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

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

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 Mechanism of Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase by a Stavudine Analogue, 4′-Ethynyl Stavudine Triphosphate

2008 ◽  
Vol 52 (6) ◽  
pp. 2035-2042 ◽  
Author(s):  
Guangwei Yang ◽  
Jimin Wang ◽  
Yao Cheng ◽  
Ginger E. Dutschman ◽  
Hiromichi Tanaka ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Steady State ◽  
Reverse Transcriptase ◽  
Structural Basis ◽  
Mechanism Of Inhibition ◽  
Steady State Kinetic ◽  
Immunodeficiency Virus ◽  
State Kinetic ◽  
Hiv 1

ABSTRACT 2′,3′-Didehydro-3′-deoxy-4′-ethynylthymidine (4′-Ed4T), a recently discovered nucleoside reverse transcriptase (RT) inhibitor, exhibits 5- to 10-fold-higher activity against human immunodeficiency virus type 1 (HIV-1) and less cytotoxicity than does its parental compound d4T (stavudine). Using steady-state kinetic approaches, we have previously shown that (i) 4′-ethynyl-d4T triphosphate (4′-Ed4TTP) inhibits HIV-1 RT more efficiently than d4TTP does and (ii) its inhibition efficiency toward the RT M184V mutant is threefold less than that toward wild-type (wt) RT. In this study we used pre-steady-state kinetic approaches in an attempt to understand its mechanism of inhibition. With wt and the M184V mutant RTs, 4′-Ed4TTP has three- to fivefold-lower Kd (dissociation constant) values than d4TTP, while d4TTP has up to eightfold-higher Kd values than dTTP. Inhibition is more effective in DNA replication with RNA template than with DNA template. In general, the M184V mutant exhibits poorer binding for all three nucleoside triphosphates than does wt RT. The structural basis for the lower binding affinity of d4TTP than of dTTP could be the lack of hydrogen bonds from the missing 3′-hydroxyl group in d4TTP to the backbone amide of Y115 and also to the side chain of Q151. The structural basis for the higher binding affinity of 4′-Ed4TTP than of d4TTP could be the additional binding of the 4′-ethynyl group in a preformed hydrophobic pocket by A114, Y115, M184, F160, and part of D185.

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