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

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).

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

Big Data Analytics in HIV/AIDS Research - Advances in Healthcare Information Systems and Administration ◽

10.4018/978-1-5225-3203-3.ch001 ◽

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.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00127-06 ◽

2006 ◽

Vol 50 (8) ◽

pp. 2772-2781 ◽

Cited By ~ 39

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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Screening of Natural Products as HIV-1 And HIV-2 Reverse Transcriptase (RT) Inhibitors

Natural Products as Antiviral Agents ◽

10.1007/978-1-4615-3414-3_10 ◽

1992 ◽

pp. 195-222 ◽

Cited By ~ 3

Author(s):

Ghee T. Tan ◽

John M. Pezzuto ◽

A. Douglas Kinghorn

Keyword(s):

Natural Products ◽

Reverse Transcriptase ◽

Rt Inhibitors ◽

Hiv 1

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Effects of the W153L Substitution in HIV Reverse Transcriptase on Viral Replication and Drug Resistance to Multiple Categories of Reverse Transcriptase Inhibitors

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02729-14 ◽

2014 ◽

Vol 58 (8) ◽

pp. 4515-4526 ◽

Cited By ~ 2

Author(s):

Hong-Tao Xu ◽

Susan P. Colby-Germinario ◽

Maureen Oliveira ◽

Daniel Rajotte ◽

Richard Bethell ◽

...

Keyword(s):

Viral Replication ◽

Reverse Transcriptase ◽

Rnase H ◽

Hiv Reverse Transcriptase ◽

Compound A ◽

Enzymatic Function ◽

Biochemical Assays ◽

Rt Inhibitors ◽

The Impact ◽

Hiv 1

ABSTRACTA W153L substitution in HIV-1 reverse transcriptase (RT) was recently identified by selection with a novel nucleotide-competing RT inhibitor (NcRTI) termed compound A that is a member of the benzo[4,5]furo[3,2,d]pyrimidin-2-one NcRTI family of drugs. To investigate the impact of W153L, alone or in combination with the clinically relevant RT resistance substitutions K65R (change of Lys to Arg at position 65), M184I, K101E, K103N, E138K, and Y181C, on HIV-1 phenotypic susceptibility, viral replication, and RT enzymatic function, we generated recombinant RT enzymes and viruses containing each of these substitutions or various combinations of them. We found that W153L-containing viruses were impaired in viral replicative capacity and were hypersusceptible to tenofovir (TFV) while retaining susceptibility to most nonnucleoside RT inhibitors. The nucleoside 3TC retained potency against W153L-containing viruses but not when the M184I substitution was also present. W153L was also able to reverse the effects of the K65R substitution on resistance to TFV, and K65R conferred hypersusceptibility to compound A. Biochemical assays demonstrated that W153L alone or in combination with K65R, M184I, K101E, K103N, E138K, and Y181C impaired enzyme processivity and polymerization efficiency but did not diminish RNase H activity, providing mechanistic insights into the low replicative fitness associated with these substitutions. We show that the mechanism of the TFV hypersusceptibility conferred by W153L is mainly due to increased efficiency of TFV-diphosphate incorporation. These results demonstrate that compound A and/or derivatives thereof have the potential to be important antiretroviral agents that may be combined with tenofovir to achieve synergistic results.

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An Approach towards the Synthesis of Potential Metal-Chelating TSAO-T Derivatives as Bidentate Inhibitors of Human Immunodeficiency virus Type 1 Reverse Transcriptase

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029800900505 ◽

1998 ◽

Vol 9 (5) ◽

pp. 412-421 ◽

Cited By ~ 1

Author(s):

C Chamorro ◽

M-J Camarasa ◽

M-J Pérez-Pérez ◽

E de Clercq ◽

J Balzarini ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Reverse Transcriptase ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Parent Compound ◽

Immunodeficiency Virus ◽

Anti Hiv ◽

Hiv 1

Novel derivatives of the potent human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor TSAO-T have been designed, synthesized and tested for their in vitro antiretro-viral activity against HIV. These TSAO-T derivatives have been designed as potential bidentate inhibitors of HIV-1 RT, which combine in their structure the functionality of a non-nucleoside RT inhibitor (TSAO-T) and a bivalent ion-chelating moiety (a β-diketone moiety) linked through an appropriate spacer to the N-3 of thymine of TSAO-T . Some of the new compounds have an anti-HIV-1 activity comparable to that of the parent compound TSAO-T, but display a markedly increased antiviral selectivity. There was a clear relationship between antiviral activity and the length of the spacer group that links the TSAO molecule with the chelating moiety. A shorter spacer invariably resulted in increased antiviral potency. None of the TSAO-T derivatives were endowed with anti-HIV-2 activity.

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The Human Immunodeficiency Virus Type 1 Nonnucleoside Reverse Transcriptase Inhibitor Resistance Mutation I132M Confers Hypersensitivity to Nucleoside Analogs

Journal of Virology ◽

10.1128/jvi.01968-08 ◽

2009 ◽

Vol 83 (8) ◽

pp. 3826-3833 ◽

Cited By ~ 11

Author(s):

Zandrea Ambrose ◽

Brian D. Herman ◽

Chih-Wei Sheen ◽

Shannon Zelina ◽

Katie L. Moore ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Reverse Transcriptase ◽

Human Immunodeficiency Virus Type ◽

Nucleoside Analogs ◽

Replication Capacity ◽

Immunodeficiency Virus ◽

Viral Replication Capacity ◽

Rt Inhibitors ◽

Hiv 1

ABSTRACT We previously identified a rare mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), I132M, which confers high-level resistance to the nonnucleoside RT inhibitors (NNRTIs) nevirapine and delavirdine. In this study, we have further characterized the role of this mutation in viral replication capacity and in resistance to other RT inhibitors. Surprisingly, our data show that I132M confers marked hypersusceptibility to the nucleoside analogs lamivudine (3TC) and tenofovir at both the virus and enzyme levels. Subunit-selective mutagenesis studies revealed that the mutation in the p51 subunit of RT was responsible for the increased sensitivity to the drugs, and transient kinetic analyses showed that this hypersusceptibility was due to I132M decreasing the enzyme's affinity for the natural dCTP substrate but increasing its affinity for 3TC-triphosphate. Furthermore, the replication capacity of HIV-1 containing I132M is severely impaired. This decrease in viral replication capacity could be partially or completely compensated for by the A62V or L214I mutation, respectively. Taken together, these results help to explain the infrequent selection of I132M in patients for whom NNRTI regimens are failing and furthermore demonstrate that a single mutation outside of the polymerase active site and inside of the p51 subunit of RT can significantly influence nucleotide selectivity.

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