Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pyrophosphate analogue, foscarnet, selectively inhibits the DNA polymerase of human herpes viruses, including cytomegalovirus, and the reverse transcriptase of HIV. Viral replication is therefore prevented, but resumes when the drug is cleared from infected cells. In vitro, the combination of foscarnet and zidovudine (azidothymidine) has an additive effect against cytomegalovirus and acts synergistically against HIV. An improvement in cytomegalovirus retinitis is obtained in over 85% of affected AIDS patients during foscarnet induction therapy, but relapse usually occurs within a month of ceasing treatment. There is a similar duration of remission during maintenance therapy given for 5 days each week, but this can be extended 4- to 5-fold with daily administration of higher doses. In allograft recipients, progression of retinitis can be halted by foscarnet until immune function recovers and eradicates the virus. The incidence of acute renal failure, which is common during foscarnet therapy, may be reduced by dosage adjustment and adequate prehydration. Anaemia, phlebitis, nausea and vomiting, and disturbances in serum calcium and phosphate levels, perhaps resulting from uptake of foscarnet into bone or chelation with ionised calcium, have also been associated with administration of the drug. Cytomegalovirus retinitis is difficult to treat, with few therapeutic options available. Although treatment with foscarnet produces some severe adverse effects, with care these can be minimised, and the drug produces clinical improvement in a large proportion of patients; this is a highly encouraging finding at this stage in its development. Preliminary comparative data indicate that foscarnet and ganciclovir are similarly effective, but foscarnet may have some theoretical advantages in AIDS patients since it can be used in combination with zidovudine without potentiating myelosuppression.
 ...
PMID:Foscarnet. A review of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with cytomegalovirus retinitis. 170 82

Zidovudine (azidothymidine (AZT)) inhibits human immunodeficiency virus replication, prolongs survival, and delays progression of acquired immune deficiency syndrome. We determined AZT-induced molecular and ultrastructural changes in the rat heart. Rats (3 per group) were given drinking water with or without AZT (0.2 to 1.0 mg/ml; 29 to 102 mg/kg/day). After 21, 35, or 49 days, hearts were glutaraldehyde-fixed by abdominal aortic perfusion, processed, and examined by transmission electron microscopy. In parallel, myocardial RNA was extracted from hearts (AZT dose: 1 mg/ml; 35 days) and subjected to Northern analysis using cDNA probes for: alpha c-actin, troponin C, mitochondrial creatine kinase and malate dehydrogenase, a portion of the mitochondrial genome containing cytochrome b coding region (pMM26), and glyceraldehyde-3-phosphate dehydrogenase. Results showed marked and widespread cardiac mitochondrial swelling with fractured and disrupted cristae after 35 days of 1 mg/ml AZT. After a 14-day recovery, these ultrastructural defects did not reverse. Changes were not present in myocardium after 21 days of AZT nor after 35 days of lower dose AZT (0.2 mg/ml). Mitochondrial cytochrome b mRNA expression was depressed in AZT-treated rat hearts (35 days; 1 mg/ml AZT). mRNAs encoding glyceraldehyde-3-phosphate dehydrogenase, alpha c-actin, troponin C, mitochondrial creatine kinase, malate dehydrogenase, and mitochondrial ribosomal RNAs remained unchanged. AZT disrupts cardiac mitochondrial ultrastructure and expression of mitochondrial cytochrome b mRNA in a dose- and time-dependent fashion. The mechanism of AZT cardiotoxicity may relate to inhibition of mitochondrial DNA replication (at the level of DNA polymerase gamma) as postulated by others.
 ...
PMID:Mitochondrial ultrastructural and molecular changes induced by zidovudine in rat hearts. 171 47

We have constructed a series of plasmids which, when introduced into Escherichia coli, induce the overexpression of soluble wild-type and mutated forms of the reverse transcriptases (RTs) from human immunodeficiency viruses types 1 and 2 (HIV-1 and HIV-2, respectively). These proteins were analyzed previously for their RNA-dependent DNA polymerase (RDDP) and ribonuclease H (RNase H) activities. In the present study we assayed the different mutant RTs for their DNA-dependent DNA polymerase (DDDP) activity, employing an in situ polyacrylamide gel activity assay. The results indicate that both the RDDP and DDDP catalytic functions of HIV-1 RT mutants are affected similarly by mutations suggesting a high degree of overlap between the catalytic domains involved in both activities. Contrariwise, many of the HIV-2 RT mutants display no correlation between these two DNA polymerase activities, that is, the DDDP activity was not affected by the mutations introduced in the native enzyme in contrast to the RDDP activity. We were thus able to generate mutants of HIV-2 RT that unlike the wild-type RT, are capable of transcribing only DNA and not RNA. The disparity in mutational-catalytic relations between the two HIV-related RTs may reflect a possible difference in the structure and folding properties of the two proteins.
AIDS Res Hum Retroviruses 1991 Nov
PMID:The DNA-dependent and RNA-dependent DNA polymerase activities of the reverse transcriptases of human immunodeficiency viruses types 1 and 2. 172 5

The interactions of azidothymidine triphosphate, the metabolically active form of the anti-AIDS drug azidothymidine (zidovudine), with the cellular DNA polymerases alpha, delta, and epsilon, as well as with the RNA primer-forming enzyme DNA primase were studied in vitro. DNA polymerase alpha was shown to incorporate azidothymidine monophosphate into a growing polynucleotide chain. This occurred 2000-fold slower than the incorporation of natural dTTP. Despite the ability of polymerase alpha to use azidothymidine triphosphate as an alternate substrate, this compound was only marginally inhibitory to the enzyme (Ki greater than 1 mM). Furthermore, the DNA primase activity associated with DNA polymerase alpha was barely inhibited by azidothymidine triphosphate (Ki greater than 1 mM). Inhibition was more pronounced for DNA polymerases delta and epsilon. The type of inhibition was competitive with respect to dTTP, with Ki values of 250 and 320 microM, respectively. No incorporation of azidothymidine monophosphate was detectable with these two DNA polymerases because their associated 3'- to 5'-exonuclease activities degraded primer molecules prior to any measurable elongation. Template-primer systems with a preformed 3'-azidothymidine-containing primer terminus inhibited the three replicative polymerases rather potently. DNA polymerase alpha was inhibited with a Ki of 150 nM and polymerases delta and epsilon with Ki values of 25 and 20 nM, respectively. The type of inhibition was competitive with respect to the unmodified substrate poly(dA).oligo(dT) for all DNA polymerases tested. Performed 3'-azidothymidine-containing primers hybridized to poly(dA) were rather resistant to degradation by the 3'- to 5'-exonuclease of DNA polymerases epsilon and more susceptible to the analogous activity that copurified with DNA polymerase delta. It is proposed that the repair of 3'-azidothymidine-containing primers might become rate-limiting for the process of DNA replication in cells that have been treated with azidothymidine triphosphate.
 ...
PMID:Interactions of azidothymidine triphosphate with the cellular DNA polymerases alpha, delta, and epsilon and with DNA primase. 173 Jun 73

Both ganciclovir, a nucleoside analogue, and foscarnet, a pyrophosphate analogue, specifically bind cytomegalovirus (CMV) DNA polymerase and inhibit CMV replication at plasma concentrations achievable with intravenous administration. The agents have similar plasma half-lives, and both are cleared solely by the kidneys. Foscarnet has a low solubility and a high degree of ionization at physiologic pH, requiring it to be administered in higher doses and larger volumes. Both drugs are administered as an initial induction regimen followed by a long-term maintenance regimen. Among patients with the acquired immune deficiency syndrome (AIDS) who have CMV retinitis, the efficacy of long-term maintenance therapy, as measured by median time to retinitis progression, appears to be similar for the two drugs. The major toxicity of ganciclovir is myelosuppression, with dose-limiting neutropenia occurring in approximately 16% and thrombocytopenia in 5% of AIDS patients. The major toxicity of foscarnet is nephrotoxicity, with dose-limiting toxicity occurring in approximately 10-23% of patients; other effects of foscarnet include hypocalcemia, which may be associated with seizure and arrhythmia. Studies in vitro indicate an additive or synergistic inhibitory effect on CMV when these two drugs are combined, suggesting that lower-dose combination regimens or higher-dose alternating regimens may result in greater efficacy with less toxicity than with either drug alone.
 ...
PMID:Approaches to the treatment of cytomegalovirus retinitis: ganciclovir and foscarnet. 184 16

2',3'-dideoxyguanosine 5'-triphosphate (ddGTP) was found to be an efficient substrate for DNA polymerase beta when activated DNA was used as the template.primer. Under the optimized reaction conditions with activated DNA, the rate of the incorporation of ddGTP into DNA was almost equal to that of the corresponding normal substrate dGTP. The Km value for ddGTP (1.8 microM) was smaller than that for dGTP (7.8 microM). In contrast, ddGTP was not utilized as a substrate for DNA polymerase gamma with any of the activated DNA and (dC)n.(dG)12-18 as the template primer. Other DNA polymerases such as DNA polymerase alpha, E coli DNA polymerase I and retroviral reverse transcriptase could poorly utilize ddGTP as a substrate. Some of the kinetic properties of DNA polymerase beta revealed toward ddGTP are also described. Since DNA polymerase beta plays a role in DNA repair, the present results predict possible appearance of cytotoxicity or clinical side effect(s) of 2',3'-dideoxyguanosine (ddG), known as a potent inhibitor of human immunodeficiency virus, when ddG is administered to the patients with acquired immune deficiency syndrome (AIDS) or AIDS-related complex.
 ...
PMID:Differential utilization of 2',3'-dideoxyguanosine 5'-triphosphate as a substrate for various DNA polymerases. 193 1

Zidovudine triphosphate inhibits the hepatitis B virus (HBV) DNA polymerase (DNAp) in vitro. Serial measurements of serum HBV DNAp activity and HBV DNA were made in 14 consecutive male homosexual patients starting zidovudine for symptomatic HIV-1 infection. Median duration of treatment was 15 weeks (range 2-72). In the 13 patients with detectable DNAp/DNA pre-treatment, no significant change in either measure of viral replication was observed during the first 16 weeks of treatment compared with the 13 weeks prior to treatment. The lack of response may be due to the opposing effect of immunosuppression, or to a failure of in vivo activity.
AIDS 1991 Feb
PMID:No effect of zidovudine on hepatitis B virus replication in homosexual men with symptomatic HIV-1 infection. 203 94

Several dideoxynucleosides, including 3'-azido-2',3'-dideoxythymidine (zidovudine, azidothymidine, AZT), 2',3'-dideoxycytidine (ddC), and 2',3'-dideoxyinosine (ddI), have been shown to be potent inhibitors of human immunodeficiency virus (HIV) replication in human T cells and macrophages. These compounds undergo anabolic phosphorylation within target cells to a 3'-triphosphate moiety; as triphosphates, they act at the level of HIV DNA polymerase (reverse transcriptase). AZT has been shown to reduce the morbidity and mortality of patients with severe HIV infection and to at least temporarily ameliorate certain cases of HIV-induced dementia. In phase 1 studies, ddC and ddI have been shown to induce immunologic and virologic improvements in patients with AIDS or related disorders; phase 2 studies of ddC and ddI are underway. The use of these drugs can be associated with toxicity. AZT can cause bone marrow toxicity or myositis with prolonged use, ddC can cause peripheral neuropathy at high doses, and ddI can cause sporadic pancreatitis and peripheral neuropathy at high doses. For each compound, however, a therapeutic window exists in which an anti-HIV effect can be attained without short-term toxicity in most patients. Dose-intensity appears to be an important determinant of the toxicity of dideoxynucleosides. Studies are underway to explore how the therapeutic profiles of these compounds may be enhanced by attention to scheduling or through the use of combination therapy.
 ...
PMID:Initial clinical experience with dideoxynucleosides as single agents and in combination therapy. 207 27

Phosphonoformate (PFA) is a simple PPi analog which inhibits the activities of a variety of viral DNA polymerase, RNA polymerase, and reverse transcriptase enzymes. PFA is a topical and parenteral treatment for human herpesvirus infections and is currently in phase I trials for treatment of acquired immunodeficiency syndrome. Pharmacokinetic properties of PFA in young (growing) and adult specific-pathogen-free cats were compared. Mean PFA clearance from plasma was twofold higher in young cats (7.52 ml/min per kg of body weight) than in adult cats (3.70 ml/min per kg). Higher PFA clearance from plasma observed in young cats may result from higher renal clearance or enhanced accumulation of PFA in bone tissue of young versus adult cats. No plasma protein binding of PFA was observed. Mean oral bioavailability was 35% in young cats. These data indicate that age-related differences in PFA clearance from plasma occur in cats.
 ...
PMID:Age-related differences in pharmacokinetics of phosphonoformate in cats. 214 79

Sera from 20 Chinese patients with chronic hepatitis B were examined for hepatitis B e antigen and hepatitis B virus (HBV) DNA. There was considerable discordance with HBV DNA not being detectable in 10 out of 13 (77%) patients who were hepatitis B e antigen positive. Further testing for anti-HBe and HBV-DNA polymerase activity confirmed the results. Possible reasons for this discordance are discussed but neither hepatitis D (delta) infection nor the acquired immunodeficiency syndrome (AIDS) could be implicated.
 ...
PMID:The absence of hepatitis B virus DNA in hepatitis B e antigen positive sera from chronic hepatitis B surface antigen carriers in China. 231 71


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>