Biological and biochemical anti-HIV activity of the benzothiadiazine class of nonnucleoside reverse transcriptase inhibitors

Buckheit, Robert W.; Fliakas-Boltz, Valerie; Decker, W. Don; Roberson, Joseph L.; Pyle, Cathi; White, E. Lucile; Bowdon, Bonnie J.; McMahon, James B.; Boyd, Michael R.; Bader, John P.; Nickell, D. G.; Barth, Hubert; Antonucci, Tammy K.

doi:10.1016/0166-3542(94)90092-2

Cited by 109 publications

(72 citation statements)

References 36 publications

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“…Despite many studies devoted to this topic, the molecular mechanism underlying the antiviral synergy of combinations of reverse transcriptase inhibitors is in most cases unknown. The synergistic inhibition of HIV replication in cell culture has been reported for many combinations of nucleosidic and NNRTI inhibitors including, among others, bis(heteroaryl)piperazine derivates (29), pyridinone derivates (30), nevirapine (13), HEPT derivates (14), TIBO derivates (15,31), or canalolide A (16). However, other studies have shown that the same combinations showed no synergy in inhibiting RT activity in vitro (17)(18)(19)(20)(21).…”

Section: Discussionmentioning

confidence: 99%

“…Because both groups of inhibitors bind to different sites on RT in a nonexclusive manner (12), combinations of nucleoside analogs and non-nucleoside inhibitors might have a potential synergistic inhibitory effect on HIV-1 RT. Synergistic inhibition of HIV replication in cell culture has been reported for many combinations of nucleoside and non-nucleoside RT inhibitors (13)(14)(15)(16). Nevertheless, several other studies have shown that the same combinations showed no synergy in inhibiting RT activity in vitro (17)(18)(19)(20)(21).…”

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confidence: 99%

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Non-nucleoside Inhibitors of HIV-1 Reverse Transcriptase Inhibit Phosphorolysis and Resensitize the 3′-Azido-3′-deoxythymidine (AZT)-resistant Polymerase to AZT-5′-triphosphate

Odriozola

Cruchaga

Andréola

et al. 2003

Journal of Biological Chemistry

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Removal of 3-azido-3deoxythymidine (AZT) 3-azido-3-deoxythymidine 5-monophosphate (AZTMP) from the terminated primer mediated by the human HIV-1 reverse transcriptase (RT) has been proposed as a relevant mechanism for the resistance of HIV to AZT. Here we compared wild type and AZT-resistant (D67N/K70R/ T215Y/K219Q) RTs for their ability to unblock the AZTMP-terminated primer by phosphorolysis in the presence of physiological concentrations of pyrophosphate or ATP. The AZT-resistant enzyme, as it has been previously described, showed an increased ability to unblock the AZTMP-terminated primer by an ATP-dependent mechanism. We found that only mutations in the p66 subunit were responsible for this ability. We also found that three structurally divergent non-nucleoside reverse transcriptase inhibitor (NNRTI), nevirapine, TIBO, and a 4-arylmethylpyridinone derivative, were able to inhibit the phosphorolytic activity of the enzyme, rendering the AZT-resistant RT sensitive to AZTTP. The 4-arylmethylpyridinone derivative proved to be about 1000-fold more potent in inhibiting phosphorolysis than nevirapine or TIBO. Moreover, combinations of AZTTP with NNRTIs exhibited an exceptionally high degree of synergy in the inhibition of AZT-resistant enzyme only when ATP or PP i were present, indicating that inhibition of phosphorolysis was responsible for the synergy found in the combination. Our results not only demonstrate the importance of phosphorolysis concerning HIV-1 RT resistance to AZT but also point to the implication of this activity in the strong synergy found in some combinations of NNRTIs with AZT.Human immunodeficiency virus, type 1 (HIV-1) 1 reverse transcriptase (RT) is responsible for the conversion of singlestranded viral RNA into double-stranded DNA prior to integration into the genome of the human host. Numerous compounds that inhibit the DNA polymerase activity of RT have been described. They can be divided into two broad classes. The first group, that of nucleoside analogs, includes dideoxynucleoside compounds, such as 2Ј,3Ј-dideoxycytidine and AZT, that inhibit viral replication by acting as chain terminators of DNA synthesis (1). The second group, the non-nucleoside reverse transcriptase inhibitors (NNRTI), includes a large number of structurally dissimilar hydrophobic compounds that bind to a site on the RT palm subdomain adjacent to but distinct from the polymerase active site (2).The FDA-approved HIV-1 therapies involve drugs that inhibit two viral enzymes, reverse transcriptase and protease. AZT was the first drug approved against HIV-1 and is still widely used in combination with other antiretroviral drugs. The prolonged clinical use of this nucleoside analog in monotherapy gives rise to highly resistant viruses containing mutations in the RT enzyme, D67N, K70R, T215F/Y, K219E/Q (3), and, in some cases, M41L and L210W. Viruses carrying at least four mutations are more than 100-fold less sensitive to AZT than wild type virus in cell culture. Although the genotype for AZT resistance is well character...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Non-nucleoside Inhibitors of HIV-1 Reverse Transcriptase Inhibit Phosphorolysis and Resensitize the 3′-Azido-3′-deoxythymidine (AZT)-resistant Polymerase to AZT-5′-triphosphate

Odriozola

Cruchaga

Andréola

et al. 2003

Journal of Biological Chemistry

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“…All stocks were diluted at least 400-fold prior to performing drug susceptibility assays. Materials required for the performance of reverse transcriptase inhibition assays, anti-HIV assays and for the growth and maintenance of established and fresh human cells have been previously described (Buckheit et al, 1994b). The MacSynergy II program was obtained from Dr Mark Prichard and Dr Charles Shipman at the University of Michigan (Ann Arbor, Mich., USA).…”

Section: Methodsmentioning

confidence: 99%

“…Evaluation of the antiviral activity of test compounds was performed in CEM-SS cells as previously described (Buckheit et al, 1994b). Antiviral and toxicity data are reported as the concentration of drug required to inhibit 50% of virus-induced cell killing or virus production (EC 50 ), and the concentration of drug required to reduce cell …”

Section: Anti-hiv Assaysmentioning

confidence: 99%

Anti-HIV-1 Activity of Calanolides Used in Combination with other Mechanistically Diverse Inhibitors of HIV-1 Replication

Buckheit

Russell

Xu³

et al. 2000

Antivir Chem Chemother

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ral activity was detected with any of the tested compounds. The combination antiviral efficacy of three-drug combinations involving the calanolides, and the efficacy of two-and three-drug combinations using a (+)-calanolide A-resistant challenge virus (bearing the T139I amino acid change in the reverse transcriptase), was also evaluated in vitro. These assays suggest that the best combination of agents based on in vitro anti-HIV assay results would include the calanolides in combination with lamivudine and nelfinavir, since this was the only three-drug combination exhibiting a significant level of synergy. Combination assays with the (+)-calanolide A-resistant strain yielded identical results as seen with the wild-type virus, although the concentration of the calanolides had to be increased.

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“…All rights reserved. SSDI 0014-5793(94)00793-4 idazole (TBZ) [11] and sulfoxamine [12], led to the suggestion that two other possible regions are crucial for the inhibition of both compounds. The first domain resides between amino acid residues 158 and 190 and the second between residues 203 and 224 [10].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of reverse transcriptase of human immunodeficiency virus type 1 and chimeric enzymes of human immunodeficiency viruses types 1 and 2 by two novel non‐nucleoside inhibitors

Rubinek¹,

McMahon²,

Hizi³

1994

FEBS Letters

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We have studied the effects of two non-nucleoside reverse transcriptase inhibitors (NNRTI), nitrophenyl phenyl sulfone (NPPS) and a potent derivative of oxathiin carboxanilide (UC-38), on enzymatically active molecular chimeras composed of complementary segments of the reverse transcriptases (RTs) of human immunodeficiency virus type 1 (HIV-I) and -2 (HIV-2). The substances inhibit only the DNA polymerase activity of HIV-1 RT with no effect on HIV-2 RT. The results suggest that there is a protein segment located between residues 158 and 190 that is critical for the inhibition by both compounds. However, there is probably a second segment that resides between residues 192 and 202, as in the case of NPPS, or residues 203 and 224, as in the case of UC-38, that is also crucial for the sensitivity of HIV-I RT to both inhibitors.

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Biological and biochemical anti-HIV activity of the benzothiadiazine class of nonnucleoside reverse transcriptase inhibitors

Cited by 109 publications

References 36 publications

Non-nucleoside Inhibitors of HIV-1 Reverse Transcriptase Inhibit Phosphorolysis and Resensitize the 3′-Azido-3′-deoxythymidine (AZT)-resistant Polymerase to AZT-5′-triphosphate

Non-nucleoside Inhibitors of HIV-1 Reverse Transcriptase Inhibit Phosphorolysis and Resensitize the 3′-Azido-3′-deoxythymidine (AZT)-resistant Polymerase to AZT-5′-triphosphate

Anti-HIV-1 Activity of Calanolides Used in Combination with other Mechanistically Diverse Inhibitors of HIV-1 Replication

Inhibition of reverse transcriptase of human immunodeficiency virus type 1 and chimeric enzymes of human immunodeficiency viruses types 1 and 2 by two novel non‐nucleoside inhibitors

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