Differential Antiviral Activity of Two TIBO Derivatives Against the Human Immunodeficiency and Murine Leukemia Viruses Alone and in Combination with Other Anti-HIV Agents

Buckheit, Robert W.; Germany-Decker, Julie; Hollingshead, Melinda G.; Allen, Lois B.; Shannon, William M.; Janßen, Paul; Chirigos, Michael A.

doi:10.1089/aid.1993.9.1097

Cited by 17 publications

(11 citation statements)

References 40 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%

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%

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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“…Various other drugs, i.e, soluble CD4 (Johnson et al, 1989a), castanospermine (Johnson et al, 1989b), PMEA (Smith et al, 1989), phosphonoformate (foscarnet) (Eriksson and Shinazi, 1989), TIBO derivatives (Buckheit et al, 1993) and aA interferon (Hartshorn et al, 1987), have been previously reported to act synergistically with AlT. Optimal AIDS therapy may require the use of a combination of agents that exhibit synergistic antiviral effects (e.g.…”

Section: In Vitro Anti-hiv Activity Of Polysulfates In Combination Wimentioning

confidence: 99%

Antiviral Portrait Series: 4. Polysuifates as Inhibitors of HIV and Other Enveloped Viruses

Witvrouw¹,

Desmyter²,

Clercq

1994

Antivir Chem Chemother

101

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Polysulfates are highly potent and selective inhibitors of the in vitro replication of HIV and other enveloped viruses. They not only inhibit the cytopathic effect of HIV, but also prevent HIV-induced syncytium (giant cell) formation. They also act synergistically with other anti-HIV drugs. The anti-HIV activity of polysulfates is a result of their shielding of the positively charged sites in the V3 loop of the viral envelope glycoprotein gp120. When polysulfates were administered intravenously to rabbits, their half-life was approximately 2h. Although they are very poorly absorbed following oral administration, they can be made orally bioavailable with the appropriate chemical modifications. Also, polysulfates may lose (much of) their anticoagulant activity upon chemical modification without giving up their anti-HIV activity. Their efficacy in the therapy and/or prophylaxis of retroviral infections remains to be demonstrated both in animal models and in humans.

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“…Compounds UC84 and UC38 were previously identified through the NCI's high capacity anti-AIDS drug screening program as highly active and specific inhibitors of HIV replication (1, 33) with similarity to a variety of structurally diverse molecules previously reported (1,9,10,12,23,27,28,31,32,36,39,44,52). To improve upon the activity of the two lead compounds, a third generation of analogs was synthesized and evaluated for activity.…”

Section: Discussionmentioning

confidence: 99%

“…The highly diverse pharmacologic class of nonnucleoside RT inhibitors (NNRTIs) has provided a variety of drug candidates which possess great potency and wide therapeutic indices (1,9,10,12,27,28,31,32,36,39,44,52). The NNRTIs inhibit HIV type 1 (HIV-1) RT by a highly specific interaction with the enzyme at the NNRTI binding site in the palm domain of the p66 subunit of the RT.…”

mentioning

confidence: 99%

Structure-activity and cross-resistance evaluations of a series of human immunodeficiency virus type-1-specific compounds related to oxathiin carboxanilide

Buckheit

Kinjerski

Fliakas-Boltz

et al. 1995

Antimicrob Agents Chemother

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A series of compounds related to the nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) oxathiin carboxanilide (UC84) were evaluated for activity against the human immunodeficiency virus (HIV) to determine structural requirements for anti-HIV activity. Twenty-seven compounds representative of the more than 400 Uniroyal Chemical Company (UC) compounds were evaluated for structure-activity relationships. Several of the compounds evaluated were highly active, with 50% effective concentrations in the nanomolar range and therapeutic indices of >1,000. Highly synergistic anti-HIV activity was observed for each compound when used in combination with 3-azido-3-deoxythymidine; additive to slightly synergistic interactions were observed with the compounds used in combination with dideoxycytidine. In combination with the NNRTI costatolide, only UC38 synergistically inhibited HIV type 1. Residues in the RT which, when mutated, impart resistance to the carboxanilide compounds were defined by evaluation of the UC compounds against a panel of NNRTI-resistant virus isolates selected in cell culture, against virus variants with site-directed mutations, and against RTs containing defined single amino acid changes. The mutations included changes in RT amino acids 100, 101, 103, 106, 108, and 181. The results with isolates selected in cell culture indicate that the carboxanilide compounds interact with the RT at two vulnerable sites, selecting UC-resistant virus isolates with the Y-to-C mutation at position 181 (Y181C) or the L100I substitution. A resistant virus isolate containing both Y181C and K101E amino acid changes and another with both Y181C and V106A mutations were isolated. In combination with calanolide A, an NNRTI which retains activity against virus isolates with the single Y181C mutation, UC10 rapidly selected a virus isolate with the K103N mutation. The merits of selecting potential candidate anti-HIV agents to be used in rational combination drug design as part of an armamentarium of highly active anti-HIV compounds are discussed.

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Differential Antiviral Activity of Two TIBO Derivatives Against the Human Immunodeficiency and Murine Leukemia Viruses Alone and in Combination with Other Anti-HIV Agents

Cited by 17 publications

References 40 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

Antiviral Portrait Series: 4. Polysuifates as Inhibitors of HIV and Other Enveloped Viruses

Structure-activity and cross-resistance evaluations of a series of human immunodeficiency virus type-1-specific compounds related to oxathiin carboxanilide

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