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Literature DB >> 2847643

Inhibition of varicella-zoster virus-induced DNA polymerase by a new guanosine analog, 9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine triphosphate.

G Abele¹, B Eriksson, J Harmenberg, B Wahren.

Abstract

The triphosphates of the antiherpesvirus acyclic guanosine analogs 9-[4-hydroxy-2(hydroxymethyl)butyl] guanine (2HM-HBG), 9-(2-hydroxyethoxymethyl)guanine (acyclovir [ACV]), and 9-(3,4-dihydroxybutyl)guanine (buciclovir) were examined for their effects on partially purified varicella-zoster virus (VZV) DNA polymerase as well as cellular DNA polymerase alpha. The triphosphate of 2HM-HBG competitively inhibited the incorporation of dGMP into DNA catalyzed by the VZV DNA polymerase. 2HM-HBG-triphosphate (2HM-HBG-TP) had a higher affinity for the dGTP-binding site on the VZV DNA polymerase than did dGTP; apparent Km and Ki values of dGTP and 2HM-HBG-TP were 0.64 and 0.034 microM, respectively. ACV-triphosphate (ACV-TP) was found to be the most potent inhibitor of VZV DNA polymerase. ACV-TP had a 14 and 464 times better direct inhibitory effect than 2HM-HBG-TP and buciclovir-triphosphate, respectively. The cellular (human embryonic lung fibroblast) DNA polymerase alpha inhibition was related to viral polymerase inhibition as efficacy ratios: 2HM-HBG-TP had a ratio of more than 1,000, which appeared to be similar to that of ACV-TP.

Entities: Chemical Disease Gene Species

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Year: 1988 PMID： 2847643 PMCID： PMC172365 DOI： 10.1128/AAC.32.8.1137

Source DB: PubMed Journal: Antimicrob Agents Chemother ISSN： 0066-4804 Impact factor: 5.191

30 in total

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Authors: P J Selby; R L Powles; B Janeson; H E Kay; J G Watson; R Thornton; G Morgenstern; H M Clink; T J McElwain; H G Prentice; R Corringharn; M G Ross; A V Hoffbrand; D Brigden
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Authors: B Eriksson; A Larsson; E Helgstrand; N G Johansson; B Oberg
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Review 2. Current and potential treatments for ubiquitous but neglected herpesvirus infections.

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Authors: D M Lake-Bakaar; B Lindborg; R Datema
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5. Efficacy of (-)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine in African green monkeys infected with simian varicella virus.

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6. The antiherpesvirus activity of H2G [(R)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine] is markedly enhanced by the novel immunosuppressive agent mycophenolate mofetil.

Authors: J Neyts; G Andrei; E De Clercq
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7. Pharmacokinetics and antiviral activity in simian varicella virus-infected monkeys of (R,S)-9-[4-hydroxy-2-(hydroxymethyl) butyl]guanine, an anti-varicella-zoster virus drug.

Authors: D M Lake-Bakaar; G Abele; B Lindborg; K F Soike; R Datema
Journal: Antimicrob Agents Chemother Date: 1988-12 Impact factor: 5.191