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)

Varicella zoster was isolated from the vitreous of a patient with the acute retinal necrosis (ARN) syndrome. We utilized a plaque reduction assay to determine the in vitro susceptibility of the ARN isolate to 6 antiviral drugs. The effective doses for 50% inhibition of plaque numbers were 5.3 microM for for acyclovir, 4.7 microM for DHPG, 8.7 microM for ARA-A, 100.7 microM for phosphonoacetic acid, 0.07 microM for BVdU and 2.4 microM for IUdR. Similar inhibitory values were obtained for the OKA vaccine strain of varicella zoster virus. These data do not support the notion that the ARN strain may represent a mutant of varicella zoster virus with significant alterations in either the viral thymidase kinase or DNA polymerase genes based upon its antiviral sensitivities. The implications of these results regarding the role of antiviral chemotherapy in the ARN syndrome are discussed.
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PMID:Antiviral sensitivities of the acute retinal necrosis syndrome virus. 303 Jun 44

Varicella zoster virus (VZV), a member of the herpesvirus family, is responsible for both primary (varicella, chickenpox) as well as reactivation (zoster, shingles) infections. In immunocompetent patients, the course of varicella is generally benign. For varicella zoster, post-herpetic neuralgia is the most common complication. In immunocompromised patients (particularly those with AIDS), transplant recipients and cancer patients, VZV infections can be life-threatening. For these patients and also for immunocompetent patients at risk such as pregnant women or premature infants, the current treatment of choice is based on either intravenous or oral aciclovir (acyclovir). The low oral bioavailability of aciclovir, as well as the emergence of drug-resistant virus strains, have stimulated efforts towards the development of new compounds for the treatment of individuals with VZV infections. Among these new compounds, penciclovir, its oral prodrug form famciclovir and the oral pro-drug form of aciclovir (valaciclovir), rank among the most promising. As with aciclovir itself, all of these drugs are dependent on the virus-encoded thymidine kinase (TK) for their intracellular activation (phosphorylation), and, upon conversion to their triphosphate form, they act as inhibitors/alternative substrate of the viral DNA polymerase. Therefore, cross-resistance to these drugs may be expected for those virus mutants that are TK-deficient and thus resistant to aciclovir. Other classes of nucleoside analogues dependent for their phosphorylation on the viral TK that have been pursued for the treatment of VZV infections include sorivudine, brivudine, fialuridine, fiacitabine and netivudine. Among oxetanocins, which are partially dependent on viral TK, lobucavir is now under clinical evaluation. Foscarnet, which does not require any previous metabolism to interact with the viral DNA polymerase, is used in the clinic when TK-deficient VZV mutants emerge during aciclovir treatment. TK-deficient mutants are also sensitive to the acyclic nucleoside phosphonates (i.e. [s]-1-[3-hydroxy-2-phosphonylmethoxypropyl]cytosine; HPMPC); these agents do not depend on the virus-encoded TK for their phosphorylation but depend on cellular enzymes for conversion to their diphosphoryl derivatives which then inhibit viral DNA synthesis. Vaccination for VZV has now come of age. It is recommended for healthy children, patients with leukaemia, and patients receiving immunosuppressive therapy or those with chronic diseases. The protection induced by the vaccine seems, to some extent, to include zoster and associated neuralgia. Passive immuniatin based on specific immunoglobulins does not effectively prevent VZV infection and is therefore restricted to high risk individuals (i.e. immunocompromised children and pregnant women).
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PMID:Current pharmacological approaches to the therapy of varicella zoster virus infections: a guide to treatment. 1018 60

Varicella zoster virus (VZV) is usually associated with mild to moderate illness in immunocompetent patients. However, older age and immune deficiency are the most important risk factors linked with virus reactivation and severe complications. Treatment of VZV infections is based on nucleoside analogues, such as acyclovir (ACV) and its valyl prodrug valacyclovir, penciclovir (PCV) as its prodrug famciclovir, and bromovinyldeoxyuridine (BVDU; brivudin) in some areas. The use of the pyrophosphate analogue foscarnet (PFA) is restricted to ACV-resistant (ACV(r)) VZV infections. Since antiviral drug resistance is an emerging problem, we attempt to describe the contributions of specific mutations in the viral thymidine kinase (TK) gene identified following selection with ACV, BVDU and its derivative BVaraU (sorivudine), and the bicyclic pyrimidine nucleoside analogues (BCNAs), a new class of potent and specific anti-VZV agents. The string of 6 Cs at nucleotides 493 to 498 of the VZV TK gene appeared to function as a hot spot for nucleotide insertions or deletions. Novel amino acid substitutions (G24R and T86A) in VZV TK were also linked to drug resistance. Six mutations were identified in the "palm domain" of VZV DNA polymerase in viruses selected for resistance to PFA, PCV, and the 2-phophonylmethoxyethyl (PME) purine derivatives. The investigation of the contributions of specific mutations in VZV TK or DNA polymerase to antiviral drug resistance and their impacts on the structures of the viral proteins indicated specific patterns of cross-resistance and highlighted important differences, not only between distinct classes of antivirals, but also between ACV and PCV.
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PMID:In vitro-selected drug-resistant varicella-zoster virus mutants in the thymidine kinase and DNA polymerase genes yield novel phenotype-genotype associations and highlight differences between antiherpesvirus drugs. 2219 Jul 13