Interactions of Conformationally Biased North and South 2‘-Fluoro-2‘,3‘-dideoxynucleoside 5‘-Triphosphates with the Active Site of HIV-1 Reverse Transcriptase

Biochemistry ◽  
2000 ◽  
Vol 39 (37) ◽  
pp. 11205-11215 ◽  
Author(s):  
Lan Mu ◽  
Stefan G. Sarafianos ◽  
Marc C. Nicklaus ◽  
Pamela Russ ◽  
Maqbool A. Siddiqui ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Active Site ◽  
North And South ◽  
Hiv 1

scholarly journals Two Coselected Distal Mutations in HIV-1 Reverse Transcriptase (RT) Alter Susceptibility to Nonnucleoside RT Inhibitors and Nucleoside Analogs

2019 ◽  
Vol 93 (11) ◽  
Author(s):  
Paul L. Boyer ◽  
Kevin Melody ◽  
Steven J. Smith ◽  
Linda L. Dunn ◽  
Chris Kline ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Reverse Transcriptase ◽  
Active Site ◽  
Nucleoside Analogs ◽  
Transcriptase Inhibitor ◽  
Drug Resistant ◽  
Resistance Mutations ◽  
Hydrophobic Region ◽  
Nnrti Resistance ◽  
Hiv 1

ABSTRACTTwo mutations, G112D and M230I, were selected in the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) by a novel nonnucleoside reverse transcriptase inhibitor (NNRTI). G112D is located near the HIV-1 polymerase active site; M230I is located near the hydrophobic region where NNRTIs bind. Thus, M230I could directly interfere with NNRTI binding but G112D could not. Biochemical and virological assays were performed to analyze the effects of these mutations individually and in combination. M230I alone caused a reduction in susceptibility to NNRTIs, while G112D alone did not. The G112D/M230I double mutant was less susceptible to NNRTIs than was M230I alone. In contrast, both mutations affected the ability of RT to incorporate nucleoside analogs. We suggest that the mutations interact with each other via the bound nucleic acid substrate; the nucleic acid forms part of the polymerase active site, which is near G112D. The positioning of the nucleic acid is influenced by its interactions with the “primer grip” region and could be influenced by the M230I mutation.IMPORTANCEAlthough antiretroviral therapy (ART) is highly successful, drug-resistant variants can arise that blunt the efficacy of ART. New inhibitors that are broadly effective against known drug-resistant variants are needed, although such compounds might select for novel resistance mutations that affect the sensitivity of the virus to other compounds. Compound 13 selects for resistance mutations that differ from traditional NNRTI resistance mutations. These mutations cause increased sensitivity to NRTIs, such as AZT.

Active site labeling of HIV-1 reverse transcriptase

Biochemistry ◽  
1993 ◽  
Vol 32 (18) ◽  
pp. 4938-4942 ◽  
Author(s):  
Nijing Sheng ◽  
Don Dennis
Keyword(s):  
Reverse Transcriptase ◽  
Active Site ◽  
Hiv 1

scholarly journals The Phenylmethylthiazolylthiourea Nonnucleoside Reverse Transcriptase (RT) Inhibitor MSK-076 Selects for a Resistance Mutation in the Active Site of Human Immunodeficiency Virus Type 2 RT

2004 ◽  
Vol 78 (14) ◽  
pp. 7427-7437 ◽  
Author(s):  
Joeri Auwerx ◽  
Miguel Stevens ◽  
An R. Van Rompay ◽  
Louise E. Bird ◽  
Jingshan Ren ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Binding Site ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Active Site ◽  
Resistance Mutation ◽  
Site Directed Mutagenesis ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The phenylmethylthiazolylthiourea (PETT) derivative MSK-076 shows, besides high potency against human immunodeficiency virus type 1 (HIV-1), marked activity against HIV-2 (50% effective concentration, 0.63 μM) in cell culture. Time-of-addition experiments pointed to HIV-2 reverse transcriptase (RT) as the target of action of MSK-076. Recombinant HIV-2 RT was inhibited by MSK-076 at 23 μM. As was also found for HIV-1 RT, MSK-076 inhibited HIV-2 RT in a noncompetitive manner with respect to dGTP and poly(rC)·oligo(dG) as the substrate and template-primer, respectively. MSK-076 selected for A101P and G112E mutations in HIV-2 RT and for K101E, Y181C, and G190R mutations in HIV-1 RT. The selected mutated strains of HIV-2 were fully resistant to MSK-076, and the mutant HIV-2 RT enzymes into which the A101P and/or G112E mutation was introduced by site-directed mutagenesis showed more than 50-fold resistance to MSK-076. Mapping of the resistance mutations to the HIV-2 RT structure ascertained that A101P is located at a position equivalent to the nonnucleoside RT inhibitor (NNRTI)-binding site of HIV-1 RT. G112E, however, is distal to the putative NNRTI-binding site in HIV-2 RT but close to the active site, implying a novel molecular mode of action and mechanism of resistance. Our findings have important implications for the development of new NNRTIs with pronounced activity against a wider range of lentiviruses.

MOLECULAR DYNAMICS, DOCKING, DENSITY FUNCTIONAL, AND ADMET STUDIES OF HIV-1 REVERSE TRANSCRIPTASE INHIBITORS

2006 ◽  
Vol 05 (03) ◽  
pp. 579-586 ◽  
Author(s):  
CARLOS H. T. P. DA SILVA ◽  
IVONE CARVALHO ◽  
CARLTON A. TAFT
Keyword(s):  
Molecular Dynamics ◽  
Reverse Transcriptase ◽  
Active Site ◽  
Density Functional ◽  
Docking Studies ◽  
Reverse Transcriptase Inhibitors ◽  
Hydrogen Bond Interaction ◽  
Receptor Interactions ◽  
Similar Mode ◽  
Hiv 1

Molecular dynamics, density functional with correlation, as well as docking studies of inhibitors of HIV-1 reverse transcriptase (RT) are reported. We propose in this work a novel potential HIV-1 RT inhibitor (RTI), which theoretically appears to bind in a similar mode as other nucleoside reverse transcriptase inhibitors, and in addition, it introduces a new hydrogen bond interaction with Trp229. Our novel RTI has high docking scores and the molecular dynamics studies, as well as the analysis of the ligand-receptor interactions in the active site and the ADMET properties suggest advantages and specificities for this potential RTI.

scholarly journals Nonnucleoside Inhibitor Binding Affects the Interactions of the Fingers Subdomain of Human Immunodeficiency Virus Type 1 Reverse Transcriptase with DNA

2004 ◽  
Vol 78 (7) ◽  
pp. 3387-3397 ◽  
Author(s):  
Elena N. Peletskaya ◽  
Alex A. Kogon ◽  
Steven Tuske ◽  
Edward Arnold ◽  
Stephen H. Hughes
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Active Site ◽  
Cross Linking ◽  
Immunodeficiency Virus ◽  
Dntp Binding ◽  
Hiv 1

ABSTRACT Site-directed photoaffinity cross-linking experiments were performed by using human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) mutants with unique cysteine residues at several positions (i.e., positions 65, 67, 70, and 74) in the fingers subdomain of the p66 subunit. Since neither the introduction of the unique cysteine residues into the fingers nor the modification of the SH groups of these residues with photoaffinity cross-linking reagents caused a significant decrease in the enzymatic activities of RT, we were able to use this system to measure distances between specific positions in the fingers domain of RT and double-stranded DNA. HIV-1 RT is quite flexible. There are conformational changes associated with binding of the normal substrates and nonnucleoside RT inhibitors (NNRTIs). Cross-linking was used to monitor intramolecular movements associated with binding of an NNRTI either in the presence or in the absence of an incoming deoxynucleoside triphosphate (dNTP). Binding an incoming dNTP at the polymerase active site decreased the efficiency of cross-linking but caused only modest changes in the preferred positions of cross-linking. This finding suggests that the fingers of p66 are closer to an extended template in the “open” configuration of the enzyme with the fingers away from the active site than in the closed configuration with the fingers in direct contact with the incoming dNTP. NNRTI binding caused increased cross-linking in experiments with diazirine reagents (especially with a diazirine reagent with a longer linker) and a moderate shift in the preferred sites of interaction with the template. Cross-linking occurred closer to the polymerase active site for RTs modified at positions 70 and 74. The effects of NNRTI binding were more pronounced in the absence of a bound dNTP; pretreatment of HIV-1 RT with an NNRTI reduced the effect of dNTP binding. These observations can be explained if the binding of NNRTI causes a decrease in the flexibility in the fingers subdomain of RT-NNRTI complex and a decrease in the distance from the fingers to the template extension.

scholarly journals Structure for an HIV-1 reverse transcriptase RNase H inhibitor bound at the active site

2008 ◽  
Vol 64 (a1) ◽  
pp. C348-C348
Author(s):  
D.M. Himmel ◽  
T.A. Pauly ◽  
J. Bauman ◽  
C. Dharia ◽  
A.D. Clark ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Active Site ◽  
Rnase H ◽  
Hiv 1

HIV-1 Reverse Transcriptase – Computational Studies on the Polymerase Active Site

2013 ◽  
pp. 989-992
Author(s):  
Thanyada Rungrotmongkol ◽  
Nadtanet Nunthaboot ◽  
Ornjira Aruksakunwong ◽  
Supot Hannongbua
Keyword(s):  
Reverse Transcriptase ◽  
Active Site ◽  
Computational Studies ◽  
Hiv 1

scholarly journals Structure of HIV-1 Reverse Transcriptase with the Inhibitor β-Thujaplicinol Bound at the RNase H Active Site

Structure ◽  
2009 ◽  
Vol 17 (12) ◽  
pp. 1625-1635 ◽  
Author(s):  
Daniel M. Himmel ◽  
Karen A. Maegley ◽  
Tom A. Pauly ◽  
Joseph D. Bauman ◽  
Kalyan Das ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Active Site ◽  
Rnase H ◽  
Hiv 1

scholarly journals Probing nonnucleoside inhibitor-induced active-site distortion in HIV-1 reverse transcriptase by transient kinetic analyses

2007 ◽  
Vol 16 (8) ◽  
pp. 1728-1737 ◽  
Author(s):  
Qing Xia ◽  
Jessica Radzio ◽  
Karen S. Anderson ◽  
Nicolas Sluis-Cremer
Keyword(s):  
Reverse Transcriptase ◽  
Active Site ◽  
Hiv 1
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