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)

A method for the detection and direct typing of herpes simplex virus (HSV) by the polymerase chain reaction (PCR) technique has been developed. One common upstream primer and two type-specific downstream primers were prepared to amplify DNA from the HSV type 1 and type 2 DNA polymerase gene. Using these three primers simultaneously in the PCR reaction mixtures, both types of HSV DNA were amplified to produce products of different sizes. By direct gel analysis, the products of standard HSV type 1 and type 2 strains had the predictive sizes of 469 and 391 base pairs, respectively, and the difference in molecular mass enabled us to type the HSV strain. A total of 24 strains (type 1; 16 and type 2; 8 strains) were examined by PCR, and the results were consistent with those determined by immunofluorescence using type-specific monoclonal antibodies. No specific amplification was observed using other herpes virus or human genomic DNAs. The PCR method was then applied to clinical specimens. Of 15 samples obtained from oral lesions of children with herpetic gingivostomatitis, all (100%) were HSV positive by PCR, compared with 13 (86.7%) using standard cell culture methods. Three specimens from vulvar lesions of women with genital herpes were positive using both PCR and cell cultures. There was complete agreement in the typing of HSV strains using the PCR method or virus isolation. On the basis of these results, it is suggested that DNA amplification and typing by PCR is particularly useful for material from which virus isolation might be difficult.
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PMID:Detection and direct typing of herpes simplex virus by polymerase chain reaction. 217 36

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 (Zovirax) is a qualified success as an effective and nontoxic antiviral chemotherapeutic agent and at present is approved for the treatment of initial genital herpes and limited life-threatening cutaneous herpes simplex viral infections in the immunocompromised host. Its efficacy in Epstein-Barr, varicella-zoster, and cytomegalorvirus infections appears less promising. According to one controlled study, its efficacy in the treatment of herpes labialis (HSV-1) infections has been disappointing. The highly selective action of acyclovir against viral DNA polymerase and its inhibition of viral DNA chain elongation result in a low incidence of human (host cell) toxicity, as manifested by local irritation at injection sites and a modest incidence of adverse renal effects, which can be reduced by judicious drug use. Newer antiviral agents now under development hold substantial promise for the future of antiviral chemotherapy.
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PMID:Acyclovir and herpesvirus infections. A review of the literature. 632 78

Acyclovir is a new antiviral drug that acts as a specific inhibitor of herpesvirus DNA polymerase. It shows good in vitro activity against herpes simplex and varicella-zoster viruses. The drug may be administered topically to the skin, intravenously, orally, or topically to the eye (only topical and intravenous preparations are currently available). Acyclovir kinetics are described by a two-compartment open model. The drug and its metabolites are excreted by the kidney via glomerular filtration and tubular secretion. Dosage adjustment is required in patients with renal failure. Safety and tolerance studies in animals and humans have shown acyclovir to be very well tolerated. The most important adverse effect is crystalluria and elevated serum creatinine related to bolus intravenous administration. Other reported adverse effects include infusion site inflammation and rash. Topical acyclovir is effective for treating initial genital herpes and mucocutaneous herpes in the compromised host, but has not been shown to be clinically useful for recurrent labial or genital herpes. Intravenous acyclovir is effective for mucocutaneous herpes infections in the compromised host and initial genital herpes in the normal host; it is being evaluated for the treatment of herpes simplex virus encephalitis and varicella-zoster infections. An investigational oral preparation may prove to be effective therapy for both initial and recurrent genital herpes. Acyclovir therapy does not eliminate latent virus or prevent subsequent recurrences.
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PMID:Acyclovir: mechanism of action, pharmacokinetics, safety and clinical applications. 635 82

Symptomatic human herpes simplex virus type 1 (HSV-1) infections are rather benign in immunocompetent individuals. The primary clinical manifestations of HSV-2 infection, which is mainly transmitted sexually, are anogenital lesions. Genital herpes affects one third of the world's population, and possibly 80% of those infected with HIV. HSV infections are especially severe and even life-threatening in people with AIDS. Only 20% of herpes seropositive persons have symptomatic infection, with the remainder asymptomatic but able to shed the virus. HSV infections are usually treated with nucleoside analogs such as acyclovir (ACV), but HSV eventually becomes resistant to ACV due to the loss or mutation of the viral thymidine kinase (TK) or changes in viral DNA polymerase. Gramicidin has recently been identified as a potent nontoxic anti-HIV agent 3-5 times more active than nonoxynol-9. Findings are reported from an assessment of the effect of gramicidin upon the replication of HSV-1 and HSV-2. Human WI-38 fibroblasts were inoculated with either HSV type in the presence of serial dilutions of gramicidin, while reduction in viral yield was measured by ELISA. The 50% inhibitory dose (IC50) of gramicidin against 3 HSV-1 and 4 HSV-2 isolates was equal to 0.3 mcg/ml and was comparable to the efficacy of ACV. The IC50 of gramicidin required to protect WI-38 from the cytolytic effect of HSV was 10 mcg/ml at day 5 postinfection, indicating that gramicidin was less active than ACV. Gramicidin nonetheless suppressed the replication of ACV-resistant thymidine kinase and DNA polymerase HSV mutants at doses effective against ACV-sensitive strains. These results suggest that gramicidin could be used against STDs and to prevent sexually transmitted HIV and HSV infections.
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PMID:The effect of gramicidin, a topical contraceptive and antimicrobial agent with anti-HIV activity, against herpes simplex viruses type 1 and 2 in vitro. 967 88

Cidofovir is a cytidine nucleotide analogue recently licensed as an intravenous treatment for CMV retinitis in AIDS patients. Three controlled clinical trials have demonstrated efficacy of cidofovir for this indication, and have generated data useful as a guideline to prevent potential toxicity. Although de novo emergence of resistance to cidofovir has not been observed clinically in patients receiving cidofovir, cross-resistance to cidofovir in ganciclovir-resistant clinical DNA polymerase mutants has been identified. Cross-resistance of cidofovir and foscarnet has not been identified to date. A broad spectrum agent with in vitro activity against human herpesviruses, adenovirus, HPV, polyomaviruses and human poxviruses, cidofovir is under clinical investigation for a variety of potential applications. Examples include intravenous administration of cidofovir for treatment of progressive multifocal leukoencephalopathy and Kaposi's sarcoma, intraocular injection for treatment of CMV retinitis, intralesional injection for treatment of respiratory papillomatosis, topical application for treatment of molluscum contagiosum, anogenital condyloma acuminata, and recurrent genital herpes, and ophthalmic instillation for treatment of viral keratoconjunctivitis. Copyright 1997 John Wiley & Sons, Ltd.
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PMID:Clinical uses of cidofovir. 1039 79

The vast majority of the world population is infected with at least one member of the human herpesvirus family. Herpes simplex virus (HSV) infections are the cause of cold sores and genital herpes as well as life-threatening or sight-impairing disease mainly in immunocompromized patients, pregnant women and newborns. Since the milestone development in the late 1970s of acyclovir (Zovirax), a nucleosidic inhibitor of the herpes DNA polymerase, no new non-nucleosidic anti-herpes drugs have been introduced. Here we report new inhibitors of the HSV helicase-primase with potent in vitro anti-herpes activity, a novel mechanism of action, a low resistance rate and superior efficacy against HSV in animal models. BAY 57-1293 (N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide), a well-tolerated member of this class of compounds, significantly reduces time to healing, prevents rebound of disease after cessation of treatment and, most importantly, reduces frequency and severity of recurrent disease. Thus, this class of drugs has significant potential for the treatment of HSV disease in humans, including those resistant to current medications.
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PMID:New helicase-primase inhibitors as drug candidates for the treatment of herpes simplex disease. 1192 30

The quiet pandemic of herpes simplex virus (HSV) infection has plagued humanity since ancient times, causing mucocutaneous infection, such as herpes labialis and herpes genitalis. Disease symptoms often interfere with everyday activities and occasionally HSV infections are the cause of life-threatening or sight-impairing disease, especially in neonates and the immunocompromised patient population. After primary or initial infection the virus persists for life in a latent form in neurons of the host, periodically reactivating and often resulting in significant psychosocial distress for the patient. Currently, no cure is available. In the mid-1950s the first antiviral, idoxuridine, was developed for topical treatment of herpes disease and, in 1978, vidarabine was licensed for systemic use to treat HSV encephalitis. Acyclovir (Zovirax), a potent, specific and tolerable nucleosidic inhibitor of the herpes DNA polymerase, was a milestone in the development of antiviral drugs in the late 1970s. In the mid-1990s, when acyclovir became a generic drug, valacyclovir (Valtrex) and famciclovir (Famvir), prodrugs of the gold standard and penciclovir (Denavir), Vectavir), a close analogue, were launched. Though numerous approaches and strategies were tested and considerable effort was expended in the search of the next generation of an antiherpetic therapy, it proved difficult to outperform acyclovir. Notable in this regard was the award of a Nobel Prize in 1988 for the elucidation of mechanistic principles which resulted in the development of new drugs such as acyclovir. Vaccines, interleukins, interferons, therapeutic proteins, antibodies, immunomodulators and small-molecule drugs with specific or nonspecific modes of action lacked either efficacy or the required safety profile to replace the nucleosidic drugs acyclovir, valacyclovir, penciclovir and famciclovir as the first choice of treatment. Recently though, new inhibitors of the HSV helicase-primase with potent in vitro antiherpes activity, novel mechanisms of action, low resistance rates and superior efficacy against HSV in animal models have been discovered. This review summarises the current therapeutic options, discusses the potential of preclinical or investigational drugs and provides an up-to-date interpretation of the challenge to establish novel treatments for herpes simplex disease.
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PMID:Novel agents and strategies to treat herpes simplex virus infections. 1255 12

In this study, the irntratypic variability of a tandem repeat locus within the DNA polymerase (pol) gene of human herpes simplex virus type 2 (HSV2) was uncovered. The locus contained variable numbers of tandem dodecanucleotide (5'-GAC GAG GAC GGG-3') repetitive units. Our result showed that approximately 95% of analyzed HSV2 clinical isolates and the current GenBank HSV2 strains contained two copies of the repetitive units. From genital herpes specimens, three new HSV2 strains, which respectively contained 1, 3, and 4 copies of the repetitive units, were identified. This variable number of tandem repeat (VNTR) locus is absent in HSV1, and thus it also contributes to the intertypic variability of HSV1 and HSV2. The intratypic variability of the locus may be useful for HSV2 strain genotyping and this application is discussed.
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PMID:Intratypic variability of a tandem repeat locus within the DNA polymerase gene of human herpes simplex virus type 2. 1473 57

Herpesviruses are the second leading cause of human viral diseases. Herpes Simplex Virus types 1 and 2 and Varicella-zoster virus produce neurotropic infections such as cutaneous and genital herpes, chickenpox, and shingles. Infections of a lymphotropic nature are caused by cytomegalovirus, HSV-6, HSV-7, and Epstein-Barr virus producing lymphoma, carcinoma, and congenital abnormalities. Yet another series of serious health problems are posed by infections in immunocompromised individuals. Common therapies for herpes viral infections employ nucleoside analogs, such as Acyclovir, and target the viral DNA polymerase, essential for viral DNA replication. Although clinically useful, this class of drugs exhibits a narrow antiviral spectrum, and resistance to these agents is an emerging problem for disease management. A better understanding of herpes virus replication will help the development of new safe and effective broad spectrum anti-herpetic drugs that fill an unmet need. Here, we present the first crystal structure of a herpesvirus polymerase, the Herpes Simplex Virus type 1 DNA polymerase, at 2.7 A resolution. The structural similarity of this polymerase to other alpha polymerases has allowed us to construct high confidence models of a replication complex of the polymerase and of Acyclovir as a DNA chain terminator. We propose a novel inhibition mechanism in which a representative of a series of non-nucleosidic viral polymerase inhibitors, the 4-oxo-dihydroquinolines, binds at the polymerase active site interacting non-covalently with both the polymerase and the DNA duplex.
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PMID:Crystal structure of the herpes simplex virus 1 DNA polymerase. 1663 52


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