Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.4.4 (adenosine deaminase)
 5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The appearance of drug resistant strains of herpes simplex virus type 1 (HSV-1) against 9-beta-D-arabinofuranosyladenine (araA), in comparison with 5-iodo-2'-deoxyuridine (IUdR) and 9-(2-hydroxyethoxymethyl)guanine (acycloguanosine, ACG), has been investigated in green monkey kidney cell cultures (Vero) and human embryo lung cell cultures (HEL). Growth curves of HSV-1 in Vero cells and HEL cells in the presence or absence of 20 micrograms/ml of araA showed that not only the viruses produced by these cells in the presence of araA but also the viruses produced in the absence of araA were resistant to the same concentration of araA. However, both viruses were unable to grow in the presence of a combination of 20 micrograms/ml of araA and 3 micrograms/ml of erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) which is an inhibitor of adenosine deaminase. On the other hand, the viruses produced only in the presence of IUdR or ACG were resistant to each drug. All virus clones obtained from five serial clonings in the presence of araA alone or araA and EHNA in combination were not resistant to araA. These results show that the strain of HSV-1 resistant to araA is an apparently resistant strain, and a truly resistant strain to araA may not be established as easily as the truly resistant strains to IUdR and ACG.
 ...
PMID:Study on the apparent resistant strains of herpes simplex virus type 1 against 9-beta-D-arabinofuranosyladenine. 285 80

Sangivamycin, 4-amino-5-carboxamido-7-(beta-D-ribofuranosyl)-pyrrolo[2,3-d]-pyrimidine is a structural analog of adenosine belonging to a group of nucleosides classified as pyrrolopyrimidines. Sangivamycin, an adenosine deaminase resistant analog, was found to inhibit the replication of three strains of herpes simplex virus type 1 (HSV-1) by 50% (ED50) at a concentration approximately equal to the concentration which inhibits cell growth by 50% (LD50). Both Vero cells and rabbit corneal stromal cells in exponential growth were about 10-fold more sensitive to the drug than quiescent cells. The selectivity indices of sangivamycin indicated that the drug was not a highly selective antiviral agent and, therefore, would offer no advantage over drugs currently available for the treatment of herpetic keratitis.
 ...
PMID:The antiherpesvirus activity and cytotoxicity of sangivamycin. 303 Jun 47

The action of adenosine deaminase on racemic carbocyclic analogues of 6-aminopurine nucleosides was investigated. When either racemic carbocyclic adenosine [(+/-)-C-Ado] or the racemic carbocyclic analogue [(+/-)-C-2,6-DAP-2'-dR] of 2,6-diaminopurine 2'-deoxyribofuranoside was incubated with this enzyme, approximately half of the material was deaminated rapidly. From the resulting solution, the D isomers of the deaminated carbocyclic analogues (D-carbocyclic inosine, D-C-Ino, or D-carbocyclic 2'-deoxyguanosine, D-2'-CDG) and the L isomers of the undeaminated carbocyclic analogues were isolated. At higher concentrations of the enzyme, deamination of L-C-Ado and L-C-2,6-DAP-2'-dR proceeded slowly, thus also making the other enantiomers accessible. In tests in vitro against herpes simplex virus, types 1 and 2, D-2'-CDG was as active and potent as (+/-)-2'-CDG, whereas L-2'-CDG displayed only modest activity. In contrast to the previously reported high activity and potency of (+/-)-C-2,6-DAP-2'-dR against these two viruses, L-C-2,6-DAP-2'-dR was inactive.
 ...
PMID:Resolution of racemic carbocyclic analogues of purine nucleosides through the action of adenosine deaminase. Antiviral activity of the carbocyclic 2'-deoxyguanosine enantiomers. 303 Dec 95

The development of herpes simplex virus (HSV)-induced disciform stromal disease produced by the intrastromal injection of the RE strain of HSV-1 is characterized by concurrent increases in adenosine deaminase (ADA) activity and corneal thickness. ADA activity increased from 8.6 units/cornea in normal corneas to about 14.1 units and 31.1 units in mock-infected controls and HSV-infected corneas respectively by 15 days postinjection. The molecular weight species of ADA in the corneas of HSV-infected rabbits appeared altered relative to that present in corneas which were not infected. A single topical dose with as low as 0.1% 2'-deoxycoformycin (dCF), an ADA inhibitor possessing immunosuppressive activity, was capable of totally inhibiting the corneal ADA activity. Titration of the free dCF in the cornea following a single topical dose of 0.25% dCF indicated that enough dCF remained in the cornea 24 hrs after instillation to totally inhibit all corneal ADA plus 66 units of additional enzyme. These data suggest that ADA may be a suitable target for immunosuppressive therapy during HSV-induced disciform stromal disease.
 ...
PMID:Adenosine deaminase in herpes simplex virus induced corneal stromal disease. 382 99

The metabolism of 9-beta-D-arabinofuranosyladenine (ara-A, vidarabine) and its effects on DNA synthesis were compared in uninfected and herpes simplex virus type-1 (HSV-1)-infected KB cells. In the absence of an inhibitor of adenosine deaminase, ara-A was deaminated to 9-beta-D-arabinofuranosylhypoxanthine and phosphorylated to ara-A-5'-mono-, di- and triphosphates in both types of cells. When an inhibitor of adenosine deaminase (coformycin) was added to cell cultures, nucleotides were the only metabolites detected--primarily the 5'-triphosphate of ara-A (aATP). Detailed studies performed in the presence of coformycin established that the net rate and extent of aATP formation were the same in uninfected and HSV-1-infected cells. After a 12-hr exposure to 50 microM ara-A, intracellular concentrations of aATP were approximately 40 microM. Levels of aATP correlated directly with inhibition of total DNA synthesis. Approximately 0.7 microM aATP was required for 50% inhibition of total DNA synthesis in both uninfected and HSV-1-infected cells. Following removal of ara-A-containing culture medium, aATP levels in uninfected cells declined with a half-life of 3.2 hr. In marked contrast, the half-life in HSV-1-infected cells was 9.3 hr; this may explain why as little as a 3-hr exposure to ara-A resulted in a significant HSV-1 titer reduction. Taken together, the data show that when ara-A was removed from culture medium, levels of aATP persisted longer in HSV-1-infected cells thereby prolonging antiviral activity. This effect could be important in vivo where levels of ara-A oscillate with dosing schedule.
 ...
PMID:Metabolism of arabinosyladenine in herpes simplex virus-infected and uninfected cells. Correlation with inhibition of DNA synthesis and role in antiviral selectivity. 608 27

Herpes simplex virus mutants PAAr5, AraAr6, AraAr7, AraAr9, and AraAr13, which previously had been shown to be resistant to arabinosyladenine (araA) alone, were found to be resistant to araA in the presence of high concentrations of the adenosine deaminase inhibitor, deoxycoformycin. The marker conferring resistance to araA and deoxycoformycin in mutant PAAr5 was mapped finely to an 0.8-kilobase-pair region in the herpes simplex virus DNA polymerase locus. These results indicate that the mutants are resistant to araA itself rather than to its deamination product and confirm the importance of the viral polymerase in the antiviral action of araA.
 ...
PMID:Herpes simplex virus mutants resistant to arabinosyladenine in the presence of deoxycoformycin. 609 55

Although the antiviral activity of erythro-9-(2-hydroxy-3-nonyl)adenine, a potent adenosine deaminase inhibitor, against herpes simplex virus type 1 in cell culture was readily confirmed, the compound was found to be totally ineffective in the treatment of experimentally induced systemic herpes simplex virus type 1 infections in Swiss mice. Data were obtained, however, which clearly indicated that the antiviral potency of 9-beta-D-arabinofuranosyladenine in vivo could be enhanced by the co-administration of low, nontoxic doses of erythro-9-(2-hydroxy-3-nonyl)adenine.
 ...
PMID:Erythro-9-(2-hydroxy-3-nonyl) Adenine alone and in combination with 9-beta-D-arabinofuranosyladenine in treatment of systemic herpesvirus infections in mice. 625 63

The severity of herpetic keratitis induced by 9-(2-hydroxyethoxymethyl) guanine-resistant strains of herpes simplex virus was significantly reduced by cotherapy with 9-beta-D-arabinofuranosyladenine (ara-A) and 2-deoxycoformycin. Therapy with 5-trifluoromethyl-2'-deoxyuridine (F3TdR) significantly reduced the severity of keratitis induced by an acyclovir-resistant strain with a defective DNA polymerase. Therapy with 3 percent acyclovir ointment slightly reduced the number of herpetic lesions produced by either deoxypyrimidine kinase or DNA polymerase defective viruses, despite these viruses being 100 to 1000 times more resistant to acyclovir than the wildtype strain. Therapy with 3 percent ara-A ointment alone significantly reduced the severity of lesions produced by the wildtype herpes strain. Therapy with ara-A alone did not reduce the severity of disease induced by any of the acyclovir-resistant mutants. The sensitivity of the wildtype and mutant viruses to nucleoside analogs was confirmed by yield-reduction assays conducted with Vero cells. These studies indicate that cotherapy with ara-A and an adenosine deaminase inhibitor was a reasonable alternative therapy for keratitis due to mutants resistant to therapy with nucleoside analogs which require the virus-specified deoxypyrimidine kinase or DNA polymerase, while ara-A alone was not an effective alternative.
 ...
PMID:Chemotherapy of herpetic keratitis induced by acyclovir-resistant strains of herpes simplex virus type 1. 628 20

The antiherpes activities of erythro- and threo-9-(2-hydroxy-3-nonyl)adenines (EHNA and THNA) have been determined. All isomers inhibited the replication of herpes simplex virus (HSV) and inhibited DNA synthesis in HSV-infected cells. The two enantiomers of EHNA, (+)-EHNA and (-)-EHNA, displayed equal antiviral activities. This is in contrast to their activities as inhibitors of adenosine deaminase (ADA); (+)-EHNA is a 250-fold more potent inhibitor of ADA than (-)-EHNA [Bessodes et al. Biochem. Pharmac. 31, 879 (1982)]. The antiherpes activity of (+)-THNA was only slightly less than that of the EHNA isomers, whereas (-)-THNA was somewhat less active. The abilities of the four isomeres of EHNA and THNA to inhibit DNA synthesis in HSV-infected cells correlated with their abilities to inhibit virus multiplication. EHNA failed to inhibit HSV DNA polymerase activity in extracts from infected cells. Moreover, addition of EHNA to infected cells at 6 hr post-infection resulted in no inhibition of DNA synthesis. These results are inconsistent with a direct inhibition of macromolecular DNA synthesis by EHNA. Treatment of HSV-infected cells with EHNA produced a 2- to 4-fold decrease in levels of the four DNA precursors, deoxyribonucleoside 5'-triphosphates (dNTPs). This treatment had much less effect on dNTP levels in uninfected cells.
 ...
PMID:Effects of chirality in 9-(2-hydroxy-3-nonyl)adenine upon deoxyribonucleic acid synthesis in herpes simplex virus-infected cells. 631 87

The inhibition of herpes simplex virus (HSV) replication by 2'-deoxyadenosine (dAdo) is greatly potentiated by the presence of the inhibitor of adenosine deaminase, erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA). HSV replication is inhibited by dAdo [in the presence of EHNA] or by 2'-deoxyguanosine (dGuo) at concentrations slightly lower than are necessary to inhibit growth of uninfected HeLa cells. Under conditions where virus replication is inhibited by greater than 99% with dAdo and EHNA, the level of dATP increases 50-fold or more, and synthesis of HSV DNA is inhibited. However, there is no depletion of any other DNA precursor, and HSV multiplication is not restored by simultaneous provision of dGuo, deoxythymidine, deoxycytidine, or a combination of all three of these nucleosides. Thus, the inhibition of HSV replication by dAdo cannot be explained as a block of precursor provision through inhibition of ribonucleotide reductase. In contrast, dGuo treatment of HSV-infected cells leads to depletion of dCTP, and virus multiplication is partially restored by provision of deoxycytidine. HSV-infected cells may serve as a useful system for study of the toxic effects of dAdo that are unrelated to inhibition of ribonucleotide reductase by dATP.
 ...
PMID:Inhibition of herpes simplex virus replication by purine deoxyribonucleosides. 632 76


<< Previous 1 2 3 4 Next >>