Inhibition of Phosphorolysis Catalyzed by HIV-1 Reverse Transcriptase Is Responsible for the Synergy Found in Combinations of 3‘-Azido-3‘-deoxythymidine with Nonnucleoside Inhibitors†

Biochemistry ◽  
2005 ◽  
Vol 44 (9) ◽  
pp. 3535-3546 ◽  
Author(s):  
Carlos Cruchaga ◽  
Leticia Odriozola ◽  
Marieline Andréola ◽  
Laura Tarrago-Litvak ◽  
Juan J. Martínez-Irujo
Keyword(s):  
Reverse Transcriptase ◽  
Nonnucleoside Inhibitors ◽  
Hiv 1

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

2006 ◽  
Vol 50 (8) ◽  
pp. 2772-2781 ◽  
Author(s):  
Zhijun Zhang ◽  
Michelle Walker ◽  
Wen Xu ◽  
Jae Hoon Shim ◽  
Jean-Luc Girardet ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Immunodeficiency Virus ◽  
Nonnucleoside Inhibitors ◽  
Rt Inhibitors ◽  
Hiv 1 ◽  
M184v Mutation

ABSTRACT 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.

ChemInform Abstract: Synthesis and Biological Activity of Novel Nonnucleoside Inhibitors of HIV-1 Reverse Transcriptase. 2-Aryl-Substituted Benzimidazoles.

ChemInform ◽  
2010 ◽  
Vol 29 (20) ◽  
pp. no-no
Author(s):  
T. ROTH ◽  
M. L. MORNINGSTAR ◽  
P. L. BOYER ◽  
S. H. HUGHES ◽  
R. W. JUN. BUCKHEIT ◽  
...  
Keyword(s):  
Biological Activity ◽  
Reverse Transcriptase ◽  
Nonnucleoside Inhibitors ◽  
Hiv 1

Novel Nonnucleoside Inhibitors of HIV-1 Reverse Transcriptase. 8. 8-Aryloxymethyl- and 8-Arylthiomethyldipyridodiazepinones1

1998 ◽  
Vol 41 (16) ◽  
pp. 2972-2984 ◽  
Author(s):  
Charles L. Cywin ◽  
Janice M. Klunder ◽  
MaryAnn Hoermann ◽  
Janice R. Brickwood ◽  
Eva David ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Nonnucleoside Inhibitors ◽  
Hiv 1

scholarly journals Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors

Science ◽  
1995 ◽  
Vol 267 (5200) ◽  
pp. 988-993 ◽  
Author(s):  
R. Spence ◽  
W. Kati ◽  
K. Anderson ◽  
K. Johnson
Keyword(s):  
Reverse Transcriptase ◽  
Mechanism Of Inhibition ◽  
Nonnucleoside Inhibitors ◽  
Hiv 1
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