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:2.7.7.7 (DNA polymerase)
17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Emtricitabine [(-)FTC; (-)-beta-L-2'-3'-dideoxy-5-fluoro-3'-thiacytidine] is an oxathiolane nucleoside analog recently approved by the Food and Drug Administration for the treatment of human immunodeficiency virus (HIV). Structurally, (-)FTC closely resembles lamivudine [(-)3TC] except that the former is 5-fluorinated on the cytosine ring. In HIV-1 reverse transcriptase (RT) enzymatic assays, the triphosphate of (-)FTC [(-)FTC-TP] was incorporated into both DNA-DNA and DNA-RNA primer-templates nearly 3- and 10-fold more efficiently than (-)3TC-TP. Animal studies and clinical trial studies have demonstrated a favorable safety profile for (-)FTC. However, a detailed study of the incorporation of (-)FTC-TP by human mitochondrial DNA polymerase gamma, a host enzyme associated with nucleoside toxicity, is required for complete understanding of the molecular mechanisms of inhibition and toxicity. We studied the incorporation of (-)FTC-TP and its enantiomer (+)FTC-TP into a DNA-DNA primer-template by recombinant human mitochondrial DNA polymerase in a pre-steady-state kinetic analysis. (-)FTC-TP was incorporated 2.9 x 10(5)-, 1.1 x 10(5)-, 1.6 x 10(3)-, 7.9 x 10(3)-, and 100-fold less efficiently than dCTP, ddCTP, (+)3TC-TP, (+)FTC-TP, and (-)3TC-TP, respectively. The rate of removal of (-)FTC-MP from the corresponding chain-terminated 24-mer DNA by polymerase gamma's 3'-->5' exonuclease activity was equal to the removal of (+)FTC-MP, 2-fold slower than the removal of (-)3TC-MP and (+)3TC-MP, and 4.6-fold slower than the excision of dCMP. These results demonstrate that there are clear differences between HIV-1 RT and polymerase gamma in terms of preferences for substrate structure.
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PMID:Relationship between antiviral activity and host toxicity: comparison of the incorporation efficiencies of 2',3'-dideoxy-5-fluoro-3'-thiacytidine-triphosphate analogs by human immunodeficiency virus type 1 reverse transcriptase and human mitochondrial DNA polymerase. 1504 33

We report a case of fatal liver failure due to reactivation of lamivudine-resistant HBV. A 53-year-old man was followed since 1998 for HBV-related chronic hepatitis. Serum HBV-DNA was 150 MEq/mL (branched DNA signal amplification assay) and ALT levels fluctuated between 50-200 IU/L with no clinical signs of liver cirrhosis. Lamivudine (100 mg/d) was started in May 2001 and serum HBV-DNA subsequently decreased below undetectable levels. In May 2002, serum HBV-DNA had increased to 410 MEq/mL, along with ALT flare (226 IU/L). The YMDD motif in the DNA polymerase gene had been replaced by YIDD. Lamivudine was continued and ALT spontaneously decreased to the former levels. On Oct 3 the patient presenting with general fatigue, nausea and jaundice was admitted to our hospital. The laboratory data revealed HBV reactivation and liver failure (ALT: 1828 IU/L, total bilirubin: 10 mg/dL, and prothrombin INR: 3.24). For religious reasons, the patient and his family refused blood transfusion, plasma exchange and liver transplantation. The patient died 10 d after admission. The autopsy revealed remarkable liver atrophy.
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PMID:Fatal liver failure due to reactivation of lamivudine-resistant HBV mutant. 1516 53

The emergence of drug-resistant hepatitis B virus (HBV) has been reported in patients with prolonged administration of lamivudine, which is a potent drug for the prevention of HBV infection. Lamivudine-resistant HBV has several types of mutations at the YMDD motif of its DNA polymerase. We successfully demonstrated that monitoring the hybridization behavior in nanostructured reverse micelles enables us to detect single nucleotide polymorphisms (SNPs). With the aid of reverse micelles, a model 40-mer oligonucleotide containing a single-base substitution was clearly distinguished from the normal, complementary oligonucleotide. In addition, we extended this technique to a high-throughput analysis. The results obtained with a 96-well micro-plate reader indicated the possibility of SNPs detection toward multiple samples of patients.
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PMID:Mutation detection in the drug-resistant hepatitis B virus polymerase gene using nanostructured reverse micelles. 1556 58

As a general rule, enzymes act on only one enantiomer of a chiral substrate and only one of the enantiomeric forms of a chiral molecule may bind effectively at the catalytic site, displaying biological activity. In recent years, some exceptions have been found among viral and cellular enzymes involved in the synthesis of deoxynucleoside triphosphates and in their polymerisation into DNA. Examples are: herpes virus thymidine kinases, cellular deoxycytidine kinase and deoxynucleotide kinases, human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, hepatitis B virus (HBV) DNA polymerase and, to a lesser extent, some cellular DNA polymerases. The lack of enantioselectivity allows herpes simplex virus (HSV) thymidine kinase and cellular deoxycytidine kinase to phosphorylate the unnatural L-beta-enantiomers of D-thymidine and D-deoxycytidine, respectively, or of their analogues to monophosphate. This phosphorylation represents the first and often the rate-limiting step of their activation to triphosphates. The L-triphosphates can then exert antiviral (anti-HSV, anti-Human cytomegalovirus, anti-HIV-1, anti-HBV) and anticancer activities. Although only one L-nucleoside (3TC) has so far gained United States of America Food and Drug Administration (USA FDA) approval for clinical use against HIV-1, other L-enantiomers of nucleoside analogues, which have shown antiviral or anticancer activity in cell cultures are in clinical trials. Their resistance to enantioselective enzymes, such as thymidine phosphorylase, thymidylate synthase, (deoxy)-cytidine and dCMP deaminases, and their lower affinity for the mitochondrial thymidine kinase can ensure a higher selectivity and lower cytotoxicity with respect to those exerted by their corresponding natural D-enantiomers and might be exploited to solve problems arising during chemotherapy, such as metabolic inactivation, cytotoxicity and drug-resistance.
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PMID:Molecular basis for the antiviral and anticancer activities of unnatural L-beta-nucleosides. 1599 31

NRTI-based therapy used to treat AIDS can cause mitochondrial toxicity resulting from the incorporation of NRTIs into mitochondrial DNA by DNA polymerase gamma (pol gamma). Pol gamma has poor discrimination against many of the currently used NRTIs resulting in aborted DNA synthesis and subsequent depletion of mtDNA. Pol gamma readily incorporates ddCTP, ddITP and D4T-TP with an efficiency similar to the incorporation of normal nucleotides, whereas AZT-TP, CBV-TP, 3TC-TP and PMPApp act as moderate inhibitors to DNA synthesis. We have sought a structural explanation for the unique selection for NRTIs by the human pol gamma. A structural model of the human pol gamma was developed to ascertain the role of active site amino acids. One residue in particular, Y951 in motif B, is primarily responsible for the selection of dideoxynucleotides and D4T-TP. Our structural model of the human pol gamma should assist in rational design of antiviral nucleoside analogs with higher specificity for HIV-RT and minimal selection and incorporation into mitochondrial DNA.
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PMID:Molecular insights into NRTI inhibition and mitochondrial toxicity revealed from a structural model of the human mitochondrial DNA polymerase. 1612 Mar 86

Hepatitis B virus (HBV) is one of the major causes of liver disease worldwide, and chronic HBV infection may progress to cirrhosis and hepatocellular carcinoma. Mutations at the active site of DNA polymerase of HBV, tyrosine-methionine-aspartate-aspartate (YMDD) motif, render infected patients resistant to antiviral drug (Lamivudine) therapy. Hence, sensitive and specific methods aimed at detecting the mutants are essential. The purpose of this study was to develop methods for detecting the mutations at YMDD by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and real-time PCR using locked nucleic acid (LNA)-mediated TaqMan probes. The results obtained by these methods were compared with those examined by conventional direct sequencing on serum samples of 77 patients treated with lamivudine. Our results show that both PCR-RFLP and real-time PCR could detect wild type, YMDD, and its mutants, tyrosine-isoleucine-aspartate-aspartate and tyrosine-valine-aspartate-aspartate. In addition, the mixtures of the wild-type virus and its mutants in the serum sample were detected. Importantly, real-time PCR is less time-consuming, and more sensitive for the detection of mixed populations than PCR-RFLP. The real-time PCR with LNA-mediated TaqMan probes is a sensitive, specific and rapid detection method for mutations at the YMDD motif, which will be essential for monitoring patients undergoing lamivudine antiviral therapy.
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PMID:Rapid detection of lamivudine-resistant hepatitis B virus mutations by PCR-based methods. 1696 Mar 47

2',3'-Didehydro-3'-deoxy-4'-ethynylthymidine (4'-Ed4T), is a recently discovered nucleoside reverse transcriptase inhibitor (NRTI) showing a 5- to 10-fold greater anti-human immunodeficiency virus type 1 (HIV-1) activity and less cellular and mitochondrial toxicity than its parental compound, stavudine (D4T). It is also active against a variety of NRTI-resistant HIV-1 mutants under non-cytotoxic concentrations. In this study, the effects of 4'-Ed4TTP, which is the triphosphate metabolite of 4'-Ed4T, on HIV-1 reverse transcriptase (RT) activity were investigated. We found that 4'-Ed4TTP was a substrate of HIV-1 RT serving as a DNA chain terminator, and it inhibited the DNA polymerase activity of RT more efficiently than D4TTP. The value of Ki(4'-Ed4TTP)/Km(dTTP) is 0.15 for DNA/RNA primer/template duplex (P/T), but 0.7 for DNA/DNA P/T, suggesting 4'-Ed4TTP inhibits RT more efficiently during RNA-dependent DNA synthesis than DNA-dependent DNA synthesis. 4'-Ed4TTP was also found to inhibit the 3TC (Lamivudine)-resistant RT mutant, M184V, with 3-fold less efficiency than the wild type (wt) RT. 4'-Ed4TTP showed much less inhibitory effects toward major host DNA polymerases. Overall, our results suggest that 4'-Ed4TTP is the active form for anti-HIV-1 activity via its inhibitory effect against RT.
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PMID:Highly selective action of triphosphate metabolite of 4'-ethynyl D4T: a novel anti-HIV compound against HIV-1 RT. 1710 75

Infection with hepatitis B virus (HBV) is extremely widespread - it infects two billion people out of the six billion world population. It is estimated that between 350 and 400 million people are chronically infected with HBV. Chronic HBV infection leads to development of complications, such as cirrhosis and hepatocellular carcinoma (HCC), which arise in 15-40% of patients. HBV-related liver disease and its complications result in approximately one million deaths each year. The ultimate goals of chronic hepatitis B (CHB) therapy are decreases in the incidence of cirrhosis, end-stage liver disease and HCC. The following six medications are currently approved by the U.S. Food and Drug Administration for the treatment of CHB: interferon (INF)-alpha2b, pegylated INF-alpha2a, lamivudine, adefovir dipivoxil, entecavir and, recently, telbivudine. Interferon therapy has many contraindications and commonly causes multiple intolerable adverse effects. Lamivudine therapy leads to increased development of resistant mutations with each year of use. Entecavir, a new guanosine nucleoside analogue with specific activity against HBV DNA polymerase, represents a third agent within the nucleoside/nucleotide HBV polymerase inhibitor class. It has distinct advantages over lamivudine and adefovir dipivoxil: it has a three-step mechanism of action, is the most potent inhibitor of HBV DNA polymerase, is not associated with any major adverse effects and has a limited potential for resistance. In clinical trials, entecavir was superior to lamivudine in all primary endpoints in both nucleoside-naive and lamivudine-refractory hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients. Preliminary data support entecavir efficacy in patients with cirrhosis and HIV/HBV coinfected patients. No resistance occurred after two years of entecavir therapy in nucleoside-naive patients. Up to 9% resistance developed in patients with documented prior lamivudine resistance during 96 weeks of entecavir therapy. Currently, entecavir should be considered a first- or second-line treatment option for the management of HBeAg-positive or -negative nucleoside-naive or lamivudine-refractory CHB patients.
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PMID:Entecavir: a new nucleoside analogue for the treatment of chronic hepatitis B. 1746 Jul 84

Three nucleotide/nucleoside analogs are currently used for the treatment of chronic hepatitis B: lamivudine, adefovir dipivoxil, and entecavir. Lamivudine and adefovir are beneficial for oral administration and safety, but only a few of the patients treated experience a sustained response after therapy withdrawal. Entecavir, a cyclopentyl guanosine analog, is a potent inhibitor of chronic hepatitis B virus DNA polymerase, inhibiting both the priming and elongation steps of viral DNA replication. In phase II and phase III clinical trials, entecavir was found to be superior to lamivudine for all primary end points evaluated in both nucleoside-naive and lamivudine-resistant patients as well as being effective in both HBeAg-positive and HBeAg-negative nucleoside-naive patients. Only one trial has shown evidence of cases of viral resistance to this drug. The approved dosage in treatment-naive patients is 0.5 mg per day orally, whereas in patients who have failed lamivudine therapy or are known to harbor lamivudine-resistant mutants, the approved dosage is 1.0 mg per day.
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PMID:Entecavir for chronic hepatitis B: a review. 1822 55

Three nucleotide/nucleoside analogs are used for chronic hepatitis B (HBV): lamivudine, adefovir dipivoxil, and entecavir. Lamivudine and adefovir are advantageous for oral administration and safety but induce a sustained response after withdrawal of therapy in only a minority of patients. Thus, the treatment should be given in trials in a majority of patients for a long period of time. In addition, the long-term efficacy of lamivudine is limited by the frequent emergence of drug-resistant HBV mutants. Adefovir is associated with a low frequency of resistance, but its antiviral effect is not optimal. Entecavir, a cyclopentyl guanosine analog, is a potent inhibitor of HBV-DNA polymerase and it inhibits both priming and elongation steps of viral DNA replication. In phase II and III clinical trials, entecavir was found to be superior to lamivudine for all primary end points evaluated in both nucleoside-naive and lamivudine-resistant patients, and it was effective in both HBeAg-positive and HBeAg-negative nucleoside-naive patients. Only one trial has shown cases of viral resistance to this drug. The approved dosage in treatment-naive patients is 0.5 mg per day orally, whereas in patients who have failed lamivudine therapy or who are known to harbor lamivudine-resistant mutants, the approved dosage is 1.0 mg per day. Recent preliminary results show that clevudine, telbivudine, and emtricitabine may be potent analogs available for the treatment of HBV. Further studies are being conducted to assess the long-term efficacy and safety of these drugs.
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PMID:New drugs for chronic hepatitis B: a review. 1835 37


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