[21] Qualitative study of drug resistance in retroviral protease using structural modeling and site-directed mutagenesis

Jc, Culberson; Bl, Bush; Vv, Sardana

doi:10.1016/0076-6879(94)41075-5

Methods in Enzymology

1994

DOI: 10.1016/0076-6879(94)41075-5

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[21] Qualitative study of drug resistance in retroviral protease using structural modeling and site-directed mutagenesis

Culberson Jc¹,

Bush Bl²,

Sardana Vv³

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Cited by 4 publications

(2 citation statements)

References 27 publications

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“…Recently, a new class of antiretroviral agent, the PR inhibitors, was approved for use in AIDS (4,5,10,27). Resistance to this class of compounds has appeared following in vitro culture of HIV in the presence of some inhibitors and in patients following therapy (3,11,22,24,40,48,49). Recently, the use of cocktails of both RT inhibitors and PR inhibitors has looked exceptionally promising (9,21,23).…”

mentioning

confidence: 99%

Dicaffeoylquinic and Dicaffeoyltartaric Acids Are Selective Inhibitors of Human Immunodeficiency Virus Type 1 Integrase

McDougall¹,

King

et al. 1998

Antimicrob Agents Chemother

202

126

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Current pharmacological agents for human immunodeficiency virus (HIV) infection include drugs targeted against HIV reverse transcriptase and HIV protease. An understudied therapeutic target is HIV integrase, an essential enzyme that mediates integration of the HIV genome into the host chromosome. The dicaffeoylquinic acids (DCQAs) and the dicaffeoyltartaric acids (DCTAs) have potent activity against HIV integrase in vitro and prevent HIV replication in tissue culture. However, their specificity against HIV integrase in cell culture has been questioned. Thus, the ability of the DCQAs and DCTAs to inhibit binding of HIV type 1 (HIV-1) gp120 to CD4 and their activities against HIV-1 reverse transcriptase and HIV RNase H were studied. The DCQAs and DCTAs inhibited HIV-1 integrase at concentrations between 150 and 840 nM. They inhibited HIV replication at concentrations between 2 and 12 μM. Their activity against reverse transcriptase ranged from 7 μM to greater than 100 μM. Concentrations that inhibited gp120 binding to CD4 exceeded 80 μM. None of the compounds blocked HIV-1 RNase H by 50% at concentrations exceeding 80 μM. Furthermore, when the effects of the DCTAs on reverse transcription in acutely infected cells were measured, they were found to have no activity. Therefore, the DCQAs and DCTAs exhibit >10- to >100-fold specificity for HIV integrase, and their activity against integrase in biochemical assays is consistent with their observed anti-HIV activity in tissue culture. Thus, the DCQAs and DCTAs are a potentially important class of HIV inhibitors that act at a site distinct from that of current HIV therapeutic agents.

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mentioning

confidence: 99%

Dicaffeoylquinic and Dicaffeoyltartaric Acids Are Selective Inhibitors of Human Immunodeficiency Virus Type 1 Integrase

McDougall¹,

King

et al. 1998

Antimicrob Agents Chemother

202

126

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show abstract

“…Multiple classes of antiretroviral drugs targeting different areas of the life cycle of human immunodeficiency virus (HIV) have been produced over the last several years (10,11,19). In each instance, however, each class of agents has had significant limitations because of toxicity, the rapid emergence of resistance, or less than optimal antiretroviral activity (8,15,18).…”

mentioning

confidence: 99%

Modeling combinations of antiretroviral agents in vitro with integration of pharmacokinetics: guidance in regimen choice for clinical trial evaluation

Drusano

Prichard

Bilello

et al. 1996

Antimicrob Agents Chemother

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We propose a method for the selection of doses and dosing schedule for drugs to be used in combination. This approach uses the simulation of steady-state concentrations of the drugs in the combination and overlays these concentrations onto a three-dimensional effect surface. The MacSynergy II program is used to construct the three-dimensional drug interaction surface from the direct evaluation of drug combination effect in vitro. The study examined the combination of an inhibitor of the human immunodeficiency virus protease, A-77003, and the nucleoside analog zidovudine. Zidovudine concentrations from a steady-state interval were simulated on the basis of the administration of 100 mg every 12 h by mouth, while for A-77003 simulation profiles were for intravenous administration of 800 mg every 4 h as well as a continuous infusion of 200 mg/h. The average percentage of the maximal effect was taken as a measure of regimen effectiveness. Three different schedules of administration were examined. If both drugs were to be administered simultaneously, the model predicts a mean maximal effect of a steady-state interval (12 h) of 67%. If the drug doses were offset by 2 h, the mean maximal effect predicted was 71%. If A-77003 was to be given by continuous infusion, the mean maximal effect predicted was 90%. This method holds promise as a way of quickly evaluating potential combinations of agents that takes into account the drug interaction in a mathematically robust way and that allows the evaluation of the effect of each drug's pharmacokinetic profile.

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Potency Comparison of Peptidomimetic Inhibitors against HIV-1 and HIV-2 Proteinases: Design of Equipotent Lead Compounds

Weber¹,

Majer²,

Litera³

et al. 1997

Archives of Biochemistry and Biophysics

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[21] Qualitative study of drug resistance in retroviral protease using structural modeling and site-directed mutagenesis

Cited by 4 publications

References 27 publications

Dicaffeoylquinic and Dicaffeoyltartaric Acids Are Selective Inhibitors of Human Immunodeficiency Virus Type 1 Integrase

Dicaffeoylquinic and Dicaffeoyltartaric Acids Are Selective Inhibitors of Human Immunodeficiency Virus Type 1 Integrase

Modeling combinations of antiretroviral agents in vitro with integration of pharmacokinetics: guidance in regimen choice for clinical trial evaluation

Potency Comparison of Peptidomimetic Inhibitors against HIV-1 and HIV-2 Proteinases: Design of Equipotent Lead Compounds

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