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)

PMEA [9-[2-(phosphonomethoxy)ethyl]adenine; adefovir] has shown anti-cytomegalovirus activity in animal models and in preliminary human trials. PMEA diphosphate (PMEApp), the active antiviral metabolite of PMEA, is a potent inhibitor of human cytomegalovirus (HCMV) DNA polymerase. PMEA is efficiently taken up and phosphorylated to PMEApp in numerous human cell lines. In vitro replication of wild type and drug resistant HCMV clinical isolates is effectively inhibited by PMEA. PMEA in combination with other anti-HCMV agents shows additive inhibition of HCMV replication.
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PMID:In vitro characterization of the anti-human cytomegalovirus activity of PMEA (Adefovir). 944 70

Hepatitis B virus (HBV) is the leading cause of chronic hepatitis throughout the world. Notwithstanding the availability of a safe and effective vaccine, the world prevalence of HBV has not declined significantly, thus resulting in the need for a selective antiviral agent. HBV is a small, partially double-stranded DNA virus which replicates through an RNA intermediate. Most efforts to develop anti-HBV agents have been targeted to the viral DNA polymerase which possesses reverse transcriptase activity. Currently, the most promising anti-HBV agents are nucleoside analogs which interfere with viral DNA replication. Although earlier nucleoside analogs such as vidarabine (ara-A) and fialuridine (FIAU) have displayed unacceptable toxicities, newer analogs such as lamivudine (3TC), bis-POM PMEA (GS-840), lobucavir, and BMS-200,475 have demonstrated clinical utility. In particular, the use of lamivudine has generated considerable interest in the development of other L-enantiomeric nucleoside analogs for use against HBV. Here, we provide an overview of HBV structure and replication strategy and discuss the use of cell culture systems, in vitro viral polymerase systems, and animal models to identify and evaluate anti-HBV agents. We also discuss the various classes of nucleoside analogs in terms of structure, mechanism of action, status in clinical development, ability to select for resistant HBV variants, and use in combination therapies. Finally, we present a discussion of novel antiviral approaches, including antisense and gene therapy, and address the various challenges to successful anti-HBV chemotherapeutic intervention.
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PMID:The identification and development of antiviral agents for the treatment of chronic hepatitis B virus infection. 967 Jul 81

L-(-)2',3'-Dideoxythiacytidine (L(-)SddC, Lamivudine) resistant hepatitis B virus (HBV) develops in patients after prolonged treatment. Point mutations detected in the viral genome from these patients have been shown to be responsible for L(-)SddC resistance. Therefore, new drugs active against L(-)SddC resistant HBV are needed. Using a transient transfection system, we studied the sensitivity of L(-)SddC resistant HBV to other anti-HBV nucleoside analogues. It was found that the L526M mutation alone caused greater resistance to penciclovir (PCV) than did the V553I mutation alone. Both mutations also caused the virus to be less sensitive to L(-)SddC and 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil (L-FMAU), although the degree of resistance was much less than that to PCV. The A546V mutation had no impact on the sensitivity to L(-)SddC, L-FMAU, and PCV. When these single mutations were coupled with the M550V/I mutation, all the double mutants were resistant to those drugs. Although 2',3'-dideoxy-2',3'-didehydro-beta-L(-)-5-fluorocytidine (L(-)Fd4C) was also less active, the IC50 of L(-)Fd4C against the L(-)SddC resistant mutant was at least fifty times lower than that against cell growth in culture. DNA polymerase associated with L(-)SddC resistant virions was also found to be less sensitive than that with wild-type HBV to those L-nucleoside triphosphates. All the L(-)SddC resistant mutants were still sensitive to 9-(2-phosphonylmethoxyethyl)-adenine (PMEA). These results suggest that different mutations in the HBV genome have a different impact on its sensitivity to those compounds, and L(-)SddC resistant HBV may also be resistant to PCV, L-FMAU, and L(-)Fd4C. A nucleoside analogue less toxic than PMEA could be developed against L(-)SddC resistant HBV.
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PMID:Sensitivity of L-(-)2,3-dideoxythiacytidine resistant hepatitis B virus to other antiviral nucleoside analogues. 1035 55

Transformed cells are characterized by imbalances in metabolic routes. In particular, different key enzymes of nucleotide metabolism and DNA biosynthesis, such as CTP synthetase, thymidylate synthase, dihydrofolate reductase, IMP dehydrogenase, ribonucleotide reductase, DNA polymerase, and DNA methyltransferase, are markedly up-regulated in certain tumor cells. Together with the concomitant down-modulation of the purine and pyrimidine degradation enzymes, the increased anabolic propensity supports the excessive proliferation of transformed cells. However, many types of cancer cells have maintained the ability to differentiate terminally into mature, non-proliferating cells not only in response to physiological receptor ligands, such as retinoic acid, vitamin D metabolites, and cytokines, but also following exposure to a wide variety of non-physiological agents such as antimetabolites. Interestingly, induction of tumor cell differentiation is often associated with reversal of the transformation-related enzyme deregulations. An important class of differentiating compounds comprises the antimetabolites of purine and pyrimidine nucleotide metabolism and nucleic acid synthesis, the majority being structural analogs of natural nucleosides. The CTP synthetase inhibitors cyclopentenylcytosine and 3-deazauridine, the thymidylate synthase inhibitor 5-fluoro-2'-deoxyuridine, the dihydrofolate reductase inhibitor methotrexate, the IMP dehydrogenase inhibitors tiazofurin, ribavirin, 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR) and mycophenolic acid, the ribonucleotide reductase inhibitors hydroxyurea and deferoxamine, and the DNA polymerase inhibitors ara-C, 9-(2-phosphonylmethoxyethyl)adenine (PMEA), and aphidicolin, as well as several nucleoside analogs perturbing the DNA methylation pattern, have been found to induce tumor cell differentiation through impairment of DNA synthesis and/or function. Thus, by selectively targeting those anabolic enzymes that contribute to the neoplastic behavior of cancer cells, the normal cellular differentiation program may be reactivated and the malignant phenotype suppressed.
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PMID:Role of antimetabolites of purine and pyrimidine nucleotide metabolism in tumor cell differentiation. 1041 91

Primarily resulting as a spin-off of the search for effective anti-HSV or anti-HIV agents, several compounds have been identified as effective and promising candidate anti-HBV drugs, i.e. famciclovir (penciclovir), BMS-200475, lamivudine (3TC), (-)FTC, L(-)Fd4C, L-FMAU, DAPD (DXG), bis(POM)-PMEA and bis(POC)-PMPA. They all inhibit HBV replication in Hep G2 2.2.15 at concentrations that are well below the cytotoxicity threshold. All these nucleoside analogues require three phosphorylation steps to be active, in their triphosphate form, as inhibitors of the HBV DNA polymerase, except for PMEA (adefovir) and PMPA (tenofovir), which need only two phosphorylation steps, to PMEApp and PMPApp, respectively, to interact as chain terminators with the HBV DNA polymerase reaction. Several of these compounds (for example, famciclovir, lamivudine and adefovir) have proven to be efficacious in the duck and/or woodchuck hepatitis models, and, accordingly, famciclovir, lamivudine and adefovir have also proven to be effective (i.e. in reducing HBV DNA levels) in patients with chronic HBV infection. Yet, famciclovir and lamivudine may lead to the emergence of resistance mutations (i.e. L528M and M552V/I) in the HBV DNA polymerase upon long-term treatment. These penciclovir- and lamivudine-resistant HBV mutants still retain susceptibility to adefovir, which, in turn, has so far not been found to engender resistance mutations in HBV. As has become obvious from the experience with the treatment of HIV infections, future HBV chemotherapy may reside in combination drug therapy so as to achieve the highest possible virus reduction, thereby minimizing the likelihood of drug resistance development.
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PMID:Perspectives for the treatment of hepatitis B virus infections. 1041 52

Drug-resistant strains of herpes simplex virus type 1 (HSV-1) were selected under the pressure of (S)-3-hydroxy-2-phosphonylmethoxypropyl (HPMP) derivatives of cytosine (HPMPC, cidofovir) and adenine (HPMPA) and 2-phosphonylmethoxyethyl (PME) derivatives of adenine (PMEA, adefovir) and 2,6-diaminopurine (PMEDAP). HPMPC-resistant (HPMPC(r)) and HPMPA(r) strains were cross-resistant to one another, but they remained sensitive to foscarnet (PFA), acyclovir (ACV) and the PME derivatives, while the PMEA(r) and PMEDAP(r) strains showed cross-resistance to PFA and ACV. The PMEA(r), PMEDAP(r) and PFA(r) mutants all revealed a single nucleotide change resulting in a Ser-724 to Asn mutation within the conserved region II of the DNA polymerase. Two HPMPA(r) clones and one HPMPC(r) clone possessed single amino acid changes in the DNA polymerase (HPMPA(r) clone D1, Leu-1007 to Met; HPMPA(r) clone B5, Ile-1028 to Thr; HPMPC(r) clone C3, Val-573 to Met). The HPMPC(r) clone A4 contained two mutations, Ala-136 to Thr and Arg-700 to Met. The mutation at position 136, located outside the catalytic domain of the enzyme, was not detected in other HPMPC(r) clones, suggesting that this mutation may not be responsible for the resistant phenotype. Residue 573 is located within the 3'-->5' exonuclease editing domain close to the catalytically important residues Tyr-577 and Asp-581. Similarly, residue 700 is located in the palm subdomain of the catalytic domain, adjacent to the Asp residues 717, 886 and 888 that are vital for polymerase activity. The HPMPA(r) mutations at residues 1007 and 1028, beyond the last conserved region, still fall within the thumb subdomain of the catalytic domain. The different drug-resistant mutants varied in neurovirulent behaviour, the HPMPC(r) strains showing reduced neurovirulence compared with the wild-type.
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PMID:Resistance of herpes simplex virus type 1 against different phosphonylmethoxyalkyl derivatives of purines and pyrimidines due to specific mutations in the viral DNA polymerase gene. 1067 1

Nasopharyngeal carcinoma (NPC) is universally associated with EBV infection. We have shown that the phosphonated nucleoside analog, (S)-1-[3-hydroxy-2-(phosphonylmethoxy)-propyl]cytosine (HPMPC) strongly inhibits growth of NPC xenografts in nude mice by causing apoptosis (J. Neyts et al., Cancer Res., 58, 384-388, 1998). We, therefore, tested two additional members of this drug family that have different degrees of antiviral activity, 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) and 9-2-(R)-(phosphonomethoxy)propyladenine (PMPA). Intratumoral injection of PMEA (75 microl of 2% solution) in C15 NPC xenografts, which are latently infected with EBV, slowed tumor growth moderately, whereas PMPA (75 microl of 2% solution) slowed tumor growth only marginally. Compared with the previous results showing complete regression of tumor, PMEA had less antitumoral effect than HPMPC, and PMPA had the least. After 4 weeks of preventive treatment, tumors formed in 12.5, 50, and 100% of mice treated with HPMPC, PMEA, and PMPA, respectively, in contrast to the development of tumors in all of the PBS-treated control mice. We also investigated the effect of each drug on the EBV-positive epithelial cell line NPC-KT in vitro. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed inhibition of growth of NPC-KT cells by HPMPC and PMEA, but not by PMPA, which correlates with the results observed in tumor xenografts. Growth inhibition was attributable to induction of apoptosis in NPC-KT cells as indicated by a DNA fragmentation assay. Cleavage of poly(ADP-ribose) polymerase after treatment of NPC-KT cells with HPMPC was observed, which suggested that the apoptosis may be mediated by caspase(s). The apoptotic effects of the drugs are independent of any effects on EBV DNA polymerase, which is not expressed in these latently infected NPCs. These results suggest that HPMPC as well as PMEA could provide an adjunctive treatment for NPC.
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PMID:Prevention and inhibition of nasopharyngeal carcinoma growth by antiviral phosphonated nucleoside analogs. 1169 6

Adefovir is a potent nucleotide analog inhibitor of hepatitis B virus (HBV) DNA polymerase. Its oral prodrug adefovir dipivoxil has been approved for the treatment of chronic HBV infection. In this study, adefovir was characterized for its in vitro effects on mitochondrial DNA (mtDNA) synthesis and compared with the nucleoside analogues lamivudine (3TC), fialuridine (FIAU), and zalcitabine (ddC). No substantial changes in mtDNA content were detected in human hepatoblastoma HepG2 cells and normal human skeletal muscle cells following a 9-day treatment with 0.3-30 microm adefovir, concentrations up to 500-fold higher than the peak serum levels in patients treated with adefovir dipivoxil. Similarly, mtDNA was unchanged in both cell types following treatment with 3TC. In contrast, 30-55% and > 90% reductions in mtDNA were observed following incubation with 30 microm FIAU and ddC, respectively. The effects of FIAU on mtDNA became more pronounced following prolonged 18-day treatment of skeletal muscle cells while the effects of other drugs remained unchanged.
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PMID:Comparative effects of adefovir and selected nucleoside inhibitors of hepatitis B virus DNA polymerase on mitochondrial DNA in liver and skeletal muscle cells. 1255 12

Varicella-zoster virus (VZV) mutants were isolated under the pressure of different classes of antiviral compounds: (i) drugs that depend on the viral thymidine kinase (TK) for their activation, i.e. acyclovir (ACV), brivudin (BVDU), penciclovir (PCV) and sorivudine (BVaraU); (ii) drugs that are independent of the viral TK for their activation, i.e. 2-phosphonylmethoxyethyl (PME) derivatives of adenine (PMEA, adefovir) and 2,6-diaminopurine (PMEDAP); and (iii) drugs that do not require any metabolism to inhibit the viral DNA polymerase, i.e. foscarnet (PFA). Drug-resistant virus strains were obtained by serial passage of the OKA strain in human embryonic lung (HEL) fibroblasts and the different drug-resistant mutants were subsequently evaluated for their in vitro susceptibility to a broad range of antiviral drugs. Virus strains emerging under the pressure of ACV, BVDU and BVaraU were cross-resistant to all drugs that depend on the viral TK for activation, but remained susceptible to the acyclic nucleoside phosphonates (i.e. PMEA, PMEDAP and the 3-hydroxy-2-phosphonylmethoxypropyl derivatives of adenine (HPMPA) and cytosine (HPMPC, cidofovir)) and PFA. In contrast, the virus strains selected under pressure of PCV were resistant to PCV, ACV, PMEA and PFA; but not BVDU, BVaraU, GCV, HPMPC or HPMPA. Similar patterns of drug susceptibility were noted for the virus strains selected under the pressure of PMEA or PFA, pointing to an alteration in the viral DNA polymerase as basis for the resistant phenotype selected by PCV, as well as PMEA and PFA. In contrast, the resistant phenotype selected by ACV as well as BVDU and BVaraU may be attributed primarily to mutations in the viral TK gene. Our data thus indicate that ACV and PCV select in vitro for different drug-resistant VZV phenotypes; whether this is also the situation in vivo remains to be investigated.
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PMID:In vitro selection of drug-resistant varicella-zoster virus (VZV) mutants (OKA strain): differences between acyclovir and penciclovir? 1516 99

Adefovir dipivoxil, a nucleotide analog of adenosine monophosphate, is an antiviral agent that suppresses hepatitis B virus (HBV) replication through inhibition of DNA polymerase and by chain termination. To determine the effectiveness of adefovir, three populations of patients with chronic hepatitis B patients were studied: hepatitis B e antigen (HBeAg)-positive patients, HBeAg-negative patients, and patients with lamivudine-resistant tyrosine-methionine-asparate-aspartate (YMDD) mutants. All three groups of patients were treated for 48 weeks with adefovir 10 mg/d, and significant reduction in serum HBV DNA and normalization of serum alanine aminotransferase (ALT) were noted. Significant improvement in liver histology was noted in HBeAg-positive and in HBeAg-negative patients. Significant HBeAg loss and HBeAg seroconversion rates were noted in HBeAg-positive patients and in lamivudine-resistant patients. No major drug-related side effects were noted. Adefovir 10 mg/d orally is safe and effective for treatment of chronic hepatitis B.
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PMID:Treatment of patients with chronic hepatitis B with adefovir dipivoxil. 1519


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