Computational Analysis of Reverse Transcriptase Resistance to Inhibitors in HIV-1

2018 ◽  
pp. 1-20
Author(s):  
Ameeruddin Nusrath Unissa ◽  
Luke Elizabeth Hanna
Keyword(s):  
Amino Acid ◽  
Reverse Transcriptase ◽  
Amino Acid Substitution ◽  
Structural Changes ◽  
Chain Termination ◽  
Nucleoside Analogues ◽  
High Affinity ◽  
Rt Inhibitors ◽  
Hiv 1 ◽  
Substrate Competition

Reverse transcriptase (RT) is a vital enzyme in the process of transcription of HIV-1. The nucleoside analogues of RT inhibitors (NRTIs) act by substrate competition and chain termination as they resemble a nucleotide. To understand the basis of RT resistance in HIV-1, in this chapter, one of the clinically essential mutants Q151M of RT which exhibits multi-resistance to many NRTIs was modeled and docked with NRTIs in comparison to wild type (WT). The results of docking indicate that the WT showed high affinity with all inhibitors compared to the mutant (MT). It can be suggested that the high affinity in WT could be attributed to the favorable interactions with all inhibitors that lacks in MT due to amino acid substitution that leads to structural changes in MT protein, which alters the favorable network of interaction and eventually imparts resistance to all inhibitors.

scholarly journals Mutation V111I in HIV-2 Reverse Transcriptase Increases the Fitness of the Nucleoside Analogue-Resistant K65R and Q151M Viruses

2014 ◽  
Vol 89 (1) ◽  
pp. 833-843 ◽  
Author(s):  
Ilona P. Deuzing ◽  
Charlotte Charpentier ◽  
David W. Wright ◽  
Sophie Matheron ◽  
Jack Paton ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Structural Changes ◽  
Novel Mutation ◽  
Rnase H ◽  
Nucleoside Analogues ◽  
Replication Capacity ◽  
Resistance Mutations ◽  
Loop Region ◽  
Polymerase Domain ◽  
Hiv 1

ABSTRACTInfection with HIV-2 can ultimately lead to AIDS, although disease progression is much slower than with HIV-1. HIV-2 patients are mostly treated with a combination of nucleoside reverse transcriptase (RT) inhibitors (NRTIs) and protease inhibitors designed for HIV-1. Many studies have described the development of HIV-1 resistance to NRTIs and identified mutations in the polymerase domain of RT. Recent studies have shown that mutations in the connection and RNase H domains of HIV-1 RT may also contribute to resistance. However, only limited information exists regarding the resistance of HIV-2 to NRTIs. In this study, therefore, we analyzed the polymerase, connection, and RNase H domains of RT in HIV-2 patients failing NRTI-containing therapies. Besides the key resistance mutations K65R, Q151M, and M184V, we identified a novel mutation, V111I, in the polymerase domain. This mutation was significantly associated with mutations K65R and Q151M. Sequencing of the connection and RNase H domains of the HIV-2 patients did not reveal any of the mutations that were reported to contribute to NRTI resistance in HIV-1. We show that V111I does not strongly affect drug susceptibility but increases the replication capacity of the K65R and Q151M viruses. Biochemical assays demonstrate that V111I restores the polymerization defects of the K65R and Q151M viruses but negatively affects the fidelity of the HIV-2 RT enzyme. Molecular dynamics simulations were performed to analyze the structural changes mediated by V111I. This showed that V111I changed the flexibility of the 110-to-115 loop region, which may affect deoxynucleoside triphosphate (dNTP) binding and polymerase activity.IMPORTANCEMutation V111I in the HIV-2 reverse transcriptase enzyme was identified in patients failing therapies containing nucleoside analogues. We show that the V111I change does not strongly affect the sensitivity of HIV-2 to nucleoside analogues but increases the fitness of viruses with drug resistance mutations K65R and Q151M.

scholarly journals A Single Amino Acid Substitution in HIV-1 Reverse Transcriptase Significantly Reduces Virion Release

2009 ◽  
Vol 84 (2) ◽  
pp. 976-982 ◽  
Author(s):  
Chien-Cheng Chiang ◽  
Shiu-Mei Wang ◽  
Yen-Yu Pan ◽  
Kuo-Jung Huang ◽  
Chin-Tien Wang
Keyword(s):  
Amino Acid ◽  
Reverse Transcriptase ◽  
Virus Replication ◽  
Amino Acid Substitution ◽  
Proteolytic Processing ◽  
Repeat Motif ◽  
Single Amino Acid Substitution ◽  
Single Amino Acid ◽  
Cleavage Efficiency ◽  
Hiv 1

ABSTRACT HIV-1 protease (PR) mediates the proteolytic processing of virus particles during or after virus budding. PR activation is thought to be triggered by appropriate Gag-Pol/Gag-Pol interaction; factors affecting this interaction either enhance or reduce PR-mediated cleavage efficiency, resulting in markedly reduced virion production or the release of inadequately processed virions. We previously showed that a Gag-Pol deletion mutation involving the reverse transcriptase tryptophan (Trp) repeat motif markedly impairs PR-mediated virus maturation and that an alanine substitution at W401 (W401A) or at both W401 and W402 (W401A/W402A) partially or almost completely negates the enhancement effect of efavirenz (a nonnucleoside reverse transcriptase inhibitor) on PR-mediated virus processing efficiency. These data suggest that the Trp repeat motif may contribute to the PR activation process. Here we demonstrate that due to enhanced Gag cleavage efficiency, W402 alanine or leucine substitution significantly reduces virus production. However, W402 replacement with phenylalanine does not significantly affect virus particle assembly or processing, but it does markedly impair viral infectivity in a single-cycle infection assay. Our results demonstrate that a single amino acid substitution at HIV-1 RT can radically affect virus assembly by enhancing Gag cleavage efficiency, suggesting that in addition to contributing to RT biological function during the early stages of virus replication, the HIV-1 RT tryptophan repeat motif in a Gag-Pol context may play an important role in suppressing the premature activation of PR during late-stage virus replication.

PASS-based approach to predict HIV-1 reverse transcriptase resistance

2017 ◽  
Vol 15 (02) ◽  
pp. 1650040 ◽  
Author(s):  
Olga Tarasova ◽  
Dmitry Filimonov ◽  
Vladimir Poroikov
Keyword(s):  
Amino Acid ◽  
Reverse Transcriptase ◽  
Open Data ◽  
Amino Acid Substitutions ◽  
Hiv Reverse Transcriptase ◽  
Hiv Rt ◽  
Hiv Drugs ◽  
Rt Inhibitors ◽  
Anti Hiv ◽  
Hiv 1

HIV reverse transcriptase (RT) inhibitors targeting the early stages of virus–host interactions are of great interest to scientists. Acquired HIV RT resistance happens due to mutations in a particular region of the pol gene encoding the HIV RT amino acid sequence. We propose an application of the previously developed PASS algorithm for prediction of amino acid substitutions potentially involved in the resistance of HIV-1 based on open data. In our work, we used more than 3200 HIV-1 RT variants from the publicly available Stanford HIV RT and protease sequence database already tested for 10 anti-HIV drugs including both nucleoside and non-nucleoside RT inhibitors. We used a particular amino acid residue and its position to describe primary structure-resistance relationships. The average balanced accuracy of the prediction obtained in 20-fold cross-validation for the Phenosense dataset was about 88% and for the Antivirogram dataset was about 79%. Thus, the PASS-based algorithm may be used for prediction of the amino acid substitutions associated with the resistance of HIV-1 based on open data. The computational approach for the prediction of HIV-1 associated resistance can be useful for the selection of RT inhibitors for the treatment of HIV infected patients in the clinical practice. Prediction of the HIV-1 RT associated resistance can be useful for the development of new anti-HIV drugs active against the resistant variants of RT. Therefore, we propose that this study can be potentially useful for anti-HIV drug development.

scholarly journals A Diarylsulphone Non-Nucleoside Reverse Transcriptase Inhibitor with a Unique Sensitivity Profile to Drug-Resistant Virus Isolates

1996 ◽  
Vol 7 (5) ◽  
pp. 243-252 ◽  
Author(s):  
R.W. Buckheit ◽  
V. Fliakas-Boltz ◽  
J.D. Russell ◽  
M. Snow ◽  
L.A. Pallansch ◽  
...  
Keyword(s):  
Amino Acid ◽  
Reverse Transcriptase ◽  
Nucleoside Reverse Transcriptase Inhibitor ◽  
Transcriptase Inhibitor ◽  
Resistant Virus ◽  
Rt Inhibitors ◽  
Reverse Transcriptase Inhibitor ◽  
Virus Isolates ◽  
Hiv 1 ◽  
Sensitivity Profile

Structure-activity relationship evaluations with a series of diarylsulphone non-nucleoside reverse transcriptase (RT) inhibitors indicated that the steric properties of the molecule and compound lipophilicity primarily contributed to the overall level of activity of the compounds against human immunodeficiency virus type 1 (HIV-1). The most active compounds in the diarylsulphone series had an orthonitro group and yielded anti-HIV activity at sub-micromolar concentrations. Compounds of the diarylsulphone class exhibited antiviral properties similar to other members of the pharmacologic class of HIV-1 specific non-nucleoside reverse transcriptase inhibitors, including activity in a wide variety of established and primary human cells, activity against a wide variety of laboratory and clinical virus isolates, and activity when challenged at high multiplicity of infection. Synergistic inhibition of HIV-1 was observed when the diarylsulphone NSC 667952 was used with the nucleoside analogues AZT, ddl, 3TC and d4T, the protease inhibitor KNI 272 and the sulphonated dye resobene; additive effects were observed when NSC 667952 was used with the nucleoside analogue ddC and other non-nucleoside RT inhibitors. The diarylsulphones exhibited a unique sensitivity profile when evaluated against both virus isolates and purified reverse transcriptase containing non-nucleoside reverse transcriptase inhibitor resistance-engendering mutations. Unlike other members of the class of non-nucleoside compounds, NSC 667952 remained active against virus isolates with the L100I amino acid change in the RT. The compound was, however, highly sensitive to Y181C., K103N and K101E amino acid changes in the RT. The diarylsulphone selected for resistant virus populations which possessed the Y181C amino acid change in the reverse transcriptase and which exhibited enhanced sensitivity to the non-nucleoside inhibitors calanolide A and costatolide.

The Amino Acid Asn136 in HIV-1 Reverse Transcriptase (RT) Maintains Efficient Association of Both RT Subunits and Enables the Rational Design of Novel RT Inhibitors

2005 ◽  
Vol 68 (1) ◽  
pp. 49-60 ◽  
Author(s):  
Jan Balzarini ◽  
Joeri Auwerx ◽  
Fátima Rodríguez-Barrios ◽  
Allel Chedad ◽  
Viktor Farkas ◽  
...  
Keyword(s):  
Amino Acid ◽  
Reverse Transcriptase ◽  
Rational Design ◽  
Rt Inhibitors ◽  
Hiv 1

Oxathiin Carboxanilide Derivatives: A Class of Non-Nucleoside HIV-1-Specific Reverse Transcriptase Inhibitors (NNRTIs) that are Active against Mutant HIV-1 Strains Resistant to other NNRTIs

1995 ◽  
Vol 6 (3) ◽  
pp. 169-178 ◽  
Author(s):  
J. Balzarini ◽  
H. Jonckheere ◽  
W.A. Harrison ◽  
D.C. Dao ◽  
J. Anné ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Structural Changes ◽  
Parent Compound ◽  
Site Directed Mutagenesis ◽  
Isopropyl Ester ◽  
Drug Candidates ◽  
Mutant Strains ◽  
Ester Moiety ◽  
Rt Inhibitors ◽  
Hiv 1

The HIV-1-specific oxathiin carboxanilide derivative 1-methylethyl 2-chloro-5-[[(5,6-dihydro-2-methyl-1,4-oxathiin-3-yl)carbonyl]amino]benzoate (NSC 615985) (designated UC84) has potent activity against HIV-1(IIIB) (50% effective concentration: 0.015 μg ml−1). UC84 was found to select for a 138-Lys mutant virus strain in HIV-1-infected CEM cell cultures. When the 138-Lys mutation was introduced solely in the p51 subunit of the p51/p66 reverse transcriptase (RT) heterodimer by site-directed mutagenesis, the enzyme proved 10-fold more resistant to UC84 than when the amino acid mutation was introduced solely in the p66 subunit of the p51/p66 RT heterodimer. These data provided clear evidence for a structural and functional role of the p51 subunit in the sensitivity/resistance of the enzyme to UC84. UC84 also proved to be virtually inactive against mutant HIV-1 strains containing the 100-lle, 106-Ala, 138-Lys or 181-Cys mutation in their RT. However, minor structural changes in the molecule, such as replacement of the oxygen of the amide moiety by sulfur, or the isopropyl ester moiety by cyclopentyl or a secondary butyl, or the methyl group of the oxathiin part by ethyl, made the compound markedly more inhibitory to one or several HIV-1 mutant strains. For example, compound 131 (1-methylethyl 2-chloro-5-[[(5,6-dihydro-2-methyl-1,4-oxathiin-3-yl)thioxomethyl]amino]benzoate was only 2-fold more active than the parent compound UC84 against wild-type HIV-1, but 30- to 100-fold more inhibitory to HIV-1 mutant strains that contained the 100-11e, 106-A1a, 138-Lys or 181-Cys in their RT. These findings should be taken into account when selecting suitable drug candidates for the treatment of HIV-1 infections, particularly those that have developed resistance to other non-nucleoside RT inhibitors (NNRTIs).

scholarly journals A new strategy to inhibit the excision reaction catalysed by HIV-1 reverse transcriptase: compounds that compete with the template–primer

2007 ◽  
Vol 405 (1) ◽  
pp. 165-171 ◽  
Author(s):  
Carlos Cruchaga ◽  
Elena Anso ◽  
María Font ◽  
Virginia S. Martino ◽  
Ana Rouzaut ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Competitive Inhibitor ◽  
Rnase H ◽  
Nucleoside Analogues ◽  
Wild Type ◽  
Antiviral Compound ◽  
New Strategy ◽  
Direct Binding ◽  
Rt Inhibitors ◽  
Hiv 1

Inhibitors of the excision reaction catalysed by HIV-1 RT (reverse transcriptase) represent a promising approach in the fight against HIV, because these molecules would interfere with the main mechanism of resistance of this enzyme towards chain-terminating nucleotides. Only a limited number of compounds have been demonstrated to inhibit this reaction to date, including NNRTIs (non-nucleoside RT inhibitors) and certain pyrophosphate analogues. We have found previously that 2GP (2-O-galloylpunicalin), an antiviral compound extracted from the leaves of Terminalia triflora, was able to inhibit both the RT and the RNase H activities of HIV-1 RT without affecting cell proliferation or viability. In the present study, we show that 2GP also inhibited the ATP- and PPi-dependent phosphorolysis catalysed by wild-type and AZT (3′-azido-3′-deoxythymidine)-resistant enzymes at sub-micromolar concentrations. Kinetic and direct-binding analysis showed that 2GP was a non-competitive inhibitor against the nucleotide substrate, whereas it competed with the binding of RT to the template–primer (Kd=85 nM). As expected from its mechanism of action, 2GP was active against mutations conferring resistance to NNRTIs and AZT. The combination of AZT with 2GP was highly synergistic when tested in the presence of pyrophosphate, indicating that the inhibition of RT-catalysed phosphorolysis was responsible for the synergy found. Although other RT inhibitors that compete with the template–primer have been described, this is the first demonstration that these compounds can be used to block the excision of chain terminating nucleotides, providing a rationale for their combination with nucleoside analogues.

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.

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