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:2.7.1.21 (thymidine kinase)
7,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phenotypic and genotypic analyses were done on 17 varicella-zoster virus (VZV) isolates recovered from 10 persons with AIDS (mean CD4 cell count, 16.4/mm3) who had chronic VZV lesions. Eleven acyclovir-resistant isolates were recovered from 10 patients after a mean of 20.1 weeks of therapy. Six susceptible isolates were recovered before acyclovir treatment (n = 1), early during therapy (n = 4; mean time, 4.2 weeks), or after discontinuation of acyclovir (n = 1). Acyclovir-resistant VZV isolates were deficient in thymidine kinase (TK) or induced a TK with altered substrate specificity; all isolates were susceptible to foscarnet. Ten of 11 acyclovir-resistant mutants contained tk gene mutations, including single nucleotide substitutions in highly conserved binding sites (n = 2) as well as nucleotide deletions (n = 4) and insertions (n = 4). These findings suggest that multiple, nonuniform mutations within the tk gene are associated with acyclovir-resistant VZV phenotypes.
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PMID:Phenotypic and genotypic characterization of acyclovir-resistant varicella-zoster viruses isolated from persons with AIDS. 801 22

The discovery of acyclovir marked the beginning of an exciting era in antiviral research. Early studies on the novel mode of action explained the selectivity of the compound and the remarkably narrow spectrum of activity against a subset of the herpesviruses. Throughout the past decade many clinical trials have demonstrated the efficacy and safety of this drug. Furthermore, the development of resistance does not appear to be a significant issue in normal individuals. Acyclovir provided the stimulus for further work in the antiherpes area, and this has led to the recent discovery of an oral prodrug (256U87), which delivers higher levels of acyclovir by the oral route, and to the discovery of 882C87, a highly selective inhibitor of varicella zoster virus. The novel mode of action of acyclovir involves an extremely selective phosphorylation step carried out by the herpesvirus thymidine kinase. It has recently been shown with another nucleoside analogue, ganciclovir, active against human cytomegalovirus (HMCV), that activation can be carried out by other unrelated kinases (in this case the UL97 gene product). Studies of this type may lead to the development of further novel inhibitors.
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PMID:The acyclovir legacy: its contribution to antiviral drug discovery. 824 80

Infection with herpes simplex viruses (HSVs) resistant to treatment with acyclovir (9-[(2-hydroxyethoxy)-methyl]guanine, Zovirax) is a growing clinical problem in patients with AIDS and other immunosuppressed states. Most virus isolates resistant to acyclovir are deficient or defective in virally coded thymidine kinase (TK), which converts acyclovir to acyclovir monophosphate in virus-infected cells. To restore acyclovir efficacy, we synthesized acyclovir diphosphate dimyristoylglycerol, an analog of a naturally occurring phospholipid, CDP-diacylglycerol. Its biological activity was tested in WI38 human lung fibroblasts infected with the acyclovir-resistant DM21 strain of HSV, which is TK negative due to an 816-base-pair deletion in the TK coding region. Acyclovir diphosphate dimyristoylglycerol has substantial activity in DM21-infected cells (IC50 = 0.25 microM), whereas acyclovir and acyclovir monophosphate were ineffective (IC50 > 100 microM). Similar results were obtained in TK-altered and TK-deficient strains of HSV-1 and in acyclovir-resistant isolates of HSV-2 obtained from two AIDS patients. The phospholipid prodrug is active by means of TK-independent metabolic pathways that liberate acyclovir monophosphate inside the host cell. Acyclovir phosphates were 56 times greater in WI38 human lung fibroblasts incubated for 24 hr with [8-3H]acyclovir diphosphate dimyristoylglycerol relative to acyclovir. Acyclovir monophosphate added to the culture medium (outside the cell) did not circumvent the acyclovir resistance of the TK-negative DM21 mutant, presumably due to its conversion to acyclovir by phosphatases. Acyclovir diphosphate diacylglycerol prodrugs may be useful in treating TK-deficient mutant and wild-type strains of HSV.
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PMID:Acyclovir diphosphate dimyristoylglycerol: a phospholipid prodrug with activity against acyclovir-resistant herpes simplex virus. 826 34

The nucleoside analog acyclovir is remarkably effective and selective in herpes simplex virus (HSF) infections. Acyclovir inhibits the viral enzyme DNA polymerase. Emergence of acyclovir-resistant HSV mutants occurs in immunocompromised patients, especially those with AIDS. Detection of HSV strains with resistance to antiviral drugs requires rapid in vitro tests to determine the IC50, i.e., the concentration of drug which inhibits viral replication by 50%. Studies of patterns of HSV resistance to the various antiviral agents used in medicine and characterization of mutant HSV strains have shown resistance to be due to loss or modification of the viral enzyme thymidine kinase or to changes in the viral DNA polymerase. The main clinically-significant acyclovir-resistant mutants are thymidine kinase-deficient and retain sensitivity to vidarabine and foscarnet. Development of resistance to both acyclovir and foscarnet due to changes in viral DNA polymerase is considerably less common but emphasizes the urgent need for new antiviral strategies for use in immunocompromised patients.
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PMID:[Resistance of herpes simplex viruses to antiviral drugs]. 839 60

Four patients with aggressive respiratory papillomatosis have been treated with oral Acyclovir as adjuvant therapy while continuing to undergo regular endoscopy and laser treatment to the lesions. The duration of Acyclovir administration ranged from 2 weeks to 3 months. Two patients had papillomatosis confined to the larynx and two in addition had disease in the lower respiratory tract. One of the four patients had less aggressive disease during the treatment period. Acyclovir does not appear to significantly influence respiratory papillomatosis. Acyclovir's activity is dependent upon the presence of virally encoded thymidine kinase. This enzyme is not known to be encoded by papilloma viruses. Acyclovir is not recommended in the treatment of juvenile respiratory papillomatosis.
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PMID:Juvenile respiratory papillomatosis: acyclovir reassessed. 844 63

Herpes simplex virus (HSV) infections are very common in the general population and can be treated with the nucleoside analogue acyclovir. Acyclovir is initially phosphorylated intracellularly in HSV-infected cells by a viral-specific thymidine kinase to acyclovir-monophosphate. The monophosphate is subsequently di- and triphosphorylated by host cellular kinases to the active form of the drug, which inhibits HSV DNA polymerase and incorporates into the elongating viral DNA and causes chain termination. Acyclovir resistance has been increasingly described and is caused by mutations in either the thymidine kinase or the DNA polymerase genes. These mutations result in decreased or absent HSV thymidine kinase production, altered affinity of the thymidine kinase for acyclovir-triphosphate, or altered affinity of the HSV DNA polymerase for acyclovir-triphosphate. Thymidine kinase deficiency accounts for approximately 95% of acyclovir-resistant isolates. Clinical disease due to acyclovir-resistant HSV occurs primarily in immunocompromised patients and is usually characterized by a chronic, progressive ulcerative mucocutaneous disease with prolonged shedding of virus. Several large surveys have been done in an effort to determine the incidence of in vitro and clinical acyclovir resistance. Among immunocompetent hosts, even those who have received > or = 6 years of continuous acyclovir, the prevalence of acyclovir-resistant isolates has remained stable at approximately 3%. Only three cases of clinical resistance of HSV to acyclovir have been reported. However, the incidence in immunocompromised patients, particularly those with AIDS and those who have had bone marrow transplants, is increasing. Transmission of acyclovir-resistant isolates from person to person has not been documented, but due to the increased use of acyclovir and newer drugs, such as famciclovir, there is great concern that this transmission might occur in the future. Continued surveillance in both immunocompetent and immunocompromised hosts for the development of clinical acyclovir-resistant HSV disease is necessary.
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PMID:Herpes simplex virus resistance to acyclovir: clinical relevance. 854 89

Twelve children ages 1 to 5 years and one adult with hand-foot-and-mouth disease were treated with oral acyclovir within one to two days of onset of the rash. Symptomatic relief, defervescence, and significant involution of lesions were seen within twenty-four hours of initiating therapy. Acyclovir was continued for five days, by which time palmar, plantar, and oral lesions were virtually gone. Acyclovir is a molecule tailored to inactivate the thymidine kinase of the herpesvirus. Since the Coxsackie A16 virus causing hand-foot-and-mouth disease lacks this enzyme, the beneficial therapeutic effect must be explained on other grounds, possibly due to enhancement of the antiviral effect of the patient's own interferon.
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PMID:Acyclovir in the treatment of hand-foot-and-mouth disease. 872 72

A recombinant retroviral vector pNTK expressing the "suicide" gene herpes simplex virus thymidine kinase (HSV-TK) gene was constructed. The recombinant vector was packaged by PA317 cells and viral supernatant was used to infect the human pancreatic carcinoma cell line PC-2. After selection in G418, resistant colonies were identified and isolated. Cytotoxic effects of the non-toxic prodrug Acyclovir (ACV) or Ganciclovir (GCV) to the NTK transformant PC-2 cells was more than 90%, while that of the control PC-2 cells was less that 10%. Furthermore, the "bystander effect" of HSV-TK on PC-2 cells was also observed.
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PMID:[Gene therapy of human pancreatic carcinoma by recombinant retroviral vector expressing herpes simplex virus thymidine kinase gene]. 873 88

Acyclovir is an effective drug for the treatment of HSV and VZV infections, which after phosphorylation to the triphosphate, inhibits viral DNA polymerase. Acyclovir has low oral bioavailability, therefore prodrugs have been developed, and the L-valyl ester, valaciclovir, recently has been licensed for the treatment of shingles. Ganciclovir is used against CMV, and famciclovir, a lipophilic prodrug of penciclovir, is marketed for shingles. The acyclic nucleoside phosphonates are active against thymidine kinase-resistant viral strains. Promising analogs are PMEA (in clinical trial for the treatment of AIDS) and (S)-HPMPC (good in vivo activity against HSV, VZV, CMV, and EBV). Oligonucleotides incorporating acyclic nucleosides at the 3'-and 5'-ends, or constituted of amino acyclic nucleosides, are resistant to cleavage by nucleases and may be useful in antisense and/or antigene therapy. HEPT is active against HIV-1: It binds in a hydrophic pocket on reverse transcriptase, rather than in the polymerase active site. Some acyclic nucleosides are potent inhibitors of purine and pyrimidine nucleoside phosphorylase. These compounds may have a therapeutic niche in combination therapy with antiviral and anticancer nucleosides, and in the treatment of diseases involving the T-cell.
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PMID:Acyclic nucleosides as antiviral compounds. 873 25

The majority of transmissions occur as a consequence of inapparent infection in the source contact, as asymptomatic viral excretion in individuals with recurrent infection. The development of type specific serological assays has allowed for a more accurate determination of herpes simplex virus (HSV) 2 prevalence and has revealed that the prevalence of HSV 2 in sexually transmitted disease clinic attenders varies from 8%-83%, in female prostitutes from 75%-96% and in antenatal clinic attenders from 6%-53%. The majority of individuals (+/-60%) exposed to HSV 2 do not develop any symptoms. Patients treated for primary genital herpes are likely to resume sexual intercourse earlier than those who do not. Long-term suppressive acyclovir will result in decrease in clinical symptoms and viral excretion and may decrease the opportunity for HSV transmission. Acyclovir is the drug of choice for the treatment of primary genital herpes and for long-term acyclovir suppression. Two new drugs, valaciclovir and famciclovir, are currently under investigation. Failure to respond to acyclovir may be due to inadequate dose, malabsorption, another condition, or resistance. Resistance is rare and occurs mainly in profoundly immunosuppressed individuals, and is usually due to the development of thymidine kinase deficient mutants. Treatment with intravenous foscarnet is usually successful. Patients with genital herpes have a number of emotional problems, particularly if the condition recurs. Recent studies suggest that emotional stress does not precipitate recurrences, but rather recurrences cause stress. Long-term acyclovir suppression can decrease psychological morbidity in patients with frequent recurrences.
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PMID:Recent advances in genital herpes. 884 93


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