Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have, in addition to the nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs), gained a definitive place in the treatment of HIV-1 infections. Starting from the HEPT and TIBO derivatives, more than 30 structurally different classes of compounds have been identified as NNRTIs, that is compounds that are specifically inhibitory to HIV-1 replication and targeted at the HIV-1 reverse transcriptase (RT). Two NNRTIs (nevirapine and delavirdine) have been formally licensed for clinical use and several others are in preclinical or clinical development [thiocarboxanilide UC-781, HEPT derivative MKC-442, quinoxaline HBY 097 and DMP 266 (efavirenz)]. The NNRTIs interact with a specific 'pocket' site of HIV-1 RT that is closely associated with, but distinct from, the NRTI binding site. NNRTIs are notorious for rapidly eliciting resistance due to mutations of the amino acids surrounding the NNRTI-binding site. However, the emergence of resistant HIV strains can be circumvented if the NNRTIs, alone or in combination, are used from the start at sufficiently high concentrations. In vitro, this procedure has proved to 'knock-out' virus replication and to prevent resistance from arising. In vivo, various triple-drug combinations of NNRTIs (nevirapine, delavirdine or efavirenz) with NRTIs (AZT, 3TC, ddI or d4T) and/or PIs (indinavir or nelfinavir) have been shown to afford a durable anti-HIV activity, as reflected by both a decrease in plasma HIV-1 RNA levels and increased CD4 T-lymphocyte counts.
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PMID:The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection. 975 86

In 1996, we interviewed 224 HIV-infected patients (54% men, 63% African American) receiving HIV medical care in St. Louis, Missouri about their recognition, prior use, and current use of HIV medications. Of 221 respondents who had heard of at least one antiretroviral drug, only 2 respondents reported they had never taken antiretroviral drugs. Multivariate logistic regression among respondents with CD4 counts <500 cells/mm3 identified sociodemographic variables (gender, race, education, and site of care) that were significantly (p < .05) associated with never having heard of, never having used, and not currently using specific antiretroviral drugs. African Americans in general, African American women, or African Americans with 12 years of schooling were more likely never to have heard of didanosine (ddI)/zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), protease inhibitors, and non-nucleoside reverse transcriptase inhibitors (NNRTIs). In addition, women were more likely never to have heard of protease inhibitors, and respondents with < or = 12 years of schooling were more likely never to have heard of NNRTIs. African Americans were more likely never to have taken azidothymidine (AZT), and African American women were more likely never to have taken 3TC and protease inhibitors. Sociodemographic variables were not significantly associated with current use of specific antiretroviral drugs among those with CD4 levels <500 cells/mm3, nor with recognition, prior use, or current use of Pneumocystis carinii pneumonia prophylaxis among those with CD4 counts <200 cells/mm3. Findings indicate that, even among patients receiving HIV care, African Americans, women, and those with < or = 12 years of schooling were more likely never to have heard of and never to have used various specific antiretroviral medications. More focused efforts are needed to help patients become aware of available antiretroviral drugs and to encourage greater use of these drugs among all patients for whom the drugs are indicated.
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PMID:Factors associated with HIV-infected patients' recognition and use of HIV medications. 983 43

We have studied the relationship between the length of HIV-1 reverse transcriptase (RT)-mediated nucleotide polymerization and inhibitors of these reactions in cell-free RT assays performed in the presence of either of two dideoxynucleoside triphosphates (ddNTPs), i.e. AZTTP or 3TCTP, or nevirapine, a non-nucleoside RT inhibitor. These reactions employed a heterologous RNA template and three DNA oligonucleotide primers, i.e. pAR, dPR and PA, that yielded distinct full-length products of 65, 192 and 376 nt, respectively, in the absence of inhibitor. We now show that the extent of inhibition of RT activity was greatest with use of the PA primer, which normally yielded the longest reaction product, and that lesser degrees of inhibition were noted in the reactions that generated shorter products. For example, at a concentration of 5 microM AZTTP, the extent of inhibition was 75% with the PA primer but only 40% and <10% when reactions were primed by the dPR and pAR primers, respectively. Similar results were obtained when either a mutated form of HIV RT (i.e. M184V), associated with resistance to 3TC, was tested in the presence of 3TCTP or when RT derived from Moloney murine leukemia virus (M-MuLV) was tested in the presence of AZTTP.
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PMID:Enhanced impairment of chain elongation by inhibitors of HIV reverse transcriptase in cell-free reactions yielding longer DNA products. 983 1

Drug-resistant human immunodeficiency virus (HIV)-1 has been detected in patients on all of the currently available antiretroviral drug regimens. Continuous, high-level virus replication with an error-prone reverse transcriptase enzyme and potential viral recombination events lead to each patient having numerous viral quasispecies and promote the emergence of drug-resistant strains. Drug resistance is associated with one or more point mutations in the HIV gene of the protein that is targeted by the drug. Factors associated with rapid emergence of drug resistance include host factors, such as advanced HIV disease and low CD4 cell counts; viral factors, such as high plasma HIV RNA, pre-existing drug-resistant virus, and possibly syncytium-inducing (SI) phenotype; and drug-related factors, such as suboptimal drug levels or poor compliance. High-level drug resistance has emerged after weeks to months of therapy for lamivudine (3TC) and nevirapine where drug-resistant quasispecies pre-exist in essentially all patients. Resistance has emerged more slowly for zidovudine (ZDV) and HIV protease inhibitors, which require the sequential accumulation of multiple mutations to develop high-level resistance. Certain drugs, such as didanosine (DDI), dideoxycytidine (DDC), and stavudine (D4T) have only produced viruses with low-level resistance, despite prolonged therapy. Development of drug-resistant HIV-1 has been associated with declining CD4 cell counts and rising plasma viral load. Zidovudine-resistant HIV-1 has been associated with adverse clinical outcomes independent of baseline CD4 cell counts and plasma HIV-1 RNA levels. Combination therapy offers the possibility of delaying or preventing the development of HIV drug resistance via interacting drug resistance mutations or potent antiviral activity. Widespread use of ZDV has been associated with transmission of ZDV-resistant HIV-1 in approximately 10% of adult seroconverters and a significant percentage of infants who fail the AIDS Clinical Trial Group (ACTG) 076 prophylactic regimen.
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PMID:Prevalence and incidence of resistance to zidovudine and other antiretroviral drugs. 984 1

Among the nucleoside inhibitors used clinically as anti-HIV drugs which target HIV-1 reverse transcriptase (RT), (-)-2', 3'-dideoxy-3'-thiacytidine [(-)SddC or 3TC] is the only analogue with the unnatural L(-) nucleoside configuration. 3TC has been shown to be more potent and less toxic than the D(+) isomer, (+)SddC, which has the natural nucleoside configuration. The mechanistic basis for the stereochemical selectivity and differential toxicity of the isomeric SddC compounds is not completely understood although a number of factors may clearly come into play including differences in uptake, metabolic activation, degradation, and transport. We used a pre-steady-state kinetic analysis to determine the maximum rate of incorporation, kpol, nucleotide-binding affinity, Kd, and efficiency of incorporation, kpol/Kd, for the (-) and (+) isomeric SddCTP compounds as well as the corresponding dideoxy and natural nucleoside triphosphates into a primer-template complex using HIV-1 reverse transcriptase. The affinity (Kd) of the dNTP was much tighter and the efficiency (kpol/Kd) of incorporation by enzyme into the primer-template complex was much higher for the DNA/RNA primer-template compared to DNA/DNA. The maximum rate of incorporation, kpol, followed the trend of dCTP > ddCTP > (+)SddCTP > (-)SddCTP while the Kd values determined for the DNA/RNA primer-template followed the order (-)SddCTP congruent with (+)SddCTP congruent with ddCTP > dCTP. The corresponding efficiency of incorporation followed the trend dCTP > ddCTP > (+)SddCTP > (-)SddCTP. These data suggest that perturbations on the ribose ring of cytidine analogues (C --> S) decrease the rate and efficiency of incorporation but enhance the binding affinity. These results are discussed in the context of a computer modeled structure of the ternary complexes of RT, DNA/RNA primer-template, and SddCTP analogues as well as implications for structure-activity relationships and further drug design. This information provides a mechanistic basis for understanding the inhibition of HIV-1 reverse transcriptase by 3TC.
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PMID:Mechanistic studies comparing the incorporation of (+) and (-) isomers of 3TCTP by HIV-1 reverse transcriptase. 989 Aug 82

Monitoring for lamivudine (3TC) resistance is important both for the clinical management of human immunodeficiency virus type 1 (HIV-1)-infected patients treated with 3TC and for surveillance of transmission of 3TC-resistant HIV-1. We developed a novel non-culture-based assay for the rapid analysis of phenotypic resistance to 3TC of HIV-1 in plasma. The assay measures the susceptibility of HIV-1 reverse transcriptase (RT) activity to 3TC triphosphate (3TC-TP) in plasma. RT detection was done by the Amp-RT assay, an ultrasensitive PCR-based RT assay. Under our assay conditions, we found that 5 microM 3TC-TP inhibited RT activity from wild-type (WT), zidovudine-resistant, or nevirapine-resistant HIV-1 but not from HIV-1 carrying either the M184V mutation or multidrug (MD) resistance mutations (77L/116Y/151M or 62V/75I/77L/116Y/151M). Mixing experiments showed a detection threshold of 10% 3TC-resistant virus (M184V) in a background of WT HIV-1. To validate the assay for the detection of phenotypic resistance of HIV-1 to 3TC in plasma samples, HIV-1 RT in 30 plasma specimens collected from 15 patients before and during therapy with 3TC was tested for evidence of phenotypic resistance by the Amp-RT assay. The results were compared with those of genotypic analysis. The RT in 12 samples was found to be 3TC sensitive, while the RT in 18 samples had evidence of phenotypic resistance. All 12 samples with 3TC-sensitive RT had WT genotypes at codon 184 and were retrieved before treatment with 3TC. In contrast, all 18 specimens with 3TC-resistant RT were posttherapy samples. This assay provides a simple, rapid, and reliable method for the detection of phenotypic resistance of HIV-1 to 3TC in plasma.
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PMID:A rapid non-culture-based assay for clinical monitoring of phenotypic resistance of human immunodeficiency virus type 1 to lamivudine (3TC). 992 16

A 54-yr-old man with lymphoma and serological evidence of prior hepatitis B virus (HBV) infection, with detectable anti-HBc and anti-HBs, was treated with intensive chemotherapy. He had reactivation of HBV infection with acute hepatitis B manifest by detectable HBsAg and elevated aminotransferase levels >1000 IU/L. He was treated with lamivudine 150 mg daily and had prompt resolution of acute hepatitis B with return of elevated aminotransferases to normal, and initial loss of HBeAg with later loss of HBsAg. Lamivudine was continued during the course of further chemotherapy as prophylaxis against repeat HBV reactivation. Lamivudine is a nucleoside analogue that is a potent inhibitor of HBV reverse transcriptase and HBV replication. Lamivudine therapy should be considered for the treatment of HBV reactivation and might play a future role as preemptive therapy of HBV reactivation in patients with prior hepatitis B or chronic hepatitis B with inactive viral replication.
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PMID:Lamivudine therapy for chemotherapy-induced reactivation of hepatitis B virus infection. 993 65

Lamivudine (3TC), the negative enantiomer of 2'-deoxy-3'-thiacytidine, is a dideoxynucleoside analogue used in combination with other agents in the treatment of human immunodeficiency virus type 1 (HIV-1) infection and as monotherapy in the treatment of hepatitis B virus (HBV) infection. Lamivudine undergoes anabolic phosphorylation by intracellular kinases to form lamivudine 5'-triphosphate, the active anabolite which prevents HIV-1 and HBV replication by competitively inhibiting viral reverse transcriptase and terminating proviral DNA chain extension. The pharmacokinetics of lamivudine are similar in patients with HIV-1 or HBV infection, and healthy volunteers. The drug is rapidly absorbed after oral administration, with maximum serum concentrations usually attained 0.5 to 1.5 hours after the dose. The absolute bioavailability is approximately 82 and 68% in adults and children, respectively. Lamivudine systemic exposure, as measured by the area under the serum drug concentration-time curve (AUC), is not altered when it is administered with food. Lamivudine is widely distributed into total body fluid, the mean apparent volume of distribution (Vd) being approximately 1.3 L/kg following intravenous administration. In pregnant women, lamivudine concentrations in maternal serum, amniotic fluid, umbilical cord and neonatal serum are comparable, indicating that the drug diffuses freely across the placenta. In postpartum women lamivudine is secreted into breast milk. The concentration of lamivudine in cerebrospinal fluid (CSF) is low to modest, being 4 to 8% of serum concentrations in adults and 9 to 17% of serum concentrations in children measured at 2 to 4 hours after the dose. In patients with normal renal function, about 5% of the parent compound is metabolised to the trans-sulphoxide metabolite, which is pharmacologically inactive. In patients with renal impairment, the amount of trans-sulphoxide metabolite recovered in the urine increases, presumably as a function of the decreased lamivudine elimination. As approximately 70% of an oral dose is eliminated renally as unchanged drug, the dose needs to be reduced in patients with renal insufficiency. Hepatic impairment does not affect the pharmacokinetics of lamivudine. Systemic clearance following single intravenous doses averages 20 to 25 L/h (approximately 0.3 L/h/kg). The dominant elimination half-life of lamivudine is approximately 5 to 7 hours, and the in vitro intracellular half-life of its active 5'-triphosphate anabolite is 10.5 to 15.5 hours and 17 to 19 hours in HIV-1 and HBV cell lines, respectively. Drug interaction studies have shown that trimethoprim increases the AUC and decreases the renal clearance of lamivudine, although lamivudine does not affect the disposition of trimethoprim. Other studies have demonstrated no significant interaction between lamivudine and zidovudine or between lamivudine and interferon-alpha-2b. There is limited potential for drug-drug interactions with compounds that are metabolised and/or highly protein bound.
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PMID:Clinical pharmacokinetics of lamivudine. 998 42

The emergence of resistant hepatitis B virus (HBV), with mutations in the YMDD motif of the polymerase gene after treatment with lamivudine, is becoming an important clinical problem. In this study, susceptibility of wild-type and lamivudine-resistant HBV M552I, M552V, and L528M/M552V mutants to other reverse transcriptase inhibitors was investigated by transient transfection of full-length HBV DNA into human hepatoma cells. HBV DNA replication was monitored by Southern blot hybridization, which showed the presence of a single-stranded band (representative of the HBV replicative intermediates) in the drug-free, wild-type HBV-transfected cells. This band was diminished in the samples of wild-type HBV DNA treated with either lamivudine, adefovir, or lobucavir. The band intensities from the lamivudine-resistant mutants were not decreased by treatment with lamivudine, but were decreased by the treatments with adefovir or lobucavir. In contrast, penciclovir and nevirapine did not diminish the intensity of the single-stranded band of wild-type HBV or the lamivudine-resistant mutants. These results demonstrate that lamivudine-resistant HBV is susceptible to adefovir and lobucavir. Lamivudine-resistant HBV should be treated with adefovir or lobucavir, and combination therapy with lamivudine and adefovir/lobucavir may prevent the emergence of lamivudine-resistant HBV.
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PMID:Susceptibility of lamivudine-resistant hepatitis B virus to other reverse transcriptase inhibitors. 1037 69

The presence of human immunodeficiency virus type 1 (HIV-1) bearing mutations resistant to nucleosidic inhibitors of the viral reverse transcriptase (RT) derived from HIV-seropositive asymptomatic and untreated volunteer blood donors was examined. The RT amplicons of 32 specimens were analyzed by using a reverse hybridization line probe assay technique that detects resistance against zidovudine (3'-azido-3'-deoxythymidine [AZT], didanosine (2',3'-dideoxyinosine [ddI], zalcitabine (2',3'-dideoxycytidine [ddC]), and lamivudine ((-)-beta-L-2',3'-dideoxy-3'-thiacytidine [3TC]) at amino acid positions 41, 69, 70, 74, 184, and 215 of the HIV RT. One sample (brp004, subtype B) showed an AZT resistance secondary mutation at position K70R. Fifteen specimens revealed one or more sites of nonreactivity to both wild-type- and mutant-specific probes (dual nonreactivity). Samples were also submitted to RT direct sequencing and phylogenetic analysis. Nine of 32 specimens belonged to non-B subtypes (C, D, F, and F/B or B/F mosaics). Three of these non-B isolates, named brp004, brp063, and brp069, revealed three other relevant AZT resistance mutations-a T215F mutation and two M41L mutations, respectively-hidden by the nonreactivity to line probe assay strips on the respective codon regions. The isolate brp004 also carried a D67N AZT resistance mutation revealed by direct sequencing. No nonnucleosidic RT inhibitor-resistant mutation was found. The analysis revealed a frequency of 2.26 x 10(-4) mutations per nucleotide for independent samples related to RT resistance. These findings emphasize the magnitude of naturally occurring reservoirs of drug-resistant virus among untreated HIV-1-positive individuals in Brazil.
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PMID:Sequence diversity of the reverse transcriptase of human immunodeficiency virus type 1 from untreated Brazilian individuals. 1039 Feb 21


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