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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To provide information on the role of nucleases in oncogenic virus infection, the activities of 3'-nucleotide phosphodiesterase (3'-NPDase), 5'-nucleotide phosphodiesterase (5'-NPDase), acid deoxyribonuclease (DNase II), and 3',5'-cyclic AMP phosphodiesterase (cAMPDase) in spleen extracts of murine sarcoma virus-infected C57BL/6 inbred mice were studied. At the peak of tumor growth and of the cell-mediated cytotoxic response (CMC) against tumor-associated antigens, 3'-NPDase, 5'-NPDase, and DNase II all showed depressed activities in the spleen, whereas the activity of cAMPDase in the spleen increased at the peak of CMC and remained elevated thereafter. Serum enzyme activities of the infected mice were also determined, and only 3'-NPD-ase in serum correlated well with CMC. Inasmuch as the correlation of the tumor growth with CMC was established in this system, further study on tumors with variance between CMC and growth is necessary to determine if serum 3'-NPDase is a useful biochemical marker for CMC in vivo.
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PMID:Nucleases and adenosine 3',5'-cyclic monophosphate phosphodiesterase activities in murine sarcoma virus (Moloney)-infected mice. 21 66

(S)-1-[3-Hydroxy-2-(phosphonylmethoxy)propyl]cytosine (HPMPC) is an antiviral phosphonate nucleotide analogue that displays activity against a range of herpesviruses. Anion exchange high performance liquid chromatography analysis of the 60% methanol extract from [14C]HPMPC-treated cells reveals the formation of three major metabolites. Two of these were identified as phosphorylated forms of HPMPC, HPMPC phosphate, and HPMPC diphosphate, by liberation of HPMPC upon acid digestion and coelution with synthetic standards on high performance liquid chromatography. The third metabolite, which is resistant to alkaline phosphatase cleavage but sensitive to phosphodiesterase, is proposed to be an HPMPC phosphate adduct. In herpes simplex virus-1-infected cells the same three metabolites are detected, at concentrations comparable to those in uninfected cells. When HPMPC is removed from the medium, the concentrations of the metabolites in cells decrease slowly, with half-lives of approximately 6, 17, and 48 hr for HPMPC phosphate, HPMPC diphosphate, and the HPMPC phosphate adduct, respectively. HPMPC diphosphate inhibits herpes simplex virus-1 and -2 DNA polymerases with a lower Ki than that for DNA polymerase alpha, and enzyme inhibition is competitive in each case. The formation and the persistence of HPMPC phosphates in cells and the selective inhibition of viral DNA polymerases by HPMPC diphosphate can explain why cells pretreated with HPMPC remain refractory to viral infection even long after HPMPC is removed from the medium.
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PMID:Intracellular metabolism of the antiherpes agent (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine. 131 Jan 43

Papaverine, an inhibitor of cAMP phosphodiesterase, reduced yields of infectious vesicular stomatitis virus in HEp-2 cells approximately 100-fold if added to cultures at a concentration of 30 microM before and after virus infection. The extent of papaverine-induced suppression of viral growth was dependent on drug dose and treatment regimen. Cells progressively recovered their viral permissive state after removal of drug. The cyclic nucleotide, cGMP, nullified the inhibitory effect of papaverine if added to cells during drug treatment. Pulse labeling experiments with [35S]methionine showed that papaverine compromises production of all virus-specific proteins in infected cells without adversely affecting host cell protein synthesis. Treatment of cells with papaverine strongly inhibited the production of viral RNA and both cellular RNA and DNA. It was found that VSV causes an immediate but transient stimulation of DNA synthesis in HEp-2 cells which is prevented by papaverine treatment. This drug also selectively blocked primary transcription of VSV in vivo and to a lesser extent in vitro RNA polymerase activity of the virion-bound transcriptase. The finding that papaverine has a strong inhibitory effect on viral biosynthesis including early transcription suggests that VSV replication may depend on host factors that regulate intracellular levels of cyclic nucleotides such as cAMP.
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PMID:Inhibitory effect of papaverine on RNA and protein synthesis of vesicular stomatitis virus. 241 Oct 62

Conversion of acute measles virus infection to an indolent state has been achieved by treatment of infected cells of neural origin with agents that affect cyclic nucleotide metabolism. Striking results were obtained with papaverine, an inhibitor of cAMP phosphodiesterase that is capable of enhancing neural differentiation. In papaverine-treated cultures, decreased production of infectious virus was accompanied by selective disappearance of intracellular matrix proton, as detected by immunofluorescence. Viral nucleocapsid protein was enhanced in the cytoplasm while three other structural proteins--polymerase, hemagglutinin, and fusion protein--showed little change in distribution or intensity of staining. These results were specific for cells of neural origin and not observed in CV-1 or Vero cultures. cAMP, dibutyryl cAMP, 8-bromo-cAMP, and isobutylmethylxanthine all inhibited replication of virus but less so than did papaverine. Inhibition of virus replication by any of these agents was rapidly reversible, either by removal of the agent or by addition of cGMP to the culture medium and was accompanied by reappearance of the matrix protein. These results suggest that measles virus replication in neural cells depends on host factors, particularly those affecting endogenous cAMP and cGMP. Viral persistence may thus be related to the state of neural differentiation. This model system may yield information on mechanisms of recrudescence observed in some chronic diseases of the nervous system.
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PMID:Reversible repression and activation of measles virus infection in neural cells. 628 Jan 93

The levels of two dsRNA-dependent enzyme activities, the pppA(2'p5'A)n synthetase (2-5A synthetase) and protein kinase were investigated in control and interferon-treated murine cells: L-929, K/Balb and NIH/3T3. Treatment of these cells with interferon resulted both in the establishment of the antiviral response and the development of anticellular effects. This latter was observed 3 days after treatment with interferon. The levels of 2-5A synthetase and protein kinase in control and interferon-treated cells seemed to vary from one cell type to the other. In L-929 cells, both the 2-5A synthetase and protein kinase were induced by interferon as has been shown previously. On the other hand, treatment of NIH/3T3 cells with interferon resulted in the induction of 2-5A synthetase in the absence of any enhanced protein kinase activity. This lack of protein kinase in interferon-treated NIH/3T3 cells was not due to the presence of high levels of protein phosphatases. A third type of mouse cells, K/Balb cells, contained very high levels of 2-5A synthetase in the absence of any apparent resistance to virus infection. On treatment with interferon the level of 2-5A synthetase in K/Balb cells remained constant while the protein kinase activity was enhanced by several fold. Both control and interferon-treated K/Balb cells showed similar sensitivity to the action of exogenous 2-5A thus suggesting that the 2-5A system (the 2-5A dependent nuclease and the phosphodiesterase which degrades 2-5A) was not altered on treatment with interferon. The significance of these results in relation to the mechanism of action of interferon is discussed.
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PMID:Lack of systematic correlation between the interferon mediated antiviral state and the levels of 2-5A synthetase and protein kinase in three different types of murine cells. 628 3

Controversy still exists concerning the therapy for viral myocarditis which manifests a wide variety of clinical symptoms. Vesnarinone, a quinolinone derivative that was developed as a positive inotropic agent with complex actions, including phosphodiesterase inhibition and cation channel modification, has recently been confirmed to improve the prognosis of patients with chronic heart failure. However, the precise mechanism of this beneficial effect is not yet clearly understood. In this study, using a murine model of acute viral myocarditis resulting from encephalomyocarditis virus infection, survival and myocardial damage were markedly improved by treatment with vesnarinone. In contrast, survival was not improved by treatment with amrinone, a phosphodiesterase inhibitor. Although vesnarinone did not inhibit viral replication or protect myocytes from viral direct cell injury, it did inhibit the increase in natural killer cell activity after viral infection. On the other hand, amrinone failed to inhibit natural killer cell activity. Both vesnarinone and amrinone suppressed the production of tumor necrosis factor-alpha. Therefore, we postulate that vesnarinone exerted its beneficial effects through an inhibition of natural killer cell activity, and that it serves as an immunomodulator providing new therapeutic possibilities for the treatment of viral myocarditis and/or immunological disorders.
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PMID:Treatment of virus-induced myocardial injury with a novel immunomodulating agent, vesnarinone. Suppression of natural killer cell activity and tumor necrosis factor-alpha production. 808 62

The block polycationic oligonucleotide (oligo) consisting of a phosphodiester 12-mer linked to the polycation chain at the 3'-end and cholesteryl group at the 5'-end was synthesized. The polycation chain was grown on the solid support using the monomer, H-phosphonate of 1-O-(4,4'-dimethoxytrityl)-1,3-butanediol. Amino groups were introduced in the polymer backbone using 1,4-diaminobutane, and then the oligo chain was formed at the free end of the polymer. The last stage of the synthesis was the attachment of the cholesteryl group to the 5'-end of the oligo prior to cleavage and deprotection of the copolymer. The nucleotide sequence of this copolymer, CGTTCCTCCTGC, was complementary to the splicing site of immediate early (IE) mRNA 4 and 5 of herpes simplex virus type 1 (HSV-1). The stability of the duplexes formed between the copolymer and the complementary 12-mer was similar to that of unmodified oligo. The stability of the block polycationic oligo against phosphodiesterase digestion was significantly increased compared to that of the unmodified oligo. The block polycationic oligo inhibited the reproduction of HSV-1 in Vero cells; however, the effect was significantly less than the effect of 12-mer oligo modified with cholesterol at the 5'-end. The decreased antiviral activity of the copolymer is explained by the polycation-induced stimulation of the virus infection.
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PMID:Block polycationic oligonucleotide derivative: synthesis and inhibition of herpes virus reproduction. 874 84

Management of acute viral myocarditis is still controversial. Amrinone, a noncatecholamine nonglycoside bipyridine agent, produces sustained improvement of cardiac function and symptomatology in congestive heart failure (CHF). Amrinone demonstrates phosphodiesterase inhibitory activity that is relatively selective for the major phosphodiesterase isozyme in cardiac muscles, PDE III, which specifically hydrolyzes cyclic 3'5' adenosine monophosphate (cAMP). We investigated the effects of amrinone in an animal model of acute CHF related to myocarditis caused by the encephalomyocarditis virus (EMCV). Female C3H mice were inoculated intraperitoneally (i.p.) with 500 plaque-forming units of EMCV in 0.1 ml of saline. A total of 96 mice were randomly assigned to four groups. Each animal was administered 0.2 ml of phosphate-buffered saline (PBS) containing amrinone at a concentration of 1, 10, or 50 mg/kg, or PBS as an infected control, injected i.p. once daily for 21 days, starting on day 1 after viral inoculation. Each group contains 20 to 30 mice. Infected untreated mice survived at 80% (n = 16), however, only 13% (n = 16) of mice treated with amrinone (50 mg/kg) survived (p < 0.01). Downregulation of cardiac cAMP occurred 1 day after the viral infection. Although amrinone (10 and 50 mg/kg) treatment significantly (p < 0.05) increased the cardiac cAMP content and the dose of 10 mg/kg could potentially retard death from CHF due to viral myocarditis. The higher (50 mg/kg) doses of amrinone may produce unfavorable effects when used to treat mammals with viral myocarditis and CHF.
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PMID:Effect of amrinone on murine viral myocarditis. 905 49

The 2-5A system is an RNA degradation pathway that can be induced by the interferons (IFNs). Treatment of cells with IFN activates genes encoding several double-stranded RNA (dsRNA)-dependent synthetases. These enzymes generate 5'-triphosphorylated, 2',5'-phosphodiester-linked oligoadenylates (2-5A) from ATP. The effects of 2-5A in cells are transient since 2-5A is unstable in cells due to the activities of phosphodiesterase and phosphatase. 2-5A activates the endoribonuclease 2-5A-dependent RNase L, causing degradation of single-stranded RNA with moderate specificity. The human 2-5A-dependent RNase is an 83.5 kDa polypeptide that has little, if any, RNase activity, unless 2-5A is present. 2-5A binding to RNase L switches the enzyme from its off-state to its on-state. At least three 2',5'-linked oligoadenylates and a single 5'-phosphoryl group are required for maximal activation of the RNase. Even though the constitutive presence of 2-5A-dependent RNase is observed in nearly all mammalian cell types, cellular amounts of 2-5A-dependent mRNA and activity can increase after IFN treatment. One well-established role of the 2-5A system is as a host defense against some types of viruses. Since virus infection of cells results in the production and secretion of IFNs, and since dsRNA is both a frequent product of virus infection and an activator of 2-5A synthesis, the replication of encephalomyocarditis virus, which produces dsRNA during its life cycle, is greatly suppressed in IFN-treated cells as a direct result of RNA decay by the activated 2-5A-dependent RNase. This review covers the organic chemistry, enzymology, and molecular biology of 2-5A and its associated enzymes. Additional possible biological roles of the 2-5A system, such as in cell growth and differentiation, human immunodeficiency virus replication, heat shock, atherosclerotic plaque, pathogenesis of Type I diabetes, and apoptosis, are presented.
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PMID:The 2-5A system: modulation of viral and cellular processes through acceleration of RNA degradation. 962 81

Viral respiratory infections are considered one of the triggers of exacerbations of asthma. In a model of virus-induced airway hyper-responsiveness (AHR), mice infected with human respiratory syncytial virus (RSV) were shown to develop AHR accompanied by lung eosinophilia. Inhibitors of cyclic nucleotide phosphodiesterase (PDE) have been shown to affect airway responsiveness and pulmonary allergic inflammation. In this study, we assessed the effects of type 4 PDE (PDE4) inhibitors on AHR following RSV infection and compared them with a PDE3 inhibitor. In mice infected by intranasal inoculation of RSV, treatment with the PDE4 inhibitor rolipram or Ro-20-1724 reduced both AHR and the eosinophil infiltration of the airways. In contrast, the PDE3 inhibitor, milrinone, did not influence airway responsiveness or eosinophilic inflammation. These results demonstrate that PDE4 inhibitors can modulate RSV-induced AHR and lung eosinophilia and indicate that they have a potential role in treating exacerbations of asthma triggered by viral infection.
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PMID:Type 4 phosphodiesterase inhibitors attenuate respiratory syncytial virus-induced airway hyper-responsiveness and lung eosinophilia. 1090 Feb 50


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