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)

Resistance of herpes simplex virus to acyclovir is a problem of growing clinical importance. Acyclovir-resistance can be due either to mutations in the viral thymidine kinase gene or in the viral DNA polymerase gene. Although clinical resistance has most frequently been associated with thymidine kinase alterations, heterogeneity in clinical isolates has not been addressed frequently. The potential for such heterogeneity has been emphasized by a report describing a pathogenic clinical isolate containing within its population at least one thymidine kinase-proficient DNA polymerase mutant as well as mutants exhibiting thymidine kinase-deficiency (Sacks, et al., 1989). We provide here additional characterization of this isolate and speculations regarding its significance.
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PMID:Heterogeneity of a herpes simplex virus clinical isolate exhibiting resistance to acyclovir and foscarnet. 132 2

Recurrent infections with herpes simplex virus (HSV), occurring in as many as 20% of the population, often interfere with dental treatment. HSV (type 1 and type 2) belongs to the family of DNA viruses. The new generation of antiviral drugs promises to provide more successful management of viral diseases. Acyclovir, an analogue of viral deoxyguanosine, is an inhibitor of viral DNA and viral DNA polymerase. The aim of the present study was to evaluate to efficacy of the Virolex ointment, an acyclovir preparation manufactured by KRKA Novo mesto, in the treatment of labial herpes. The results show that Virolex is a highly effective agent. If started in the initial phase of infection it can prevent the development of herpetic lesions. Compared to other antiviral drugs used in the treatment of labial herpes, the duration of acyclovir therapy is shorter.
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PMID:[Treatment of labial herpes with acyclovir]. 209 38

The current progress in antiviral therapy is related to our better understanding of the viral multiplication, with potential targets for specific antiviral action at each step of the multiplication cycle inside the infected cell. Amantadine and Rimantadine are anti-influenza A drugs interfering with the penetration and the release of the virus. Most of the other antiviral drugs which are clinically available have the same target in common, namely the viral DNA polymerase. This holds true for modified nucleosides such as Acycloguanosine (Acyclovir), DHPG, Adenine-Arabinoside, Azidothymidine as well as pyrophosphate derivatives such as phosphonoformic acid. Unfortunately the antiviral chemotherapy must confront 3 obstacles: 1) a possible interference with the normal cellular metabolism, leading to residual cytotoxic side effects; 2) the genetic variability of the viruses, producing drug-resistant mutants and 3) the inability of any antiviral chemotherapeutic agent known to date to eradicate latent viral infection. A new approach of the control of latent infection is suggested with anti sense oligonucleotides of hybridons.
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PMID:Perspectives in antiviral chemotherapy. 221 May 92

Acyclovir triphosphate (ACVTP) was a substrate for herpes simplex virus type 1 (HSV-1) DNA polymerase and was rapidly incorporated into a synthetic template-primer designed to accept either dGTP or ACVTP followed by dCTP. HSV-1 DNA polymerase was not inactivated by ACVTP, nor was the template-primer with a 3'-terminal acyclovir monophosphate moiety a potent inhibitor. Potent inhibition of HSV-1 DNA polymerase was observed upon binding of the next deoxynucleoside 5'-triphosphate coded by the template subsequent to the incorporation of acyclovir monophosphate into the 3'-end of the primer. The Ki for the dissociation of dCTP (the "next nucleotide") from this dead-end complex was 76 nM. In contrast, the Km for dCTP as a substrate for incorporation into a template-primer containing dGMP in place of acyclovir monophosphate at the 3'-primer terminus was 2.6 microM. The structural requirements for effective binding of the next nucleotide revealed that the order of potency of inhibition of a series of analogs was: dCTP much greater than arabinosyl-CTP greater than 2'-3'-dideoxy-CTP much greater than CTP, dCMP, dCMP + PPi. In the presence of the next required deoxynucleotide (dCTP), high concentrations of dGTP compete with ACVTP for binding and thus retard the formation of the dead-end complex. This results in a first-order loss of enzyme activity indistinguishable from that expected for a mechanism-based inactivator. The reversibility of the dead-end complex was demonstrated by steady-state kinetic analysis, analytical gel filtration, and by rapid gel filtration through Sephadex G-25. Studies indicated that potent, reversible inhibition by ACVTP and the next required deoxynucleoside 5'-triphosphate also occurred when poly(dC)-oligo(dG) or activated calf thymus DNA were used as the template-primer.
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PMID:Herpes simplex virus type 1 DNA polymerase. Mechanism of inhibition by acyclovir triphosphate. 254 Jan 93

NPC-KT cl.S61, a subclone derived from an epithelial-nasopharyngeal carcinoma hybrid cell line (NPC-KT), showed cytopathic changes characteristic of herpesvirus replication, including formation of multinucleated giant cells and inclusion bodies, when Epstein-Barr virus replicative cycle was induced by 5-iodo-2'-deoxyuridine. Acyclovir (an inhibitor of herpesvirus DNA polymerase), Epstein-Barr virus-immune human serum, or 2-deoxyglucose (an inhibitor of the glycosylation) interfered with syncytium formation, indicating that a virus-specified glycoprotein belonging to the late group is responsible for cell fusion induced by Epstein-Barr virus replication in cl.S61 cells.
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PMID:Cytopathic effects induced by Epstein-Barr virus replication in epithelial nasopharyngeal carcinoma hybrid cells. 254 26

A series of clinical isolates of herpes simplex virus type 2 were taken from a patient with chronic lymphocytic leukemia. Acyclovir (ACV) susceptibility assays revealed that some isolates were resistant to ACV and cross-resistant to ganciclovir but not to phosphonoacetic acid. The nature of the resistance was examined further. A number of cloned variants were generated, and thymidine kinase and DNA polymerase assays were carried out. Variants that were resistant to ACV were found to be thymidine kinase deficient. Evidence for alteration in the DNA polymerase was not found when ACV triphosphate or phosphonoacetic acid was used as the inhibitor. In vivo studies with the plaque-purified viruses showed that ACV resistance was associated with a reduced neurovirulence. In a zosteriform model, virus resistant to ACV was unable to induce secondary spread in the same dermatome, to invade the peripheral nervous system or the central nervous system, or to establish latent infections.
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PMID:Biological and biochemical characterization of clinical isolates of herpes simplex virus type 2 resistant to acyclovir. 254 86

A screening program for antiviral drugs begun at Burroughs Wellcome in the 1960s resulted in the discovery of acyclovir in 1974. Preclinical investigation brought the drug to clinical trials in 1977 and the first form of the drug (topical) was available to physicians in 1982. Activity of acyclovir is greatest against herpes 1 and herpes 2, less against varicella zoster, still less against Epstein-Barr, and very little against cytomegalovirus. Acyclovir is an antiviral agent only after it is phosphorylated in infected cells by a viral-induced thymidine kinase. Acyclovir monophosphate is phosphorylated to diphosphate and triphosphate forms by cellular enzymes in the infected host cell where the drug is concentrated. Acyclovir triphosphate inactivates viral deoxyribonucleic acid polymerase. Acyclovir incorporation into the growing viral deoxyribonucleic acid chain causes its termination. The antiviral process has relatively little effect on normal, uninfected cells. An important toxic effect of acyclovir is its potential to cause obstructive nephropathy. The drug is excreted primarily by the kidney, which may require smaller doses in patients with decreased kidney function. Oral dosages of acyclovir as recommended for herpes simplex are probably not adequate for varicella zoster infections.
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PMID:History, pharmacokinetics, and pharmacology of acyclovir. 282 40

Acyclovir is a specific antiviral agent. The triphosphate form inhibits viral DNA replication by competing for incorporation into the replicating DNA chain or by inhibiting viral DNA polymerase. Cells not infected with herpesvirus are generally unaffected. Oral acyclovir inhibits most herpes simplex virus types 1 and 2, and varicella-zoster virus at concentrations used clinically. Oral acyclovir has an average plasma half-life of three hours and is eliminated primarily by renal mechanisms. Peak plasma concentrations occur 1.5 to 2.5 hours after administration and the oral bioavailability is 15 to 30 percent. Acyclovir distributes into most body tissues, including vesicular fluid and the central nervous system. Oral acyclovir is effective treatment of initial and recurrent genital herpes and can suppress frequently recurring genital herpes in both immunocompetent and immunocompromised patients. It is also effective for acute herpes zoster in the immunocompetent and possibly immunocompromised patient. No role is established in either Epstein-Barr virus or cytomegalovirus infections. Oral acyclovir appears to be effective and relatively safe, nontoxic therapy when administered in doses of 1-4 g/d. Oral acyclovir represents a major therapeutic advance in the treatment of herpesvirus infections.
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PMID:Evaluation of oral acyclovir therapy. 299 99

Acyclovir and suramin were examined for their efficacy alone and in combination, against duck hepatitis B virus (DHBV) in persistently infected Pekin ducks. The pharmacokinetics of acyclovir in ducks showed that the peak plasma concentration was reached 30 min after oral administration. Oral acyclovir and suramin administered intravenously suppressed the replication and production of infectious virions as measured by marked reduction of DNA polymerase activity during treatment. However, rebound of enzyme activity was observed soon after cessation of drug therapy. In contrast, sustained reduction of polymerase activity was attained by combined therapy of acyclovir followed by suramin, demonstrating a significant enhancement of anti-DHBV activity which requires confirmation in a larger experimental study. This report reviews the work with the duck model, demonstrating that it is ideal for screening antiviral compounds for treatment of infection with hepadna viruses.
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PMID:Screening of antiviral drugs for hepadna virus infection in Pekin ducks: a review. 331 65

Acyclovir and suramin were examined for their efficacy alone and in combination against duck hepatitis B virus (DHBV) in persistently infected Pekin ducks. In ducks the peak plasma concentration of acyclovir was reached thirty minutes after oral administration. Oral acyclovir and suramin administered intravenously suppressed the replication and production of infectious virions as measured by marked reduction of DNA polymerase activity during treatment. However, rebound of enzyme activity was observed soon after cessation of drug therapy. In contrast, sustained reduction of polymerase activity was attained by combined therapy of acyclovir followed by suramin, demonstrating a significant enhancement of anti-DHBV activity which requires confirmation in a larger experimental study. This report establishes that the duck model is ideal for screening antiviral compounds in treatment of infection with Hepadna viruses.
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PMID:Antiviral activity of the polybasic anion, suramin and acyclovir in Hepadna virus infection. 379 62


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