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)

Varicella-zoster virus (VZV), a member of the herpesvirus family, is responsible for both primary (varicella or chickenpox) as well as recurrent (zoster or shingles) infections. Acyclovir has been the mainstay for treating VZV infections in both immunocompetent and immunocompromised patients. Recently, newer anti-VZV drugs, i.e., valaciclovir (the oral prodrug form of acyclovir) and famciclovir (the oral prodrug form of penciclovir) have been developed and have enlarged the therapeutic options to treat VZV infections. Both acyclovir and penciclovir are dependent on the virus-encoded thymidine kinase (TK) for their intracellular activation. Although emergence of drug-resistant strains does not occur in immunocompetent patients, several reports have documented the isolation of drug-resistant VZV strains following long-term acyclovir therapy in immunocompromised patients. Mutations at the level of the TK are responsible for development of resistance to drugs that depend on the viral TK for their phosphorylation (i.e., acyclovir and penciclovir). Foscarnet, a direct inhibitor of the viral DNA polymerase, which does not require activation by the viral TK, is the drug of choice for the treatment of TK-deficient VZV mutants emerging under acyclovir therapy. Recently, emergence of foscarnet-resistant strains has also been reported. Both TK-deficient strains and foscarnet-resistant mutants are sensitive to the acyclic nucleoside phosphonate cidofovir, CDV, HPMPC, (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine. This agent does not depend on the virus-encoded TK, but on cellular enzymes for its conversion to the diphosphoryl derivative, which then inhibits the viral DNA polymerase.
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PMID:Novel agents for the therapy of varicella-zoster virus infections. 1106 Jul 73

Human herpesviruses are found worldwide and are among the most frequent causes of viral infections in immunocompetent as well as in immunocompromised patients. During the past decade and a half a better understanding of the replication and disease causing state of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV) has been achieved due in part to the development of potent antiviral compounds that target these viruses. While some of these antiviral therapies are considered safe and efficacious (acyclovir, penciclovir), some have toxicities associated with them (ganciclovir and foscarnet). In addition, the increased and prolonged use of these compounds in the clinical setting, especially for the treatment of immunocompromised patients, has led to the emergence of viral resistance against most of these drugs. While resistance is not a serious issue for immunocompetent individuals, it is a real concern for immunocompromised patients, especially those with AIDS and the ones that have undergone organ transplantation. All the currently approved treatments target the viral DNA polymerase. It is clear that new drugs that are more efficacious than the present ones, are not toxic, and target a different viral function would be of great use especially for immunocompromised patients. Here, we provide an overview of the diseases caused by the herpesviruses as well as the replication strategy of the better studied members of this family for which treatments are available. We also discuss the various drugs that have been approved for the treatment of some herpesviruses in terms of structure, mechanism of action, and development of resistance. Finally, we present a discussion of viral targets other than the DNA polymerase, for which new antiviral compounds are being considered.
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PMID:Current and potential therapies for the treatment of herpesvirus infections. 1141 15

The isolation of drug-resistant strains of herpesviruses, including Herpes Simplex Virus type I (HSV-1) and type 2 (HSV-2), Varicella-Zoster Virus (VZV), and cytomegalovirus (CMV), has been reported with increasing frequency in immunocompromised patients and is a matter of major concern. Determination of antiviral drug susceptibilities is a prerequisite for the management of drug-resistant herpesvirus infections. Phenotyping studies should be correlated with genotyping, i.e., characterization of the mutations in the target genes. The isolation of drug-resistant virus in the laboratory and the determination of their phenotype and genotype may be useful to clarify the mechanisms of selective drug action. We describe here the procedures used for in vitro selection of drug-resistant herpesvirus mutants and the determination of their patterns of drug-susceptibility. The subcloning of the HSV-1 DNA polymerase gene is described as an example of the methodology followed to determine the mutation(s) in the drug-target viral gene that are associated with the resistant phenotype. To avoid the introduction of mutations by PCR amplification, all subcloning experiments were executed directly on viral DNA. Viral DNA was prepared from each plaque-purified viral strain and a 3.4 kb BamHI fragment containing 87% of the HSV-1 DNA polymerase gene coding region was purified and further digested with SacI; the two resulting fragments were subcloned into pU18 and propagated in Escherichia coli. Plasmid DNA was isolated and the inserts were sequenced using dideoxynucleotide chain termination method with T7 DNA polymerase and Taq DNA polymerase in an automated laser fluorescent DNA sequencer. pUC/M13 reverse, universal primers and oligonucleodite primers based on the wild-type virus sequence were used. The nucleotide sequences of the DNA polymerase genes of the different mutants was then compared with the nucleotide sequence of the wild-type HSV-1 KOS strain.
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PMID:Evaluating phenotype and genotype of drug-resistant strains in herpesviruses. 1147 57

Human herpesviruses are found worldwide and are among the most frequent causes of viral infections in immunocompetent as well as in immunocompromised patients. During the past decade and a half a better understanding of the replication and disease causing state of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV) has been achieved due in part to the development of potent antiviral compounds that target these viruses. While some of these antiviral therapies are considered safe and efficacious (acyclovir, penciclovir), some have toxicities associated with them (ganciclovir and foscarnet). In addition, the increased and prolonged use of these compounds in the clinical setting, especially for the treatment of immunocompromised patients, has led to the emergence of viral resistance against most of these drugs. While resistance is not a serious issue for immunocompetent individuals, it is a real concern for immunocompromised patients, especially those with AIDS and the ones that have undergone organ transplantation. All the currently approved treatments target the viral DNA polymerase. It is clear that new drugs that are more efficacious than the present ones, are not toxic, and target a different viral function would be of great use especially for immunocompromised patients. Here, we provide an overview of the diseases caused by the herpesviruses as well as the replication strategy of the better studiedmembers of this family for which treatments are available. We also discuss the various drugs that have been approved for the treatment of some herpesviruses in terms of structure, mechanism of action, and development of resistance. Finally, we present a discussion of viral targets other than the DNA polymerase, for which new antiviral compounds are being considered.
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PMID:Current and potential therapies for the treatment of herpesvirus infections. 1154 8

The nucleotide changes of the DNA polymerase gene and the susceptibility of acyclovir (ACV)-resistant varicella-zoster virus (VZV) mutants to anti-herpetic drugs were determined and compared to those of herpes simplex virus type 1 (HSV-1) mutants. The seven ACV-resistant VZV mutants were classified into three groups, N(779)S, G(805)C and V(855)M, according to the sequences of their DNA polymerase genes. The amino acid substitutions N(779)S and G(805)C were identical in position to the N(815)S and G(814)C mutations in the HSV-1 DNA polymerase mutants, respectively, and the V(855)M amino acid substitution was similar to the HSV-1 V(892)M mutation. All three groups of VZV mutants were susceptible to ACV, phosphonoacetic acid, vidarabine and aphidicolin, at levels similar to those seen with the respective HSV-1 mutants, except for subtle differences that were due possibly to the non-conserved regions in their sequences. Although both the HSV-1 and the VZV DNA polymerase genes show 53% sequence similarity, both viruses essentially show a similar biochemical behaviour.
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PMID:Characterization of the DNA polymerase gene of varicella-zoster viruses resistant to acyclovir. 1160 87

Through broad screening of the compound library at Pharmacia, a naphthalene carboxamide was identified as a nonnucleoside inhibitor of human cytomegalovirus (HCMV) polymerase. Structure-activity relationship studies demonstrated that a quinoline ring could be substituted for naphthalene, resulting in the discovery of a 4-hydroxyquinoline-3-carboxamide (4-HQC) class of antiviral agents with unique biological properties. In vitro assays with the 4-HQCs have demonstrated potent inhibition of HCMV, herpes simplex virus type 1 (HSV-1), and varicella-zoster virus (VZV) polymerases but no inhibition of human alpha, delta, and gamma polymerases. Antiviral cell culture assays have further confirmed that these compounds are active against HCMV, HSV-1, HSV-2, VZV, and many animal herpesviruses. However, these compounds were not active against several nonherpesviruses representing different DNA and RNA virus families. A strong correlation between the viral DNA polymerase and antiviral activity for this class of compounds supports inhibition of the viral polymerase as the mechanism of antiviral activity. Northern blot analysis of immediate-early and late viral transcripts also pointed to a block in the viral life cycle consistent with inhibition of viral DNA replication. In vitro HCMV polymerase assays indicate that the 4-HQCs are competitive inhibitors of nucleoside binding. However, no cross-resistance could be detected with ganciclovir-resistant HCMV or acyclovir-resistant HSV-1 mutants. The unique, broad-spectrum activities of the 4-HQCs may offer new opportunities for treating many of the diseases caused by herpesviruses.
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PMID:Broad-spectrum antiherpes activities of 4-hydroxyquinoline carboxamides, a novel class of herpesvirus polymerase inhibitors. 1185 Feb 54

(E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) is a potent inhibitor of herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV). Its mechanism of action is based on a specific conversion to its 5'-mono- and 5'-diphosphate derivative by HSV-1- and VZV-encoded thymidine kinase, and after further conversion to its 5'-triphosphate derivative, inhibition of the viral DNA polymerase and eventual incorporation into the viral DNA. Recently, a new structural class of bicyclic pyrimidine nucleoside analogues (designated BCNAs) with highly specific and selective anti-VZV activity in cell culture has been discovered. The compounds need a long alkyl or alkylaryl side-chain at the base moiety for pronounced biological activity. This property makes these compounds highly lipophilic. They are also endowed with fluorescent properties when exposed to light with short UV wavelength. In striking contrast to BVDU, the members of this class of compounds are active only against VZV, but not against any other virus, including the closely related HSV-1, HSV-2 and cytomegalovirus. The most active compounds inhibit VZV replication at subnanomolar concentrations and are not toxic at high micromolar concentrations. The compounds lose their antiviral activity against thymidine kinase (TK)-deficient VZV strains, pointing to a pivotal role of the viral TK in their activation (phosphorylation). Kinetic studies with purified enzymes revealed that the compounds were recognized by VZV TK as a substrate, but not by HSV-1 TK, nor by cytosolic or mitochondrial TK. VZV TK is able to phosphorylate the test compounds not only to their corresponding 5'-mono- but also to their 5'-diphosphate derivatives. These data may readily explain and rationalize the anti-VZV selectivity of the BCNAs. There is no clear-cut correlation between the antiviral potency of the compounds and their affinity for VZV TK, pointing to a different structure/activity relationship of the eventual antiviral target of these compounds. The compounds are stable in solution and, in contrast to BVDU, not susceptible to degradation by thymidine phosphorylase. The bicyclic pyrimidine nucleoside analogues represent an entirely new class of highly specific anti-VZV compounds that should be further pursued for clinical development.
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PMID:Chemotherapy of varicella-zoster virus by a novel class of highly specific anti-VZV bicyclic pyrimidine nucleosides. 1208 70

Nucleoside analogues such as acyclovir and ganciclovir have been the mainstay of therapy for alphaherpesviruses (herpes simplex virus (HSV) and varicella-zoster virus (VZV)) and cytomegalovirus (CMV) infections, respectively. Drug-resistant herpesviruses are found relatively frequently in the clinic, almost exclusively among severely immunocompromised patients receiving prolonged antiviral therapy. For instance, close to 10% of patients with AIDS receiving intravenous ganciclovir for 3 months excrete a drug-resistant CMV isolate in their blood or urine and this percentage increases with cumulative drug exposure. Many studies have reported that at least some of the drug-resistant herpesviruses retain their pathogenicity and can be associated with progressive or relapsing disease. Viral mutations conferring resistance to nucleoside analogues have been found in either the drug activating/phosphorylating genes (HSV or VZV thymidine kinase, CMV UL97 kinase) and/or in conserved regions of the viral DNA polymerase. Currently available second line agents for the treatment of herpesvirus infections--the pyrophosphate analogue foscarnet and the acyclic nucleoside phosphonate derivative cidofovir--also inhibit the viral DNA polymerase but are not dependent on prior viral-specific activation. Hence, viral DNA polymerase mutations may lead to a variety of drug resistance patterns which are not totally predictable at the moment due to insufficient information on specific drug binding sites on the polymerase. Although some CMV and HSV DNA polymerase mutants have been found to replicate less efficiently in cell cultures, further research is needed to correlate viral fitness and clinical outcome.
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PMID:Resistance of herpesviruses to antiviral drugs: clinical impacts and molecular mechanisms. 1213 84

The human herpesviruses are a well characterized group of viruses that are responsible for a wide spectrum of human diseases. Included in this group of pathogens are the alphaherpesviruses (herpes simplex types 1 and 2 and varicella-zoster virus), the betaherpesviruses (cytomegalovirus, human herpesvirus types 6 and 7) and the gammaherpesviruses (Epstein-Barr virus and human herpesvirus 8). An important feature of these viruses is that they cause latent infections that can be reactivated to cause disease. The herpesviruses encode for a large number of structural and non-structural proteins, and several of the non-structural proteins, such as thymidine kinase, DNA polymerase, and ribonucleotide reductase, have been utilized as targets for the development of anti-herpesvirus agents. Another herpesvirus encoded enzyme that has received little attention as a potential target for the development of specific anti-herpesvirus agents is deoxyuridine triphosphate nucleotidohydrolase (dUTPase). Furthermore, little is known concerning the role of the herpesviruses' encoded dUTPases in virus replication and in modulating the chemotherapeutic efficiency of other anti-herpes agents. Because of recent advances in molecular virology and biochemistry, it is now possible to rationally develop "designer" drugs based upon the structural/functional interaction of the drug with a specific viral protein. The purpose of this review is to describe previous studies demonstrating the potential use of the herpesvirus encoded dUTPase as a drug target, to describe problems associated with using the dUTPase as a target and to discuss new approaches that can be used.
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PMID:The herpesvirus encoded dUTPase as a potential chemotherapeutic target. 1237 96

The 4-oxo-dihydroquinolines (PNU-182171 and PNU-183792) are nonnucleoside inhibitors of herpesvirus polymerases (R. J. Brideau et al., Antiviral Res. 54:19-28, 2002; N. L. Oien et al., Antimicrob. Agents Chemother. 46:724-730, 2002). In cell culture these compounds inhibit herpes simplex virus type 1 (HSV-1), HSV-2, human cytomegalovirus (HCMV), varicella-zoster virus (VZV), and human herpesvirus 8 (HHV-8) replication. HSV-1 and HSV-2 mutants resistant to these drugs were isolated and the resistance mutation was mapped to the DNA polymerase gene. Drug resistance correlated with a point mutation in conserved domain III that resulted in a V823A change in the HSV-1 or the equivalent amino acid in the HSV-2 DNA polymerase. Resistance of HCMV was also found to correlate with amino acid changes in conserved domain III (V823A+V824L). V823 is conserved in the DNA polymerases of six (HSV-1, HSV-2, HCMV, VZV, Epstein-Barr virus, and HHV-8) of the eight human herpesviruses; the HHV-6 and HHV-7 polymerases contain an alanine at this amino acid. In vitro polymerase assays demonstrated that HSV-1, HSV-2, HCMV, VZV, and HHV-8 polymerases were inhibited by PNU-183792, whereas the HHV-6 polymerase was not. Changing this amino acid from valine to alanine in the HSV-1, HCMV, and HHV-8 polymerases alters the polymerase activity so that it is less sensitive to drug inhibition. In contrast, changing the equivalent amino acid in the HHV-6 polymerase from alanine to valine alters polymerase activity so that PNU-183792 inhibits this enzyme. The HSV-1, HSV-2, and HCMV drug-resistant mutants were not altered in their susceptibilities to nucleoside analogs; in fact, some of the mutants were hypersensitive to several of the drugs. These results support a mechanism where PNU-183792 inhibits herpesviruses by interacting with a binding determinant on the viral DNA polymerase that is less important for the binding of nucleoside analogs and deoxynucleoside triphosphates.
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PMID:Amino acid changes within conserved region III of the herpes simplex virus and human cytomegalovirus DNA polymerases confer resistance to 4-oxo-dihydroquinolines, a novel class of herpesvirus antiviral agents. 1252 21


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