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)

Long-term side effects of antiretroviral therapy are attributed to the mitochondrial (mt) toxicity of nucleoside analogue reverse transcriptase inhibitors (NRTIs) and their ability to deplete mtDNA. Studies in hepatocytes suggest that uridine is able to prevent and treat mtDNA depletion by pyrimidine NRTls [zalcitabine (ddC) and stavudine (d4T)] and to fully abrogate hepatocyte death, elevated lactate production and intracellular steatosis. Uridine was also found to improve the liver and haematopoietic toxicities of zidovudine (AZT), which are unrelated to mtDNA depletion, and to prevent neuronal cell death induced by ddC. Most recently, uridine was found to prevent the onset of a lipoatrophic phenotype (reduced intracellular lipids, increased apoptosis, mtDNA depletion and mt depolarization) in adipocytes incubated long-term with d4T and AZT. Various steps of mt nucleoside utilization may be involved in the protective effect, but competition of uridine metabolites with NRTIs at polymerase y or other enzymes is a plausible explanation. Pharmacokinetic studies suggest that uridine serum levels can be safely increased in humans to achieve concentrations which are protective in vitro (50-200 microM). Uridine was not found to interfere with the antiretroviral activity of NRTIs. Mitocnol, a sugar cane extract which effectively increases uridine in human serum, was beneficial in individual HIV patients with mt toxicity and is now being tested in placebo-controlled randomized trials. Until these data become available, the risk-benefit calculation of using uridine should be individualized. The current safety data justify the closely monitored use of uridine in individuals who suffer from mt toxicity but who cannot be switched to less toxic NRTIs.
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PMID:Uridine in the prevention and treatment of NRTI-related mitochondrial toxicity. 1615 13

We have developed quantitative structure-activity relationship (QSAR) models for 44 non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) of the pyridinone derivative type. The k nearest neighbor (kNN) variable selection approach was used. This method utilizes multiple descriptors such as molecular connectivity indices, which are derived from two-dimensional molecular topology. The modeling process entailed extensive validation including the randomization of the target property (Y-randomization) test and the division of the dataset into multiple training and test sets to establish the external predictive power of the training set models. QSAR models with high internal and external accuracy were generated, with leave-one-out cross-validated R2 (q2) values ranging between 0.5 and 0.8 for the training sets and R2 values exceeding 0.6 for the test sets. The best models with the highest internal and external predictive power were used to search the National Cancer Institute database. Derivatives of the pyrazolo[3,4-d]pyrimidine and phenothiazine type were identified as promising novel NNRTIs leads. Several candidates were docked into the binding pocket of nevirapine with the AutoDock (version 3.0) software. Docking results suggested that these types of compounds could be binding in the NNRTI binding site in a similar mode to a known non-nucleoside inhibitor nevirapine.
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PMID:Quantitative structure-activity relationship analysis of pyridinone HIV-1 reverse transcriptase inhibitors using the k nearest neighbor method and QSAR-based database mining. 1616 50

In order to introduce pyrimidine C5-propynyl modification into boranophosphate oligodeoxyribonucleotides (BP- ODNs), 5-(1-propynyl)-2'-deoxyuridine 5'-(alpha-P-borano) triphosphate (d5PUTPalphaB) was synthesized. The two diastereomers were separated by reverse-phase HPLC. Kinetic studies showed that the Rp isomer was a slightly better substrate for MMLV reverse transcriptase than thymidine triphosphate or Rp-thymidine 5'-(alpha-P-borano)triphosphate. Using the Rp isomers of d5PUTPalphaB and the other three 5'-(alpha-P-borano) triphosphates, a DNA primer could be extended to the full length of the template.
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PMID:Synthesis of 5-(1-propynyl)-2'-deoxyuridine 5'-(alpha-P-borano)triphosphate and kinetic characterization as a substrate for mmlv reverse transcriptase. 1624 69

Chronic hepatitis B is a common disease and approximately 20% of infected patients with compensated cirrhosis will decompensate over 5 years. If untreated, the survival of decompensated cirrhosis is poor (15% at 5 years). The extent of hepatitis B virus (HBV) replication, as assessed by serum HBV-DNA level, is a strong predictor of the risk of disease progression and hepatocellular carcinoma. This provides a rationale for antiviral therapy to arrest progression of liver disease. Lamivudine is a pyrimidine analogue that inhibits HBV-DNA reverse transcriptase. It decreases HBV replication, normalises alanine aminotransferase levels and reduces hepatic inflammation and fibrosis in patients with chronic hepatitis B. This article will focus on the use of lamivudine in patients with HBV-cirrhosis. In patients with compensated HBV-cirrhosis, a randomised, placebo-controlled trial has shown that lamivudine significantly reduced the rate of disease progression and hepatocellular carcinoma development over a 3-year period. In patients with decompensated cirrhosis, treatment with lamivudine can produce spectacular improvements of liver function, but the improvement is slow and a clinical benefit is usually not observed until after at least 3-6 months of treatment. A major drawback of lamivudine treatment is the development of resistance, observed in 15-20% of patients after 1 year and up to 70% after 5 years of continued treatment. Thus, patients with HBV-cirrhosis treated with lamivudine should have regular monitoring of serum HBV-DNA levels and prompt institution of additional antiviral therapy if viral breakthrough is observed. Adefovir, tenofovir and entecavir have demonstrated efficacy in patients with lamivudine resistance. In patients with decompensated cirrhosis, in whom the development of resistance can be fatal, combination therapy (such as lamivudine plus adefovir) may prove more effective than monotherapy and this issue needs further study.
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PMID:Lamivudine treatment in patients with chronic hepatitis B and cirrhosis. 1692 9

Apricitabine (ATC) is a novel deoxycytidine analog reverse transcriptase inhibitor in development for the treatment of human immunodeficiency virus infection. Studies were performed to characterize the excretion of ATC and its metabolite, BCH-335 (-1-(2-hydroxymethyl-[1,3]oxathiolan-4-yl)-1H-pyrimidine-2,4-dione), in the isolated perfused rat kidney (IPK). A second objective was to investigate the effect of trimethoprim on ATC excretion because trimethoprim inhibits the excretion of lamivudine, structurally similar to ATC, in the IPK. ATC excretion was nonlinear at doses of 80 to 1600 microg. The excretion ratio (ratio of clearance to glomerular filtration rate, assuming negligible protein binding) was greater than 1.0, indicating net tubular secretion. In contrast, the excretion of BCH-335 was independent of the dose of BCH-335. Concomitant administration of ATC and BCH-335 did not affect the excretion of either compound. Trimethoprim significantly inhibited the excretion of both ATC and BCH-335, with IC(50) values of 0.45 and 0.54 microg/ml, respectively. In the presence of trimethoprim, the excretion ratios for both compounds were less than 1.0, indicating tubular reabsorption. Trimethoprim inhibited the excretion of ATC and lamivudine to similar extents. Following concomitant administration of ATC, lamivudine, and trimethoprim, there was no evidence of an interaction between ATC and lamivudine. These results suggest that ATC undergoes active tubular secretion in the kidney. Because the renal excretion of both ATC and lamivudine is inhibited by trimethoprim to similar extents, in clinical practice exposure to ATC, it would be expected to be increased in the presence of therapeutic concentrations of trimethoprim to a similar extent as has been shown previously for lamivudine.
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PMID:Effects of trimethoprim on the clearance of apricitabine, a deoxycytidine analog reverse transcriptase inhibitor, and Lamivudine in the isolated perfused rat kidney. 1692 64

Novel compounds, which can be considered as conformationally restricted analogues of MKC-442, have been synthesized and tested as inhibitors of the reverse transcriptase of human immunodeficiency virus type-1 (HIV-1). Reaction of urea with a beta-ketoester furnished 6,7,8,9-tetrahydro-9-phenyl-1H-cyclohepta[d]pyrimidine-2,4-(3H,5H)-dione (6a) and 6,7,8,9-tetrahydro-9-p-tolyl-1H-cyclohepta[d]pyrimidine-2,4-(3H,5H)-dione (6b) which were then alkylated at the N-1 position with chloromethyl ether, allyl bromide and benzyl bromide to afford the target compounds 7a-b, 8a-b, 9 and 10, respectively. The seven-membered, annelated compounds have a relatively rigid structures and can lock the orientation of the aromatic ring. Chemical modification at N-1 of the pyrinidine ring and the 9-phenyl ring was attempted, with the aim of improving the antiretroviral activity. In particular, replacement of the aliphatic group with the phenyl moiety at the terminus of N-1 side chain can enhance the activity. The most active compounds showed activity in the low micromolar range with IC50 values comparable to that of nevirapine. The biological activity results are in accordance with the docking results.
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PMID:The design and synthesis of 9-phenylcyclohepta[d]pyrimidine-2,4-dione derivatives as potent non-nucleoside inhibitors of HIV reverse transcriptase. 1703 13

Etravirine [TMC 125] is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) that is being developed by Tibotec (Tibotec-Virco Group; now Johnson & Johnson) for the treatment of HIV-1 infections. Etravirine is a highly flexible, di-aryl-pyrimidine (DAPY) compound. The flexibility enables favourable binding interactions with mutant HIV strains as well as wild-type virus. Etravirine has superseded dapivirine as Tibotec's lead NNRTI in clinical development worldwide. Tibotec merged with Virco to form Tibotec-Virco Group in March 2001. Subsequently, Tibotec-Virco Group was acquired by Johnson & Johnson on 18 April 2002. Etravirine was discovered by Tibotec in collaboration with the Janssen Research Foundation. However, the Janssen Research Foundation is no longer involved in the development of etravirine. Etravirine has received fast-track status from the US FDA for the treatment of HIV-1 infections. An expanded access programme for etravirine began in the US in September 2006. The programme made etravirine available to HIV-1 infected adults who have limited treatment options due to virological failure or intolerance to multiple antiretroviral regimens. The progamme will also be introduced in Canada and Europe. In November 2005, Tibotec initiated two randomised, placebo-controlled phase III trials of etravirine in treatment-experienced HIV-1 infected patients with NNRTI resistance and at least three primary protease mutations. The two trials will each enroll 600 patients and will be conducted in 18 countries. Darunavir will be used as the background protease inhibitor in the trials. This is the first time that two investigational antivirals have been evaluated in combination in heavily treatment-experienced patients. The trial design is supported by the FDA, the Committee for Medicinal Products for Human Use (CHMP) of the EMEA and the HIV patient community. Patient enrolment in the two phase III trials was completed in September 2006. A multicentre phase IIb dose-finding study (TMC125 C223) in Europe, Canada and the US found etravirine significantly reduced the HIV viral load in a subset of heavily treatment-experienced patients. Tibotec discontinued a single exploratory open-label phase II trial (TMC 125-C227) of etravirine in November 2005. The discontinuation was a result of 12-week data, which demonstrated a difference in the proportion of patients achieving or maintaining undetectable viral load in favour of the control group, who were receiving protease inhibitor-based treatment. There were no safety concerns and the discontinuation had no effect on phase III registration trials. Phase IIa clinical trials of etravirine for the treatment of HIV infections, initiated in November 2001, have been completed. Tibotec has conducted a phase I trial (TMC125-C157 study) evaluating etravirine + didanosine among healthy volunteers in Belgium; trial results have been presented.
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PMID:Etravirine: R165335, TMC 125, TMC-125, TMC125. 1707 19

The nucleoside reverse transcriptase inhibitors (NRTIs) make up a family of antiretroviral drugs widely used in the treatment of HIV-1 infection. Human concentrative nucleoside transporters and equilibrative nucleoside transporters, encoded by SLC28 and SLC29 gene families, respectively, are known to be involved in the uptake of a variety of nucleoside analogues used in anticancer treatment. We therefore examined whether SLC28- and SLC29-encoded proteins contribute to the entry of these NRTls into the human leukaemic T-cell line Molt-4. Cis-inhibition experiments demonstrated that nucleoside transporters have a negligible role in antiviral drug uptake. Moreover, the previously identified 3'-azido-2',3'-dideoxythymidine (zidovudine; AZT) carriers, organic anion transporters (organic anion transporter [hOATs], members of the SLC22 gene family) have not been detected in T cells, either functionally or at the mRNA level, thus ruling out a role for hOATs in antiviral drug uptake in these cells. Nevertheless, the data provided here argue against the hypothesis of simple diffusion across the plasma membrane as the unique mechanism of AZT uptake. Actually, this pyrimidine derivative seems to have a temperature-sensitive route of entrance, a finding that, along with the evidence that, AZT inhibits its own uptake and its transport into phytohaemagglutinin-stimulated peripheral blood mononuclear cells is upregulated, strongly support the idea that AZT uptake into T-cells is associated with a mediated and regulated, transport mechanism.
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PMID:3'-Azido-2',3'-dideoxythymidine (zidovudine) uptake mechanisms in T lymphocytes. 1731 Aug 25

We identified a deletion at codon 70 (Delta70) of HIV-1 reverse transcriptase (RT) occurring together with L74V and Q151M mutations in a sample from a tenofovir (TFV)- and abacavir (ABC)-treated patient with extensive prior antiretroviral treatment. To investigate the characteristics of this mutant, we studied the drug susceptibility, relative infectivity, and fitness of viruses carrying Delta70 and associated RT mutations. The Delta70, L74V, and Q151M mutations were introduced into Hxb2 RT by site-directed mutagenesis and expressed in HIV-1 recombinants. The Delta70 mutation increased resistance to lamivudine and emtricitabine alone and in combination with various resistance mutations and augmented resistance to ABC and didanosine when present together with L74V. A recombinant virus expressing RT from the original clinical viral sample (Delta70-PRT) exhibited greater fitness than one in which the deletion had been repaired (K70-PRT). The Delta70 mutation also increased fitness of Hxb2 wild-type and 74V and Q151M mutants. Recombinants carrying Delta70-PRT showed greater relative infectivity in the presence of ABC (but not TFV) compared with K70-PRT recombinants. These results show that Delta70 enhances resistance to certain purine and pyrimidine analogues and contributes to multinucleoside resistance in the appropriate viral genetic background.
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PMID:Virologic characterization of HIV type 1 with a codon 70 deletion in reverse transcriptase. 1749 61

(-)-(2R,4R)-1-(2-Hydroxymethyl-1,3-dioxolan-4yl)thymine (DOT) is a thymidine analogue that has potent in vitro activity against wild-type and nucleoside reverse transcriptase inhibitor (NRTI)-resistant HIV. For nucleoside analogues to inhibit viral replication, they must be metabolized to the active triphosphate, which inhibits the viral reverse transcriptase (RT). Using purified enzymes, the kinetics of DOT phosphorylation, inhibition of wild-type and drug-resistant HIV-1 reverse transcriptase activity, and excision of DOT-5'-monophosphate (DOT-MP) from a chain-terminated primer were examined. DOT was phosphorylated by human thymidine kinase-1 (TK-1) but not by other pyrimidine nucleoside kinases, including the mitochondrial thymidine kinase (TK-2). Resistance to NRTIs involves decreased binding/incorporation and/or increased excision of the chain-terminating NRTI. RTs containing the D67N/K70R/T215Y/K219Q or T695-SS/T215Y mutations show enhanced removal of DOT-MP from terminated primer as well as approximately four-fold decreased binding/incorporation. The Q151M and K65R mutations appear to cause decreased inhibition by DOT-TP. However, both the K65R and Q151M mutations show decreased excision, which would confer greater stability on the terminated primer. These opposing mechanisms could offset the overall resistance profile and susceptibility. Little or no resistance was observed with the enzymes harbouring mutations resistant to lamivudine (M184V) and non-nucleoside RT inhibitors (K103N).
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PMID:Mechanism of action of (-)-(2R,4R)-1-(2-hydroxymethyl-1,3-dioxolan-4-yl) thymine as an anti-HIV agent. 1754 53


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