Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A1110U (BW 1110U81) is an inactivator of herpesvirus ribonucleotide reductases and a potentiator of the antiviral activity of acyclovir (ACV) (T. Spector, J. A. Harrington, R. W. Morrison, Jr., C. U. Lambe, D. J. Nelson, D. R. Averett, K. Biron, and P. A. Furman, Proc. Natl. Acad. Sci. USA 86:1051-1055, 1989) that was subsequently found to cause hematological toxicity at high oral doses in rats. Eleven structurally related inactivators of herpes simplex virus (HSV) ribonucleotide reductase were therefore tested in vivo for hematological toxicity and for potentiation of ACV. None of the novel ribonucleotide reductase inactivators was hematologically toxic to rats following oral dosing at 60 mg/kg/day for 30 days. Four of these inactivators statistically improved the antiviral topical potency of ACV on HSV type 1-infected nude mice. A promising compound, 2-acetylpyridine 5-[(2-chloroanilino)thiocarbonyl]thiocarbonohydrazone (BW 348U87), was studied more extensively in two in vivo models: dorsum-infected athymic nude mice and snout-infected hairless mice. BW 348U87 significantly potentiated the antiviral activity of ACV against all virus strains tested, i.e., wild-type (ACV-sensitive) HSV type 1 and HSV type 2 strains and three mutant (ACV-resistant) HSV type 1 strains. The latter included a virus expressing a DNA polymerase resistant to inhibition by ACV triphosphate, a virus deficient in thymidine kinase (the enzyme responsible for phosphorylating ACV), and a virus expressing an altered thymidine kinase, which catalyzes the normal phosphorylation of thymidine but not of ACV. BW 348U87 and ACV are currently being developed as a combination topical therapy for cutaneous herpes infections.
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PMID:Inactivators of herpes simplex virus ribonucleotide reductase: hematological profiles and in vivo potentiation of the antiviral activity of acyclovir. 132 41

Cryopreserved donor skin-cell survival was tested after allo- and isotransplantation by DNA amplification of male donor-cell genes which detects trace quantities of cells. Essentially, all cryopreserved allograft skin cells were rejected at the recipient site. Fine-haired, cryopreserved, belly skin of male BALB/c mice was transplanted onto the coarser-haired back of either female Swiss-Webster mice (allograft) or female BALB/c mice (isograft). Six weeks later, skin samples from the graft sites were tested by DNA polymerase chain reaction (PCR) amplification. Although allografts initially engrafted, more than 99.9 percent of male allograft skin cells were subsequently rejected, and gradually replaced by hairless host scar tissue. Clinically, all isografts, including hair follicles, engrafted permanently and maintained donor-cell SRY gene sequences in fine-haired graft site cells. Thus, cryopreservation maintained both the viability and antigenicity of mouse skin cells, because allografts were rejected and isografts survived. Furthermore, DNA amplification, quantified at multiple control dilutions and amplification cycles, can conclusively determine the fate of transplanted cells.
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PMID:DNA amplification determines donor-cell fate in cryopreserved skin allografts. 935 1

The immunosuppressive agent mycophenolate mofetil (MMF) has been approved for use in kidney transplant recipients and may thus be used concomitantly for the treatment of intercurrent herpesvirus infections with drugs such as acyclovir (ACV), ganciclovir (GCV), and penciclovir (PCV). We found that MMF and its parent compound mycophenolic acid (at concentrations that are attainable in plasma) strongly potentiate the antiherpesvirus (herpes simplex virus [HSV] type 1 [HSV-1], HSV-2, thymidine kinase-deficient [TK-] HSV-1, both wild-type and TK- varicella-zoster virus, and human cytomegalovirus) activities of ACV, PCV, and GCV (up to 350-fold increases in their activities). The mechanism of potentiation was found to reside in the depletion of endogenous dGTP pools, which favored the inhibitory effect of the triphosphate of ACV, GCV, or PCV on the viral DNA polymerase. The combination of topically applied 5% MMF with 0.1% ACV strongly protected against HSV-1-induced cutaneous lesions in hairless mice, whereas therapy with either compound used singly had no protective effect. Interestingly, the combination of topically applied 5% MMF with 5% ACV was also highly effective in protecting against TK- HSV-2-induced cutaneous lesions (that were refractory to ACV treatment) in athymic nude mice. Topical therapy with MMF was very well tolerated, and no signs of irritation were observed. When given perorally at 200 mg/kg of body weight/day, MMF potentiated to some extent the growth retardation induced by GCV in young NMRI mice. These observations may have clinical implications (i) for those transplant recipients who receive both MMF and either ACV, GCV, or PCV and (ii) for the treatment of ACV-resistant mucocutaneous HSV infections.
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PMID:The novel immunosuppressive agent mycophenolate mofetil markedly potentiates the antiherpesvirus activities of acyclovir, ganciclovir, and penciclovir in vitro and in vivo. 952 62

Mycophenolic acid (MPA), the active form of the immunosuppressive agent mycophenolate mofetil (MMF), was found to markedly potentiate the anti-herpesvirus activity of the novel anti-herpesvirus agent A-5021, (1'S,2'R)-9-[[1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]guanine. For example, at a concentration of 1 microg/ml MPA, the activity of A-5021 against HSV-1, HSV-2 and TK(-) HSV-1 increased by a factor of 130, 14 and > or = 189, respectively. Exogenously added guanosine reversed this potentiating effect, suggesting that a depletion of the endogenous dGTP pools enhanced the inhibitory effect of the 5'-triphosphate metabolite of A-5021 on the viral DNA polymerase. The combined effect of A-5021 and MPA on the growth of uninfected Vero cells was additive rather than synergistic. The combination of topically applied MMF (5%) with 0.05% A-5021 (a subactive concentration) completely protected against HSV-1-induced cutaneous lesions in hairless mice, whereas therapy with either compound used alone had no protective effect. These findings may have implications for those transplant recipients that receive MMF as (part of) their immunosuppressive therapy and that develop intercurrent herpesvirus infections for which they need treatment.
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PMID:The anti-herpesvirus activity of (1'S,2'R)-9-[[1',2'-bis(hydroxymethyl)-cycloprop-1'-yl]methyl]guanine is markedly potentiated by the immunosuppressive agent mycophenolate mofetil. 1124 64