Synergistic antiviral activity of acyclovir and vidarabine against herpes simplex virus types 1 and 2 and varicella-zoster virus

Suzuki, Mikiko; Okuda, Tomoko; Shiraki, Kimíyasu

doi:10.1016/j.antiviral.2006.05.001

Cited by 38 publications

(24 citation statements)

References 31 publications

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“…Unlike the other purine nucleoside derivatives tested in this report, AraA is known to be phosphorylated to its active triphosphate form by cellular kinases and is not dependent for its activation on viral kinases (44). Hence, no alterations in antiviral activity of AraA were seen for the MHV-68 PK mutant or for the HVS and MHV-68 TK mutant strains in this study.…”

Section: Figmentioning

confidence: 50%

Spectrum of Activity and Mechanisms of Resistance of Various Nucleoside Derivatives against Gammaherpesviruses

Coen

Duraffour

Topalis

et al. 2014

Antimicrob Agents Chemother

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The susceptibilities of gammaherpesviruses, including Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and animal rhadinoviruses, to various nucleoside analogs was investigated in this work. Besides examining the antiviral activities and modes of action of antivirals currently marketed for the treatment of alpha-and/or betaherpesvirus infections (including acyclovir, ganciclovir, penciclovir, foscarnet, and brivudin), we also investigated the structure-activity relationship of various 5-substituted uridine and cytidine molecules. The antiviral efficacy of nucleoside derivatives bearing substitutions at the 5 position was decreased if the bromovinyl was replaced by chlorovinyl. 1-␤-D-Arabinofuranosyl-(E)-5-(2-bromovinyl)uracil (BVaraU), a nucleoside with an arabinose configuration of the sugar ring, exhibited no inhibitory effect against rhadinoviruses but was active against EBV. On the other hand, the fluoroarabinose cytidine analog 2=-fluoro-5-iodo-aracytosine (FIAC) showed high selectivity indices against gammaherpesviruses that were comparable to those of brivudin. Additionally, we selected brivudin-and acyclovir-resistant rhadinoviruses in vitro and characterized them by phenotypic and genotypic (i.e., sequencing of the viral thymidine kinase, protein kinase, and DNA polymerase) analysis. Here, we reveal key amino acids in these enzymes that play an important role in substrate recognition. Our data on drug susceptibility profiles of the different animal gammaherpesvirus mutants highlighted cross-resistance patterns and indicated that pyrimidine nucleoside derivatives are phosphorylated by the viral thymidine kinase and purine nucleosides are preferentially activated by the gammaherpesvirus protein kinase.T he gammaherpesvirus subfamily includes two major genera, the lymphocryptovirus and rhadinovirus, of which the human tumor viruses Epstein-Barr virus (EBV) and Kaposi's sarcomaassociated herpesvirus (KSHV), respectively, are the best-characterized members (1). A hallmark of these human herpesviruses is that they do not easily replicate in primary infection in cells in culture (2). In contrast, other members of the rhadinovirus genus, murine gammaherpesvirus 68 (MHV-68), herpesvirus saimiri (HVS), and rhesus rhadinovirus (RRV), are able to replicate to high titers in cell culture, and thus, they may serve as model systems for human gammaherpesviruses in experimental settings (3).Overall, antiherpesvirus therapies are aimed at selectively inhibiting the lytic replication of the virus. At present, the antiviral agents used in EBV and KSHV viral infections are those that are approved for the treatment of other herpesvirus infections (4), in particular ganciclovir (GCV) for both EBV and KSHV and also acyclovir (ACV) in the case of EBV. Other structurally related antiherpetics that are currently marketed, such as penciclovir (PCV) and brivudin (BVDU), have also been evaluated in vitro against EBV and KSHV replication (5-8) but have not been used in the clinic. Differences in antiviral act...

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Section: Figmentioning

confidence: 50%

Spectrum of Activity and Mechanisms of Resistance of Various Nucleoside Derivatives against Gammaherpesviruses

Coen

Duraffour

Topalis

et al. 2014

Antimicrob Agents Chemother

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“…To analyze the interaction of ganciclovir and mizoribine in the plaque reduction assay of CMV graphically, infected cells in 60-mm Petri dishes were overlaid with methylcellulose containing a mixture of ganciclovir (0, 0.1, 0.2, 0.5, 1, 2, 5, and 10 g/ml) and mizoribine (0, 1, 2, 5, 10, 20, 50, and 100 g/ml), and the EC 50 values of these agents in their various concentrations were plotted as an isobologram (Kurokawa et al, 2001;Tallarida, 2001;Suzuki et al, 2006). Synergy and antagonism were defined as deviations from dose-wise additivity, which occurs when two drugs interact as though they were the same drug.…”

Section: Methodsmentioning

confidence: 99%

Novel Anticytomegalovirus Activity of Immunosuppressant Mizoribine and Its Synergism with Ganciclovir

Kuramoto

Daikoku²,

Yoshida³

et al. 2010

J Pharmacol Exp Ther

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Cytomegalovirus (CMV) infection is a prominent infection in transplant recipients. The immunosuppressive drug mizoribine was shown to have anti-CMV activity in vitro and was reported to have an anti-CMV effect in renal transplantation. This study characterized the anti-CMV activity of mizoribine in vitro and its synergistic activity with ganciclovir. Mizoribine suppressed replication and at the EC 50 for plaque inhibition of 12.0 g/ml.Mizoribine and ganciclovir exerted a strong synergism in anti-CMV activity. Mizoribine depletes guanosine nucleotides by inhibiting inosine monophosphate dehydrogenase and may increase the ratio of ganciclovir to guanosine in treated cells, resulting in a strong synergistic augmentation of the anti-CMV activity of ganciclovir. Two clinical isolates with UL97 mutations were less susceptible to mizoribine than the Towne strain but were equally susceptible in the presence of guanine. Two mizoribine-resistant strains were isolated after culture for 3 months with 100 g/ml mizoribine, but they were as sensitive to ganciclovir as the parent Towne strain. The anti-CMV activity of mizoribine was antagonized by 2Ј-deoxyguanosine. Mizoribine inhibited CMV replication directly, and the sequence of mizoribine-resistant mutants of UL97 and UL54 was identical to that of the parent Towne strain, indicating the different anti-CMV action from ganciclovir, foscarnet, and maribavir. Mizoribine as an immunosuppressive and anti-CMV drug in the clinical regimen was suggested to suppress replication of CMV in vivo and control CMV infection in transplant recipients in combination with ganciclovir.

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“…14 The chemical modification of drugs in vivo is an important issue for pharmacokinetics and drug efficacy, this has been shown with many pharmacological agents. Both AZT (used to slow the progression of HIV) and acyclovir (used to treat herpes infections) are activated in vivo by phosphorylation, 22 while levodopa (used in the management of Parkinson's disease) is known to be converted by DOPA decarboxylase to active dopamine in vivo. Knowledge of the in vivo modifications required for drug efficacy can be used to design drugs that will have enhanced specificity and toxicity towards diseased cells.…”

mentioning

confidence: 99%

Mechanistic Studies on Hsp90 Inhibition by Ansamycin Derivatives

Onuoha

Mukund

Coulstock

et al. 2007

Journal of Molecular Biology

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Synergistic antiviral activity of acyclovir and vidarabine against herpes simplex virus types 1 and 2 and varicella-zoster virus

Cited by 38 publications

References 31 publications

Spectrum of Activity and Mechanisms of Resistance of Various Nucleoside Derivatives against Gammaherpesviruses

Spectrum of Activity and Mechanisms of Resistance of Various Nucleoside Derivatives against Gammaherpesviruses

Novel Anticytomegalovirus Activity of Immunosuppressant Mizoribine and Its Synergism with Ganciclovir

Mechanistic Studies on Hsp90 Inhibition by Ansamycin Derivatives

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