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DNA polymerase inhibition

Fig. (5). DNA polymerase inhibition dose response curves of kohamaic acid. (A) Mammalian DNA polymerases. The enzymes used (0.05 units of each) were calf DNA polymerase a ( ), rat DNA polymerase P (o), human DNA polymerase Y (A), calf DNA polymerase 8 (0) and human DNA polymerase 8 ( ). (B) Sea urchin DNA polymerases. The enzymes used (0.05 units of each) were DNA polymerase a ( ) and DNA polymerase p (o). The DNA polymerase activities were measured as described in the Material and methods. DNA polymerase activity in the absence of these compounds was taken as 100%. Data are shown as mean S.E. for three independent experiments. Fig. (5). DNA polymerase inhibition dose response curves of kohamaic acid. (A) Mammalian DNA polymerases. The enzymes used (0.05 units of each) were calf DNA polymerase a ( ), rat DNA polymerase P (o), human DNA polymerase Y (A), calf DNA polymerase 8 (0) and human DNA polymerase 8 ( ). (B) Sea urchin DNA polymerases. The enzymes used (0.05 units of each) were DNA polymerase a ( ) and DNA polymerase p (o). The DNA polymerase activities were measured as described in the Material and methods. DNA polymerase activity in the absence of these compounds was taken as 100%. Data are shown as mean S.E. for three independent experiments.
Vidarabine (Vira A) Phosporylated metabolite inhibits viral DNA polymerase. Inhibits mammalian DNA polymerase to lesser extent. Herpes simplex encephalitis, herpes zoster. [Pg.114]

The histones added to an incubation mixture containing single-stranded DNA as primer, the four triphosphates (one of which is labeled), and DNA polymerase inhibit the incorporation of the labeled triphosphate into DNA. Whether this is a specific interaction of histones with the primer that operates in vivo, or whether it is simply the result of precipitating the primer out of the incubation mixture is not established. [Pg.92]

Intoxication by aflatoxkis is referred to as aflatoxicosis. Edema and necrosis of hepatic and renal tissues seem characteristic of aflatoxicosis, and hemorrhagic enteritis accompanied by nervous symptoms often appear ki experimental animals. The mode of action of aflatoxkis kivolve an kiteraction with DNA and inhibition of the polymerases responsible for DNA and RNA synthesis (96). [Pg.480]

Amino-3 -deoxyadenosine. 3 -Amino-3 -deoxyadenosine (17) is elaborated by Cordyceps militarise Aspergillus nidulanSe and Helminthosporium (3,4). The biosynthesis proceeds direcdy from adenosine. Compound (17) inhibits RNA polymerase, but not DNA polymerase, and replaces the adenosyl residue at the 3 -terminus of tRNA. Phenylalanyl-(3 -amino-3 -deoxyadenosyl)-tRNA has acceptor but not donor activity (31,32). Compound (17) also inhibits retroviral RNA-dependent DNA polymerase (33). [Pg.121]

One of the simplest molecules found to inhibit the repHcation of DNA vimses in animals is phosphonoformic acid [4428-95-9] (PEA, 1) CH O P. Both PEA (as the trisodium salt CNa O P, foscamet [63585-09-1] audits homologue phosphono acetic acid [4408-78-0] (PAA, 2) C2H O P, were developed by Astra Pharmaceuticals (6) and show selective inhibition of DNA polymerase in various herpes vimses. [Pg.303]

BVdU differs from IdU and F TdU by being specifically phosphorylated in the 5 -position by herpes simplex vims type-1 (HSV-1) induced thymidine kinase. This restricts its action to cells infected by HSV-1. It is less active against genital herpes (HSV-2). HSV-l-induced thymidine kinase converts BVdU to the corresponding 5 -mono- and diphosphate, but HSV-2-induced thymidine kinase stops at the stage of the 5 -phosphate of BVdU. Apparendy, cellular kinases phosphorylate BVdU-5 -diphosphate to the corresponding 5 -triphosphate, which inhibits HSV-1 DNA polymerase to a greater extent than similar cellular DNA polymerases. [Pg.305]

P-D-Arabinofuranosylcytosine [147-94-4] (ara-C, 16), C H N O, reportedly has had significant therapeutic effects in patients with localized herpes zoster, herpes eye infections, and herpes encephaUtis (33), although several negative results have also been reported (34) (Fig. 2). Ara-C, also known as cytarabine, is quite toxic and is only recommended for very severe viral infections. It is rapidly deaminated in humans to the relatively inactive ara-U Ara-C is converted in the cell to the 5 -monophosphate by deoxycytidine kinase, followed by formation of the corresponding di- and triphosphate. The triphosphate has been shown to inhibit DNA polymerase. [Pg.305]

FIAC also strongly inhibits HCMV and Epstein-Barr vims (EBV) in vitro the two vimses known not to induce a specific viral thymidine kinase for their repHcation. However, HCMV may stimulate cellular kinases that can anabolize FIAC to its 5 -triphosphate, which specifically inhibits the HCMV-encoded DNA polymerase. This selective activity suggests that FIAC should be evaluated against HCMV infections. FIAC-ttiphosphate incorporated into DNA has shown strong in vitro activity against the DNA polymerases of human hepatitis B vims (HBV) and of woodchuck hepatitis vims (WHV) (37). [Pg.306]

It is likely that ara-HxMP similarly exerts its antiviral activity in the form of the triphosphate, ara-HxTP, since ara-HxTP inhibits HSV-1 DNA polymerase (49). Another possible explanation of the antiviral activity of ara-HxTP is that it is metaboHcaHy converted to ara-AMP. In fact, it has been shown at Wellcome Research Laboratories that ara-HxMP is a substrate for adenylosuccinate synthetase, and that the resulting arabinofuranosyladenylosuccinate is cleaved to ara-AMP by adenylosuccinate lyase (1). The selective action of ara-A against HSV appears to be a consequence of the preferential inhibition of ara-ATP against HSV-1 and HSV-2 polymerases. Ara-ATP also inhibits normal cellular DNA polymerases, which may be the reason for its cellular toxicity. Also, it has been observed that ara-A is incorporated uniformly throughout the HSV-1 genome, which may result in defective viral DNA (50). [Pg.307]

The antiviral mechanism of action of acyclovir has been reviewed (72). Acyclovir is converted to the monophosphate in herpes vims-infected cells (but only to a limited extent in uninfected cells) by viral-induced thymidine kinase. It is then further phosphorylated by host cell guanosine monophosphate (GMP) kinase to acyclovir diphosphate [66341 -17-1], which in turn is phosphorylated to the triphosphate by unidentified cellular en2ymes. Acyclovir triphosphate [66341 -18-2] inhibits HSV-1 viral DNA polymerase but not cellular DNA polymerase. As a result, acyclovir is 300 to 3000 times more toxic to herpes vimses in an HSV-infected cell than to the cell itself. Studies have shown that a once-daily dose of acyclovir is effective in prevention of recurrent HSV-2 genital herpes (1). HCMV, on the other hand, is relatively uninhibited by acyclovir. [Pg.308]

Poly(L-malate) decomposes spontaneously to L-ma-late by ester hydrolysis [2,4,5]. Hydrolytic degradation of the polymer sodium salt at pH 7.0 and 37°C results in a random cleavage of the polymer, the molecular mass decreasing by 50% after a period of 10 h [2]. The rate of hydrolysis is accelerated in acidic and alkaline solutions. This was first noted by changes in the activity of the polymer to inhibit DNA polymerase a of P. polycephalum [4]. The explanation of this phenomenon was that the degradation was slowest between pH 5-9 (Fig. 2) as would be expected if it were acid/base-catalyzed. In choosing a buffer, one should be aware of specific buffer catalysis. We found that the polymer was more stable in phosphate buffer than in Tris/HCl-buffer. [Pg.100]

Figure 2 Stability of /3-poly(L-malate) measured by its activity to inhibit purified DNA polymerase a of P. polyceph-alum. The relative degree of inhibition is shown (100 rel. units refer to complete inhibition). The DNA polymerase assay was carried out in the presence of 5 /tg/ml /S-poly(L-malate) as described [4]. The polymer was preincubated for 7 days at 4°C in the following buffer solutions (50 mM) KCl/HCl (—A—). Citrate (—V—). 2-(A/-Morpholino)-ethanesulfonic acid, sodium salt (—O—). Sodium phosphate (— —). N-(2-Hydroxyethyl)piperazine-N -(2-ethanesul-fonic acid), sodium salt (— — ). N,N-b s (2-Hydroxyethyl)-glycine, sodium salt (—T—). Tris/HCl (— —). 3-(Cyclo-hexylamino)-l-propanesulfonic acid, sodium salt (— —). Figure 2 Stability of /3-poly(L-malate) measured by its activity to inhibit purified DNA polymerase a of P. polyceph-alum. The relative degree of inhibition is shown (100 rel. units refer to complete inhibition). The DNA polymerase assay was carried out in the presence of 5 /tg/ml /S-poly(L-malate) as described [4]. The polymer was preincubated for 7 days at 4°C in the following buffer solutions (50 mM) KCl/HCl (—A—). Citrate (—V—). 2-(A/-Morpholino)-ethanesulfonic acid, sodium salt (—O—). Sodium phosphate (— —). N-(2-Hydroxyethyl)piperazine-N -(2-ethanesul-fonic acid), sodium salt (— — ). N,N-b s (2-Hydroxyethyl)-glycine, sodium salt (—T—). Tris/HCl (— —). 3-(Cyclo-hexylamino)-l-propanesulfonic acid, sodium salt (— —).
Ficellomycin was found to inhibit semiconservative DNA replication in Eschir-ichia coli, and this was found not to be due to direct inhibition of DNA polymerase [166]. It has been suggested that ficellomycin may exert its biological activity by alkylation of DNA [165], in common with the azinomyins. The biosynthesis of ficellomycin has not been studied, but it seems highly probable that its 1-azabicy-clo[3.1.0]hexane ring system will arise from a pathway related to that for the azinomycins. [Pg.428]

Terminase inhibition is an antiviral approach that may also be of consequence for other members of the herpesvirus group. In addition, since a similar DNA maturation process does not occur in higher cells, this principle offers the potential for high selectivity, in contrast to many of the viral DNA polymerase inhibitors, which also interact with cellular enzymes and hence can have severe side effects. [Pg.168]


See other pages where DNA polymerase inhibition is mentioned: [Pg.532]    [Pg.56]    [Pg.336]    [Pg.15]    [Pg.16]    [Pg.151]    [Pg.242]    [Pg.326]    [Pg.1085]    [Pg.532]    [Pg.56]    [Pg.336]    [Pg.15]    [Pg.16]    [Pg.151]    [Pg.242]    [Pg.326]    [Pg.1085]    [Pg.118]    [Pg.122]    [Pg.134]    [Pg.304]    [Pg.308]    [Pg.309]    [Pg.97]    [Pg.100]    [Pg.150]    [Pg.151]    [Pg.155]    [Pg.342]    [Pg.4]    [Pg.35]    [Pg.71]    [Pg.82]    [Pg.245]    [Pg.245]    [Pg.247]    [Pg.258]   
See also in sourсe #XX -- [ Pg.183 ]




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Inhibition of DNA polymerase

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