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:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Almost all of the approved antiviral drugs have become available during the past two decades. Approximately one half of these agents are for the treatment of human immunodeficiency virus (HIV) infections and comprise five classes. The first three classes all act to inhibit reverse transcriptase: nucleoside analogs; nonnucleoside analogs; and nucleotide analogs. The fourth class, protease inhibitors, prevent viral packaging; the fifth class, fusion inhibitors, prevent fusion between HIV and the target cell. Four nucleoside analogs, acyclovir, valacyclovir, famciclovir and penciclovir, are approved for the therapy of herpes simplex and varicella zoster infections. Interferon alpha is approved in the injectable form for condyloma acuminatum and Kaposi's sarcoma, but the more efficient method of delivering this agent is via interferon induction following topical use of imiquimod cream. Antiviral agents are also approved for infections with cytomegalovirus, hepatitis B and C, respiratory syncytial virus, and influenza viruses. Most of these antiviral drugs are virastatic and not viracidal. Vaccines and public health measures are much more effective and cost effective than antiviral drugs and must be promoted accordingly in the defense against viral infections.
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PMID:Changing paradigms in dermatology: antivirals in dermatology. 1467 23

For more than two decades, retroviral biology has been the most intensely studied field in virology. The retroviral genome is encoded by a 7-11 kb positivesense single-stranded RNA molecule, two of which homodimerize and package in lipid-enveloped viral particles. Following attachment and receptor-mediated entry into host cells, viral reverse transcriptase and integrase enzymes mediate reverse transcription and integration of the virus genome into the host-cell chromatin. The ability of a replication competent retrovirus to incorporate a herpes simplex virus thymidine kinase (tk) gene into the genome of a mouse cell and to convert NIH-3T3 TK- cells into TK+ transformants was first described in 1981 (1,2). These studies established the basis of using retroviruses as vehicles for efficient therapeutic gene delivery into mammalian cells. Twenty years of extensive research of retrovirus-vector biology resulted in major improvements in vector design and retrovirus-vector production. High-titer concentrated retrovirus vectors (>10(9) infectious units [IU]/mL) can be generated by several retrovirusvector stable producer lines. The ability to pseudotype retrovirus vectors with a variety of envelope proteins, including the vesicular stomatitis virus G glycoprotein (VSV-G), significantly broadens the tropism of replication-defective retrovirus vectors.
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PMID:Gene delivery by lentivirus vectors an overview. 1497 Jun 5

The current armamentarium for the chemotherapy of viral infections consists of 37 licensed antiviral drugs. For the treatment of human immunodeficiency virus (HIV) infections, 19 compounds have been formally approved: (i) the nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and emtricitabine; (ii) the nucleotide reverse transcriptase inhibitor (NtRTI) tenofovir disoproxil fumarate; (iii) the non-nucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine, delavirdine and efavirenz; (iv) the protease inhibitors saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir (combined with ritonavir at a 4/1 ratio) and atazanavir; and the viral entry inhibitor enfuvirtide. For the treatment of chronic hepatitis B virus (HBV) infections, lamivudine as well as adefovir dipivoxil have been approved. Among the anti-herpesvirus agents, acyclovir, valaciclovir, penciclovir (when applied topically), famciclovir, idoxuridine and trifluridine (both applied topically) as well as brivudin are used in the treatment of herpes simplex virus (HSV) and/or varicella-zoster virus (VZV) infections; and ganciclovir, valganciclovir, foscarnet, cidofovir and fomivirsen (the latter upon intravitreal injection) have proven useful in the treatment of cytomegalovirus (CMV) infections in immunosuppressed patients (i.e. AIDS patients with CMV retinitis). Following amantadine and rimantadine, the neuraminidase inhibitors zanamivir and oseltamivir have recently become available for the therapy (and prophylaxis) of influenza virus infections. Ribavirin has been used (topically, as aerosol) in the treatment of respiratory syncytial virus (RSV) infections, and the combination of ribavirin with (pegylated) interferon-alpha has received increased acceptance for the treatment of hepatitis C virus (HCV) infections.
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PMID:Antiviral drugs in current clinical use. 1512 67

Various factors have been implicated in the pathogenesis of schizophrenia. Evidence for an infectious cause includes the 5-8% increased risk among those born in the winter-spring months, when infectious diseases are more prevalent and at times when other infections (measles, varicella, poliomyelitis) show increased activity. Herpes simplex virus (HSV) has been implicated in schizophrenia as it has a tropism for the nervous system and is capable of replication in the brain. Although post-mortem studies of brain tissue of schizophrenic patients have failed to detect the virus, these studies have been hampered by the unknown cellular localization of HSV genomes and by attempting to detect the virus years after the symptom onset. A more recent, nested, case-control study evaluated pregnant women between 1959 and 1966 and identified 27 surviving offspring who were later diagnosed with schizophrenia. Analysis of stored blood samples showed an association between high levels of maternal antibody to HSV-2 and subsequent development of adult psychosis. No association was found between HSV-1 infection and psychosis. There is also evidence that human endogenous retroviruses (HERVs) may play a role in schizophrenia, as antibodies to these agents have been found at a greater frequency in the sera of affected individuals compared with controls. This is supported by the presence of reverse transcriptase, a retroviral marker, at levels four times higher in the cerebrospinal fluid (CSF) of people with recent onset schizophrenia compared with controls, and by its elevated presence in long-term schizophrenic patients. Further research to investigate the relationship between virus infection and schizophrenia is warranted.
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PMID:Viruses and schizophrenia: a focus on herpes simplex virus. 1531 94

Inflammatory cytokines and infiltrating T cells are readily detected in herpes simplex virus (HSV) infected mouse cornea and trigeminal ganglia (TG) during the acute phase of infection, and certain cytokines continue to be expressed at lower levels in infected TG during the subsequent latent phase. Recent results have shown that HSV infection activates Toll-like receptor signaling. Thus, we hypothesized that chemokines may be broadly expressed at both primary sites and latent sites of HSV infection for prolonged periods of time. Real-time reverse transcriptase-polymrease chain reaction (RT-PCR) to quantify expression levels of transcripts encoding chemokines and their receptors in cornea and TG following corneal infection. RNAs encoding the inflammatory-type chemokine receptors CCR1, CCR2, CCR5, and CXCR3, which are highly expressed on activated T cells, macrophages and most immature dendritic cells (DC), and the more broadly expressed CCR7, were highly expressed and strongly induced in infected cornea and TG at 3 and 10 days postinfection (dpi). Elevated levels of these RNAs persisted in both cornea and TG during the latent phase at 30 dpi. RNAs for the broadly expressed CXCR4 receptor was induced at 30 dpi but less so at 3 and 10 dpi in both cornea and TG. Transcripts for CCR3 and CCR6, receptors that are not highly expressed on activated T cells or macrophages, also appeared to be induced during acute and latent phases; however, their very low expression levels were near the limit of our detection. RNAs encoding the CCR1 and CCR5 chemokine ligands MIP-1alpha, MIP-1beta and RANTES, and the CCR2 ligand MCP-1 were also strongly induced and persisted in cornea and TG during the latent phase. These and other recent results argue that HSV antigens or DNA can stimulate expression of chemokines, perhaps through activation of Toll-like receptors, for long periods of time at both primary and latent sites of HSV infection. These chemokines recruit activated T cells and other immune cells, including DC, that express chemokine receptors to primary and secondary sites of infection. Prolonged activation of chemokine expression could provide mechanistic explanations for certain aspects of HSV biology and pathogenesis.
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PMID:Persistent expression of chemokine and chemokine receptor RNAs at primary and latent sites of herpes simplex virus 1 infection. 1550 26

Since some antiviral drugs have a broad spectrum of action, the aim of this study was to assess whether o-(acetoxyphenyl)hept-2-ynyl sulphide (APHS), a recently described inhibitor of human immunodeficiency virus type 1 (HIV-1) replication, has an effect on the replication of other retroviruses, (-) and (+) RNA viruses and DNA viruses. APHS did not affect the replication of feline immunodeficiency virus, HIV-2 and a HIV-1 strain resistant to non-nucleoside reverse transcriptase inhibitors (NNRTI). APHS could also not inhibit the replication of the RNA viruses, respiratory syncytium virus or mouse hepatitis virus. In contrast, APHS did inhibit the replication of wild-type herpes simplex virus type 1 (HSV-1) as well as acyclovir-resistant HSV-1 and HSV-2 mutant. These results suggest that APHS is a NNRTI of HIV-1 replication, but not HIV-2 replication, and that APHS is an inhibitor of both HSV-1 and HSV-2 replication.
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PMID:Spectrum of antiviral activity of o-(acetoxyphenyl)hept-2-ynyl sulphide (APHS). 1584 98

Phyllanthus urinaria Linnea (Euphorbiaceae) is one of the traditional medicinal plants that are widely applied by oriental people, especially by Chinese and Indian, to ameliorate various kinds of ailments. Many biological activities, including anti-hepatitis B virus, anti-Epstein-Barr virus and anti-retroviral reverse transcriptase, of P. urinaria have been reported, but not against herpes simplex virus (HSV). In this study, the anti-HSV-1 and HSV-2 activities of different solvents extracted from P. urinaria were investigated in vitro by plaque reduction assay. Results showed that acetone, ethanol and methanol extracts of P. urinaria inhibited HSV-2 but not HSV-1 infection. The 50% inhibitory concentration against HSV-2 infection (IC50) of acetone, ethanol and methanol extracts was 4.3 +/- 0.5, 5.0 +/ -0.4 and 4.0 +/- 0.9 mcg/ml, respectively. All three extracts showed no cytotoxic effect against Vero cells at concentrations of 10.0 mcg/ml or below. The time-of-addition study demonstrated that these three extracts were only effective when added during the HSV-2 infection which, therefore, suggested that they disturb the initial stage of HSV-2 infection. Furthermore, they can diminish virus infectivity without significantly affecting incubation time and temperature. Therefore, the acetone, ethanol and methanol extracts of P. urinaria were concluded to likely inhibit HSV-2 infection through disturbing the early stage of virus infection and through diminishing the virus infectivity.
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PMID:Acetone, ethanol and methanol extracts of Phyllanthus urinaria inhibit HSV-2 infection in vitro. 1588 15

As a general rule, enzymes act on only one enantiomer of a chiral substrate and only one of the enantiomeric forms of a chiral molecule may bind effectively at the catalytic site, displaying biological activity. In recent years, some exceptions have been found among viral and cellular enzymes involved in the synthesis of deoxynucleoside triphosphates and in their polymerisation into DNA. Examples are: herpes virus thymidine kinases, cellular deoxycytidine kinase and deoxynucleotide kinases, human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, hepatitis B virus (HBV) DNA polymerase and, to a lesser extent, some cellular DNA polymerases. The lack of enantioselectivity allows herpes simplex virus (HSV) thymidine kinase and cellular deoxycytidine kinase to phosphorylate the unnatural L-beta-enantiomers of D-thymidine and D-deoxycytidine, respectively, or of their analogues to monophosphate. This phosphorylation represents the first and often the rate-limiting step of their activation to triphosphates. The L-triphosphates can then exert antiviral (anti-HSV, anti-Human cytomegalovirus, anti-HIV-1, anti-HBV) and anticancer activities. Although only one L-nucleoside (3TC) has so far gained United States of America Food and Drug Administration (USA FDA) approval for clinical use against HIV-1, other L-enantiomers of nucleoside analogues, which have shown antiviral or anticancer activity in cell cultures are in clinical trials. Their resistance to enantioselective enzymes, such as thymidine phosphorylase, thymidylate synthase, (deoxy)-cytidine and dCMP deaminases, and their lower affinity for the mitochondrial thymidine kinase can ensure a higher selectivity and lower cytotoxicity with respect to those exerted by their corresponding natural D-enantiomers and might be exploited to solve problems arising during chemotherapy, such as metabolic inactivation, cytotoxicity and drug-resistance.
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PMID:Molecular basis for the antiviral and anticancer activities of unnatural L-beta-nucleosides. 1599 31

Previous gene transfer studies of the herpes simplex virus type 1 (HSV-1) using the latency-associated transcript (LAT) promoter have reported a decrease in transgene expression in the brain over time, but the extent of this decrease has not been measured and it is unknown if expression eventually stabilizes. We examined LAT promoter-mediated transgene expression in the mouse brain for 1 year following intracranial injection with a HSV-1 vector expressing human beta-glucuronidase (GUSB). The vector genome copy number remained stable from 2 to 52 weeks. Quantitative reverse transcriptase PCR detected a peak of LAT intron expression at 2 weeks (corresponding to the end of the acute phase of viral infection), followed by stable expression during latency (13-52 weeks). The number of GUSB-positive cells also had a peak in the acute phase and then was stable during latency (13-52 weeks). GUSB enzymatic activity was maintained at 11% of normal at 6 and 12 months, indicating that the LAT promoter is capable of driving stable transgene expression in the brain.
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PMID:Stable levels of long-term transgene expression driven by the latency-associated transcript promoter in a herpes simplex virus type 1 vector. 1612 87

Integration of a therapeutic gene into the host cell genome permits stable expression of the gene product in the target cells and its progeny. However, non-directional integration of any given gene can pose the risk of activating tumor genes or silencing tumor suppressor genes. Therefore, including a safety-control element into integrating vector systems is an important advance towards safer human gene therapy. Here, we report on a gene expression cassette that can be potentially exploited in integrating vector systems to eliminate post-therapeutic tumorigenesis. The Herpes simplex virus thymidine kinase (hsvTK) gene under the transcriptional control of the human telomere reverse transcriptase promoter (hTERTp) was incorporated into a self-inactivating HIV-based lentiviral vector. The hTERT promoter is silent in normal somatic cells and re-activated in tumor cells. Therefore, normal gene-corrected cells should not express hsvTK from the promoter. However, if some gene-corrected cells subsequently become tumorigenic and the hTERT promoter is re-activated, application of ganciclovir (GCV), a clinically used antiviral drug, will achieve selective deletion of the cancerous cells. Our experimental data indicated that the hTERTp-hsvTK cassette in the lentiviral vector was sufficient to differentiate between tumor cells and normal cells, thus eradicating tumor cells selectively in vitro and in vivo. These results proved the principle of using the element in integrating vectors for safer gene delivery.
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PMID:Conditional expression of a suicide gene by the telomere reverse transcriptase promoter for potential post-therapeutic deletion of tumorigenesis. 1612 46


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