P. Riska, M. Lamson, T. MacGregor, J. Sabo, S. Hattox, J. Pav, and J. Keirns (1999)
Drug Metab. Dispos. 27, 895-901
   Abstract »    Full Text »
The Thiocarboxanilide Nonnucleoside Inhibitor UC781 Restores Antiviral Activity of 3'-Azido-3'-Deoxythymidine (AZT) against AZT-Resistant Human Immunodeficiency Virus Type 1.
G. Borkow, D. Arion, M. A. Wainberg, and M. A. Parniak (1999)
Antimicrob. Agents Chemother. 43, 259-263
   Abstract »    Full Text »
Cell Cycle Arrest by Vpr in HIV-1 Virions and Insensitivity to Antiretroviral Agents.
B. Poon, K. Grovit-Ferbas, S. A. Stewart, and I. S. Chen (1998)
Science 281, 266-269
   Abstract »    Full Text »
S-1153 Inhibits Replication of Known Drug-Resistant Strains of Human Immunodeficiency Virus Type 1.
T. Fujiwara, A. Sato, M. El-Farrash, S. Miki, K. Abe, Y. Isaka, M. Kodama, Y. Wu, L. B. Chen, H. Harada, et al. (1998)
Antimicrob. Agents Chemother. 42, 1340-1345
   Abstract »    Full Text »
A Randomized, Double-blind Trial Comparing Combinations of Nevirapine, Didanosine, and Zidovudine for HIV-Infected Patients: The INCAS Trial.
J. S. G. Montaner, P. Reiss, D. Cooper, S. Vella, M. Harris, B. Conway, M. A. Wainberg, D. Smith, P. Robinson, D. Hall, et al. (1998)
JAMA 279, 930-937
   Abstract »    Full Text »    PDF »
1,1,3-Trioxo-2H,4H-Thieno[3,4-e][1,2,4]Thiadiazine (TTD) Derivatives: a New Class of Nonnucleoside Human Immunodeficiency Virus Type 1 (HIV-1) Reverse Transcriptase Inhibitors with Anti-HIV-1 Activity.
M. Witvrouw, M. E. Arranz, C. Pannecouque, R. Declercq, H. Jonckheere, J.-C. Schmit, A.-M. Vandamme, J. A. Diaz, S. T. Ingate, J. Desmyter, et al. (1998)
Antimicrob. Agents Chemother. 42, 618-623
   Abstract »    Full Text »
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.
R. M. Esnouf, J. Ren, A. L. Hopkins, C. K. Ross, E. Y. Jones, D. K. Stammers, and D. I. Stuart (1997)
PNAS 94, 3984-3989
   Abstract »    Full Text »    PDF »
Metabolism of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Inhibitor Delavirdine in Rats.
M. Chang, V. K. Sood, G. J. Wilson, D. A. Kloosterman, P. E. Sanders, M. J. Hauer, and P. E. Fagerness (1997)
Drug Metab. Dispos. 25, 228-242
   Abstract »    Full Text »
Enzymatic Characterization of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Resistant to Multiple 2`,3`-Dideoxynucleoside 5`-Triphosphates.
T. Ueno, T. Shirasaka, and H. Mitsuya (1995)
J. Biol. Chem. 270, 23605-23611
   Abstract »    Full Text »    PDF »
Nevirapine Alters the Cleavage Specificity of Ribonuclease H of Human Immunodeficiency Virus 1 Reverse Transcriptase.
C. Palaniappan, P. J. Fay, and R. A. Bambara (1995)
J. Biol. Chem. 270, 4861-4869
   Abstract »    Full Text »    PDF »
Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors.
R. Spence, W. Kati, K. Anderson, and K. Johnson (1995)
Science 267, 988-993
   Abstract »    PDF »
A Short-Term Clinical Evaluation of L-697,661, a Non-Nucleoside Inhibitor of HIV-1 Reverse Transcriptase.
M. S. Saag, E. A. Emini, O. L. Laskin, J. Douglas, W. I. Lapidus, W. A. Schleif, R. J. Whitley, C. Hildebrand, V. W. Byrnes, J. C. Kappes, et al. (1993)
N. Engl. J. Med. 329, 1065-1072
   Abstract »    Full Text »
Therapy for Human Immunodeficiency Virus Infection.
M. S. Hirsch and R. T. D'Aquila (1993)
N. Engl. J. Med. 328, 1686-1695
   Full Text »
Present status and future prospects for HIV therapies.
M. Johnston and D. Hoth (1993)
Science 260, 1286-1293
   Abstract »    PDF »
Zidovudine: Five Years Later.
G. X. McLeod and S. M. Hammer (1992)
Ann Intern Med 117, 487-501
   Abstract »    PDF »
Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor.
L. Kohlstaedt, J Wang, J. Friedman, P. Rice, and T. Steitz (1992)
Science 256, 1783-1790
   Abstract »    PDF »
The Pharmacological Treatment of Human Immunodeficiency Virus Infection.
R. J. Wong (1992)
Journal of Pharmacy Practice 5, 121-130
   Abstract »    PDF »
The Growing Anti-HIV Armamentarium.
J. PALCA (1991)
Science 253, 263
   PDF »
A POTENT, POSSIBLY NONTOXIC HIV INHIBITOR.
(1990)
Journal Watch (General) 1990, 8
   Full Text »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)